technological advancements essay introduction

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Introduction Paragraph for Technology Essay: Effective Guide

Table of Contents

The introduction is an integral part of any essay and an excellent opportunity to impact your reader. It sets the tone for the argument and gives the reader an insight into the topic. A good  introduction of essay about technology  comprises three main parts.

The hook grabs the reader’s attention and encourages them to read on. Background presents more details on the topic, and the thesis statement summarizes the essay’s central focus. 

The introduction can be challenging to write, but with some guidance, anyone can master the art of writing a compelling introduction. This guide discusses how to write an effective introductory paragraph for a technology essay.

What is A Technology Essay?

Technology has a significant impact on our society. Its numerous benefits have become a vital part of our life. It has improved and is still improving the efficiency of medicine, transportation, education, entertainment, and more. Technology also impacts social interaction; you can easily find lost friends on social networks. 

A technology essay discusses a technological phenomenon or technological advancement. It could also discuss a personal experience related to a technological issue. Depending on your professor’s instructions, a technology essay could be argumentative, informative, persuasive, or otherwise.

How to Write An Introduction Paragraph For Technology Essay

Like other essays, a technology essay comprises three main parts: the introduction, the body, and the conclusion. The introduction provides the reader with an overview of the argument you’ll develop in the body of your essay.

Body of the paper is where you discuss the details of the argument. The conclusion represents the logical ending you reach regarding the idea presented in the essay’s body.

The introduction paragraph of a technology essay should provide context for the technological trends you address and the argument you develop. It should include a hook that will pull the reader in and keep him/her interested.

Here’s how to write a good introduction paragraph .

1. Hook the reader

The essay’s opening sentence sets the tone for the entire piece; it should intrigue the readers and pull them in. Begin with a hook that will grab the reader’s attention, hold their interest and make them want to read the rest of your work.

The hook should be exciting and lead the reader into the essay, giving them an idea of the topic you’re writing about. It should also be clear, catchy, and concise and spark the reader’s curiosity. Here’s how you can grab the attention of your audience.

• Present a shocking statistic or fact.
• Offer an anecdote or a relevant example.
• Ask a thoughtful rhetorical question.

2. Create Context and Provide Background

Now that you have the reader’s attention, provide details on your topic. The next two to three sentences you make should explain how the hook connects to the rest of the essay.

Provide necessary background information to help the readers better understand your argument and the points you intend to make. If you include key terms that may be wrongly interpreted, let your readers know what the term means in your essay.

3. Present Your Thesis

A thesis is the pivot point of your paper, and the single most important idea that you convey in your work. Present the main points you intend to make throughout your essay.

Provide your readers with a roadmap of what you’ll cover in the rest of the paper to support your thesis statement. The last sentence of your introduction should allow smooth transition into the body of the essay.

Introduction of Essay About Technology

Technology has made our lives more comfortable. The products we use, our lifestyle, and our society are products of technology. Without technological advancements, the world would be different and most likely unrecognizable to us. Today, technology extends to every part of our life. Experts, business entrepreneurs, and non-professionals use technology to expand their livelihoods. However, with the good comes bad. Technology, quite frankly, harms society. Pollution, cybercrime, and war are only a few of the effects of technology on society. But does the good outweigh the bad? 

Technology has impacted modern life immensely. It has drastically changed our world. We now travel in planes and cars and have better health facilities and education. We also have ways to communicate with people worldwide in seconds. However, these increased levels of technology did not come about by accident. It resulted from planned and systematic research by a group of people. 

Technology is giving us a new shape. We’ve made more progress in the last 200 years than in the previous 20000 years. Earth has become a global village where most countries and people can connect through the internet, but it has some deadly consequences. Many countries have nuclear weapons, global warming and growing Co2 emissions threaten the existence of the whole population.

With the advent of technology, we are making such amazing developments that couldn’t even be imagined 100 or 200 years ago. We’ve found cures for deadly diseases, we’re constantly working on education, and most people have freedom to express themselves. Science has made huge leaps, but at the same time new diseases, deadlier than before, kill millions of people every year.

Technology is the application of information for building and developing devices and equipment that can be used in diverse ways. We live a very active day-to-day life with technology today. While technology has done a lot to make life easier for everyone, it has also had a few adverse effects that can’t be ignored. Here’s a look at how technology has affected our lives and how we can balance it to overcome it.

Example 6 

Technology has changed society drastically. Before modern technology came along, life was too hard, and everyday chores took up a lot of time. We’re getting many opportunities out of technologies that play a significant role in our lives. Access to medicine, education, industry, and transportation is easier. Our lives have changed dramatically. 

A technology essay can be tricky to write, but a good essay introduction paragraph is key to the successful execution of your topic .

The introduction to a technology essay must be clear, concise, and persuasive to draw the reader in. It should establish the topic and provide as much detail as possible to help readers understand and empathize with the topic. This guide on introduction of essay about technology would help you write a gripping essay introduction.

Abir Ghenaiet

Abir is a data analyst and researcher. Among her interests are artificial intelligence, machine learning, and natural language processing. As a humanitarian and educator, she actively supports women in tech and promotes diversity.

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Essay on Technological Advancement

Students are often asked to write an essay on Technological Advancement in their schools and colleges. And if you’re also looking for the same, we have created 100-word, 250-word, and 500-word essays on the topic.

Let’s take a look…

100 Words Essay on Technological Advancement

What is technological advancement.

Technological advancement refers to the development of new and innovative technologies that improve our lives, making things easier and faster. It encompasses a wide range of fields, such as communication, transportation, medicine, and energy.

How does technological advancement impact our lives?

Technological advancement has a profound impact on our daily lives. It makes communication easier and faster, allowing us to stay connected with friends and family around the world. Transportation has become more convenient and accessible, enabling us to travel longer distances in less time. Medical technology has improved healthcare, leading to better treatments and longer lifespans. Energy advancements have made it possible to harness renewable sources, such as solar and wind power, reducing our reliance on fossil fuels.

What are the benefits of technological advancement?

Technological advancement brings numerous benefits to society. It enhances productivity, leading to economic growth and improved living standards. It also creates new jobs and opportunities, especially in the tech industry. Additionally, technological advancements improve education and access to information, enabling people to learn and stay informed.

What are the challenges associated with technological advancement?

While technological advancement offers many benefits, it also presents challenges. One concern is the potential loss of jobs due to automation and artificial intelligence. Another challenge is the digital divide, where certain populations lack access to technology and its benefits. Ethical considerations also arise, such as privacy concerns and the potential misuse of technology.

250 Words Essay on Technological Advancement

What is technological advancement.

Technological advancement refers to the development of new and improved technologies that make people’s lives easier, more convenient, and more efficient. It involves the creation of new products, processes, and systems that address various challenges and improve the way people live and work.

Benefits of Technological Advancement

Technological advancement has brought many benefits to society. It has improved communication, transportation, healthcare, and education. For example, the internet has made it possible for people to connect with others around the world instantly. Mobile phones have made it easy for people to stay in touch with friends and family members who live far away.

Challenges of Technological Advancement

While technological advancement has many benefits, it also comes with some challenges. One challenge is that new technologies can be expensive, and not everyone can afford them. Another challenge is that new technologies can sometimes be harmful to the environment. For example, the use of fossil fuels to generate electricity releases greenhouse gases into the atmosphere, which contributes to climate change.

The Future of Technological Advancement

It is likely that technological advancement will continue to accelerate in the years to come. This will bring both benefits and challenges. It is important to be aware of both the potential benefits and challenges of new technologies so that we can make informed decisions about how to use them.

Technological advancement is a complex and ever-changing field. It has the potential to improve people’s lives in many ways, but it also comes with some challenges. It is important to be aware of both the benefits and challenges of new technologies so that we can use them wisely.

500 Words Essay on Technological Advancement

A transformative power: technological advancement, communication and connectivity.

The advent of the internet has revolutionized communication and connectivity. Social media platforms, instant messaging, and video conferencing have made it possible to stay connected with friends and family across vast distances. The world has become a smaller place, fostering global collaboration and understanding.

Medical Breakthroughs

Technological advancements have also led to significant breakthroughs in healthcare. Medical imaging techniques, such as X-rays and MRI scans, have enabled early detection and more accurate diagnosis of diseases. Advanced treatments like robotic surgery and targeted drug therapies have improved patient outcomes and enhanced the quality of life for millions.

Education and Knowledge Access

Industrial and business evolution.

Technological advancements have transformed industries and businesses. Automation and robotics have streamlined production processes, increasing efficiency and productivity. Supply chain management systems have optimized logistics, ensuring faster and more efficient delivery of goods and services. These advancements have also led to the creation of new industries and jobs, driving economic growth and innovation.

Challenges and Ethical Considerations

While technological advancements have brought immense benefits, they also pose challenges and raise ethical considerations. The rapid pace of change can lead to job displacement and the need for continuous upskilling. Moreover, the increasing reliance on technology can result in privacy concerns, data security breaches, and the spread of misinformation. Navigating these challenges and addressing ethical implications requires careful consideration and responsible action.

Technology’s Impact on Society

Technological advancement is a continuous journey, marked by both challenges and opportunities. It has transformed the way we live, work, and communicate, and its impact will continue to shape our future. As technology advances, it is essential to embrace its benefits while addressing its potential drawbacks responsibly and ethically. By doing so, we can ensure that technological advancements contribute to a more equitable, sustainable, and prosperous world.

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Feb 13, 2023

200-500 Word Example Essays about Technology

Got an essay assignment about technology check out these examples to inspire you.

Technology is a rapidly evolving field that has completely changed the way we live, work, and interact with one another. Technology has profoundly impacted our daily lives, from how we communicate with friends and family to how we access information and complete tasks. As a result, it's no surprise that technology is a popular topic for students writing essays.

But writing a technology essay can be challenging, especially for those needing more time or help with writer's block. This is where Jenni.ai comes in. Jenni.ai is an innovative AI tool explicitly designed for students who need help writing essays. With Jenni.ai, students can quickly and easily generate essays on various topics, including technology.

This blog post aims to provide readers with various example essays on technology, all generated by Jenni.ai. These essays will be a valuable resource for students looking for inspiration or guidance as they work on their essays. By reading through these example essays, students can better understand how technology can be approached and discussed in an essay.

Moreover, by signing up for a free trial with Jenni.ai, students can take advantage of this innovative tool and receive even more support as they work on their essays. Jenni.ai is designed to help students write essays faster and more efficiently, so they can focus on what truly matters – learning and growing as a student. Whether you're a student who is struggling with writer's block or simply looking for a convenient way to generate essays on a wide range of topics, Jenni.ai is the perfect solution.

The Impact of Technology on Society and Culture

Introduction:.

Technology has become an integral part of our daily lives and has dramatically impacted how we interact, communicate, and carry out various activities. Technological advancements have brought positive and negative changes to society and culture. In this article, we will explore the impact of technology on society and culture and how it has influenced different aspects of our lives.

Positive impact on communication:

Technology has dramatically improved communication and made it easier for people to connect from anywhere in the world. Social media platforms, instant messaging, and video conferencing have brought people closer, bridging geographical distances and cultural differences. This has made it easier for people to share information, exchange ideas, and collaborate on projects.

Positive impact on education:

Students and instructors now have access to a multitude of knowledge and resources because of the effect of technology on education . Students may now study at their speed and from any location thanks to online learning platforms, educational applications, and digital textbooks.

Negative impact on critical thinking and creativity:

Technological advancements have resulted in a reduction in critical thinking and creativity. With so much information at our fingertips, individuals have become more passive in their learning, relying on the internet for solutions rather than logic and inventiveness. As a result, independent thinking and problem-solving abilities have declined.

Positive impact on entertainment:

Technology has transformed how we access and consume entertainment. People may now access a wide range of entertainment alternatives from the comfort of their own homes thanks to streaming services, gaming platforms, and online content makers. The entertainment business has entered a new age of creativity and invention as a result of this.

Negative impact on attention span:

However, the continual bombardment of information and technological stimulation has also reduced attention span and the capacity to focus. People are easily distracted and need help focusing on a single activity for a long time. This has hampered productivity and the ability to accomplish duties.

The Ethics of Artificial Intelligence And Machine Learning

The development of artificial intelligence (AI) and machine learning (ML) technologies has been one of the most significant technological developments of the past several decades. These cutting-edge technologies have the potential to alter several sectors of society, including commerce, industry, healthcare, and entertainment. 

As with any new and quickly advancing technology, AI and ML ethics must be carefully studied. The usage of these technologies presents significant concerns around privacy, accountability, and command. As the use of AI and ML grows more ubiquitous, we must assess their possible influence on society and investigate the ethical issues that must be taken into account as these technologies continue to develop.

What are Artificial Intelligence and Machine Learning?

Artificial Intelligence is the simulation of human intelligence in machines designed to think and act like humans. Machine learning is a subfield of AI that enables computers to learn from data and improve their performance over time without being explicitly programmed.

The impact of AI and ML on Society

The use of AI and ML in various industries, such as healthcare, finance, and retail, has brought many benefits. For example, AI-powered medical diagnosis systems can identify diseases faster and more accurately than human doctors. However, there are also concerns about job displacement and the potential for AI to perpetuate societal biases.

The Ethical Considerations of AI and ML

A. Bias in AI algorithms

One of the critical ethical concerns about AI and ML is the potential for algorithms to perpetuate existing biases. This can occur if the data used to train these algorithms reflects the preferences of the people who created it. As a result, AI systems can perpetuate these biases and discriminate against certain groups of people.

B. Responsibility for AI-generated decisions

Another ethical concern is the responsibility for decisions made by AI systems. For example, who is responsible for the damage if a self-driving car causes an accident? The manufacturer of the vehicle, the software developer, or the AI algorithm itself?

C. The potential for misuse of AI and ML

AI and ML can also be used for malicious purposes, such as cyberattacks and misinformation. The need for more regulation and oversight in developing and using these technologies makes it difficult to prevent misuse.

The developments in AI and ML have given numerous benefits to humanity, but they also present significant ethical concerns that must be addressed. We must assess the repercussions of new technologies on society, implement methods to limit the associated dangers, and guarantee that they are utilized for the greater good. As AI and ML continue to play an ever-increasing role in our daily lives, we must engage in an open and frank discussion regarding their ethics.

The Future of Work And Automation

Rapid technological breakthroughs in recent years have brought about considerable changes in our way of life and work. Concerns regarding the influence of artificial intelligence and machine learning on the future of work and employment have increased alongside the development of these technologies. This article will examine the possible advantages and disadvantages of automation and its influence on the labor market, employees, and the economy.

The Advantages of Automation

Automation in the workplace offers various benefits, including higher efficiency and production, fewer mistakes, and enhanced precision. Automated processes may accomplish repetitive jobs quickly and precisely, allowing employees to concentrate on more complex and creative activities. Additionally, automation may save organizations money since it removes the need to pay for labor and minimizes the danger of workplace accidents.

The Potential Disadvantages of Automation

However, automation has significant disadvantages, including job loss and income stagnation. As robots and computers replace human labor in particular industries, there is a danger that many workers may lose their jobs, resulting in higher unemployment and more significant economic disparity. Moreover, if automation is not adequately regulated and managed, it might lead to stagnant wages and a deterioration in employees' standard of life.

The Future of Work and Automation

Despite these difficulties, automation will likely influence how labor is done. As a result, firms, employees, and governments must take early measures to solve possible issues and reap the rewards of automation. This might entail funding worker retraining programs, enhancing education and skill development, and implementing regulations that support equality and justice at work.

IV. The Need for Ethical Considerations

We must consider the ethical ramifications of automation and its effects on society as technology develops. The impact on employees and their rights, possible hazards to privacy and security, and the duty of corporations and governments to ensure that automation is utilized responsibly and ethically are all factors to be taken into account.

Conclusion:

To summarise, the future of employment and automation will most certainly be defined by a complex interaction of technological advances, economic trends, and cultural ideals. All stakeholders must work together to handle the problems and possibilities presented by automation and ensure that technology is employed to benefit society as a whole.

The Role of Technology in Education

Introduction.

Nearly every part of our lives has been transformed by technology, and education is no different. Today's students have greater access to knowledge, opportunities, and resources than ever before, and technology is becoming a more significant part of their educational experience. Technology is transforming how we think about education and creating new opportunities for learners of all ages, from online courses and virtual classrooms to instructional applications and augmented reality.

Technology's Benefits for Education

The capacity to tailor learning is one of technology's most significant benefits in education. Students may customize their education to meet their unique needs and interests since they can access online information and tools. 

For instance, people can enroll in online classes on topics they are interested in, get tailored feedback on their work, and engage in virtual discussions with peers and subject matter experts worldwide. As a result, pupils are better able to acquire and develop the abilities and information necessary for success.

Challenges and Concerns

Despite the numerous advantages of technology in education, there are also obstacles and considerations to consider. One issue is the growing reliance on technology and the possibility that pupils would become overly dependent on it. This might result in a lack of critical thinking and problem-solving abilities, as students may become passive learners who only follow instructions and rely on technology to complete their assignments.

Another obstacle is the digital divide between those who have access to technology and those who do not. This division can exacerbate the achievement gap between pupils and produce uneven educational and professional growth chances. To reduce these consequences, all students must have access to the technology and resources necessary for success.

In conclusion, technology is rapidly becoming an integral part of the classroom experience and has the potential to alter the way we learn radically. 

Technology can help students flourish and realize their full potential by giving them access to individualized instruction, tools, and opportunities. While the benefits of technology in the classroom are undeniable, it's crucial to be mindful of the risks and take precautions to guarantee that all kids have access to the tools they need to thrive.

The Influence of Technology On Personal Relationships And Communication 

Technological advancements have profoundly altered how individuals connect and exchange information. It has changed the world in many ways in only a few decades. Because of the rise of the internet and various social media sites, maintaining relationships with people from all walks of life is now simpler than ever. 

However, concerns about how these developments may affect interpersonal connections and dialogue are inevitable in an era of rapid technological growth. In this piece, we'll discuss how the prevalence of digital media has altered our interpersonal connections and the language we use to express ourselves.

Direct Effect on Direct Interaction:

The disruption of face-to-face communication is a particularly stark example of how technology has impacted human connections. The quality of interpersonal connections has suffered due to people's growing preference for digital over human communication. Technology has been demonstrated to reduce the usage of nonverbal signs such as facial expressions, tone of voice, and other indicators of emotional investment in the connection.

Positive Impact on Long-Distance Relationships:

Yet there are positives to be found as well. Long-distance relationships have also benefited from technological advancements. The development of technologies such as video conferencing, instant messaging, and social media has made it possible for individuals to keep in touch with distant loved ones. It has become simpler for individuals to stay in touch and feel connected despite geographical distance.

The Effects of Social Media on Personal Connections:

The widespread use of social media has had far-reaching consequences, especially on the quality of interpersonal interactions. Social media has positive and harmful effects on relationships since it allows people to keep in touch and share life's milestones.

Unfortunately, social media has made it all too easy to compare oneself to others, which may lead to emotions of jealousy and a general decline in confidence. Furthermore, social media might cause people to have inflated expectations of themselves and their relationships.

A Personal Perspective on the Intersection of Technology and Romance

Technological advancements have also altered physical touch and closeness. Virtual reality and other technologies have allowed people to feel physical contact and familiarity in a digital setting. This might be a promising breakthrough, but it has some potential downsides. 

Experts are concerned that people's growing dependence on technology for intimacy may lead to less time spent communicating face-to-face and less emphasis on physical contact, both of which are important for maintaining good relationships.

In conclusion, technological advancements have significantly affected the quality of interpersonal connections and the exchange of information. Even though technology has made it simpler to maintain personal relationships, it has chilled interpersonal interactions between people. 

Keeping tabs on how technology is changing our lives and making adjustments as necessary is essential as we move forward. Boundaries and prioritizing in-person conversation and physical touch in close relationships may help reduce the harm it causes.

The Security and Privacy Implications of Increased Technology Use and Data Collection

The fast development of technology over the past few decades has made its way into every aspect of our life. Technology has improved many facets of our life, from communication to commerce. However, significant privacy and security problems have emerged due to the broad adoption of technology. In this essay, we'll look at how the widespread use of technological solutions and the subsequent explosion in collected data affects our right to privacy and security.

Data Mining and Privacy Concerns

Risk of Cyber Attacks and Data Loss

The Widespread Use of Encryption and Other Safety Mechanisms

The Privacy and Security of the Future in a Globalized Information Age

Obtaining and Using Individual Information

The acquisition and use of private information is a significant cause for privacy alarm in the digital age. Data about their customers' online habits, interests, and personal information is a valuable commodity for many internet firms. Besides tailored advertising, this information may be used for other, less desirable things like identity theft or cyber assaults.

Moreover, many individuals need to be made aware of what data is being gathered from them or how it is being utilized because of the lack of transparency around gathering personal information. Privacy and data security have become increasingly contentious as a result.

Data breaches and other forms of cyber-attack pose a severe risk.

The risk of cyber assaults and data breaches is another big issue of worry. More people are using more devices, which means more opportunities for cybercriminals to steal private information like credit card numbers and other identifying data. This may cause monetary damages and harm one's reputation or identity.

Many high-profile data breaches have occurred in recent years, exposing the personal information of millions of individuals and raising serious concerns about the safety of this information. Companies and governments have responded to this problem by adopting new security methods like encryption and multi-factor authentication.

Many businesses now use encryption and other security measures to protect themselves from cybercriminals and data thieves. Encryption keeps sensitive information hidden by encoding it so that only those possessing the corresponding key can decipher it. This prevents private information like bank account numbers or social security numbers from falling into the wrong hands.

Firewalls, virus scanners, and two-factor authentication are all additional security precautions that may be used with encryption. While these safeguards do much to stave against cyber assaults, they are not entirely impregnable, and data breaches are still possible.

The Future of Privacy and Security in a Technologically Advanced World

There's little doubt that concerns about privacy and security will persist even as technology improves. There must be strict safeguards to secure people's private information as more and more of it is transferred and kept digitally. To achieve this goal, it may be necessary to implement novel technologies and heightened levels of protection and to revise the rules and regulations regulating the collection and storage of private information.

Individuals and businesses are understandably concerned about the security and privacy consequences of widespread technological use and data collecting. There are numerous obstacles to overcome in a society where technology plays an increasingly important role, from acquiring and using personal data to the risk of cyber-attacks and data breaches. Companies and governments must keep spending money on security measures and working to educate people about the significance of privacy and security if personal data is to remain safe.

In conclusion, technology has profoundly impacted virtually every aspect of our lives, including society and culture, ethics, work, education, personal relationships, and security and privacy. The rise of artificial intelligence and machine learning has presented new ethical considerations, while automation is transforming the future of work. 

In education, technology has revolutionized the way we learn and access information. At the same time, our dependence on technology has brought new challenges in terms of personal relationships, communication, security, and privacy.

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Home — Essay Samples — Business — Technology in Business — The Impact of Technological Advancements

The Impact of Technological Advancements

• Categories: Employment Technology in Business

About this sample

Words: 643 |

Published: Jan 31, 2024

Words: 643 | Page: 1 | 4 min read

Table of contents

Introduction, history of technological advancements, positive effects of technological advancements, negative effects of technological advancements, counterargument and refutation.

• "The impact of Technology on Employment," World Economic Forum
• "How Technology is Changing Our Lives," Forbes
• "The Future of Healthcare: How Technology is Changing the Industry," Harvard Business Review
• "The Impact of Technology on Society," Technology Innovation Management Review

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Technological Advancement Essay

1. introduction.

Technological systems comprise the utilization of information with the help of hardware, software, and associated services aided by humans. The society utilizes technology in various ways, which results in positives and negatives, both impacting the economic system and society. Our current world is characterized by the advancement of technology. Over the past years, technology has significantly changed the lives of the people. The continuous technological developments in recent times have undergone tremendous improvements, which have intensified the impact on society. The modern technological advancement is very crucial in the fast production of goods and services. Both the expectations of society and the needs of the economy have led to technological development in the modern world. To discuss modern technological advancements, it is very important to categorize what modern technology is nowadays. This is because modern world technology is divided into different sectors, for example, medicine, technology, business, education, among many others. Through life experiences and extensive research on technological developments, it's convinced that the technological development in modern times is not questioned at all because many forms of technology are being produced in a fast way. It is a fact that the modern world has embraced the most contemporary means of communication and information technology that has come up. In addition, globalization has also been triggered by technological development. The utilization of technology in our world today is never taken for granted. It is the very nature of society to be mobile and social. Nowadays, information and knowledge are available everywhere and to everybody through the aid of technology. Modern technology has helped businesses increase production. Humans are slow and sometimes they fail to deliver on time and quality. Many companies have integrated modern technology into their production line, increasing output and allowing for high-quality products. But the overall impact of technology has been quite substantial, especially as it has been growing for the past years. The most significant impact of modern technological advancement is the way it makes society more modern, especially in today's modern world. The transfer of knowledge with the utilization of technology is a significant achievement in order to improve people's lives. Technology is usually the key to the accomplishment of goals and allows humans to take advantage of new learning and experiences. Thanks to continuous technological development, all communications around the globe have become easy and quick. The utilization of technology in different sectors has become an essential necessity in the modern world. It is quite true that we cannot avoid the impact of technology in our lives, but humans need to create a balance. All these wonders are to be addressed and could be achievable only with continuous monitoring and development. And this is very important to the typical essence which we feel the need to utilize in order to improve our standard of living. Terminologically, technology represents the utility of scientific knowledge, which is employed in industries for the production of goods and services.

1.1 Definition of Technological Advancement

The phrase "technological advancement" is used to describe the current state of technology and the various technologies available. Although there may be many variations, the core idea is that a society's technology must be suitable to the current state of development and the needs of its people. With the invention of the microprocessor in the 1970s, many people believed that humanity was on the cusp of an information revolution. What followed was a period of rapidly accelerating change in the technologies and techniques available to us. This period is known as the "digital revolution", and it is an increasingly common focus for historians and sociologists who are interested in how technology is shaping society. This kind of technological determinism - the belief that technological change is the most important factor in shaping a society's development - is perhaps more strongly associated with the digital revolution. This is owed to the impressive range of technologies that have emerged and the profound ways in which they have affected everyday life. For example, the development of the internet has produced new ways of dispensing and receiving information on an unprecedented scale. It has also allowed the emergence of new forms of social interaction, business practice, and art that were previously unthinkable. Such has been its significance that it has been used as evidence to suggest that we are living in a point in time at which a new "information society" is beginning, having far-reaching social, political, and economic consequences. However, some historians and sociologists argue that the focus on such a recent period of history is misguided. They suggest that theories which argue that technology drives a society's development ignore the way in which technology is shaped by its society. For example, there may be social or cultural reasons why particular technologies were, or were not, developed. Equally, the implementation of a new technology may be influenced by wider social factors - such as levels of wealth or the availability of a workforce with the necessary skills.

1.2 Importance of Technological Advancement

Technology is such an integral part of the modern world. This might seem very obvious, given the amount of technology we use in our day to day lives. When we think of technology, we often think of the latest phones, computers, or game consoles. But it is easy to forget that 'technology' includes all the things that are around us. Things like the bricks in a house, a pen, a book, a cup - these are all things that were built or created using knowledge and processes that are part of the area of study that we call technology. The people working in all kinds of fields - from engineering to architecture, from accountancy to product design - need knowledge of technology. This is an area that is always changing. New ideas, new materials, new techniques, and new methods are developed all the time. This means that technology is always moving forward and so what counts as 'hi-tech' in one year may be considered old-fashioned or out-of-date just a few years later. Whether we are realizing it or not, our lives are shaped by technology. But why exactly is it so important? Well, to answer that question we need to explore what is meant by technology as well as considering its many facets - such as social, technical, and cultural. What follows is a general explanation covering each of these areas.

1.3 Historical Overview of Technological Advancement

The period of invention known as the Industrial Revolution was a period of great change in the world. The Industrial Revolution is defined as the time from around 1750 to 1850, during which the means of producing goods changed from hand labor to machines, and from human and animal power to steam power. It is a time in history when the world was in a state of revolutionary change. The process began in Britain in the 18th century and from there spread to other parts of the world, and this period saw the first major technological advances. These had a massive impact on society and everyday life, and it really was a time of huge change. Some of the most important inventions of the Industrial Revolution were invented there. For example, we can first find an improved steam engine, developed by James Watt, in the mid to late 18th century. This engine used steam to generate power, and so it replaced traditional water-powered mills and the need for horses. This invention is used today in nuclear and coal powered electricity plants, and it really was a key development in the history of the world. Another example is the Cotton Gin, invented by Eli Whitney in 1794. Whitney's invention made the mass production of cotton possible, but unfortunately it also led to the spread of slavery in the southern United States, in order to keep up with the vastly increased productivity. The very first true factory was invented in around 1760, by Richard Arkwright. It used a water-wheel power source and the first moving machine. These were used in making textiles. This meant that the seeds of the Industrial Revolution were sown in the textile industry - and it led the way for all sorts of other industries to industrialize. This period was also one of great expansion, as people were now able to transport goods far and wide. Pioneering canals were built in Britain - it helped that there was lots of money that could be invested into such schemes. The first canal was known as the 'Father of all Canals', and it opened in 1761. Then, in 1830, the world's first intercity railway line was begun. This was the Liverpool and Manchester Railway. Railways then gained more and more importance, and by 1870 there were 13,500 miles of railway in Britain - a huge amount for the time. These huge increases in the amount of trade and also the types of goods that people could buy had a huge impact on the world, and most people were able to buy a far greater variety of clothes, food and other goods, as well as na

2. Impact of Technological Advancement

During the course of the history, the impact of technological advancement on the environment has been huge. Also, the economic, social and environment impact has changed the way society and human live. First, because of the scientific and technological advances environmental impact increased. Scientific research have gave birth to industrialization which again is the main cause of environment pollution. Many environment problems are the results of technological advancement which damages the environment in many ways. For instance, invention of cars and industries is the how the world is most affected by environmental problems. Because of the increase of number of care on the city road, the traffic jams are big problems of most city in the world. By that, the air pollution is increase every day and it is affected to human and living being lives. Also, the carbon monoxide is the biggest air pollutant and it releases from the burning of gasoline in car engines. Nowadays, lots of people have been suffer from this problem, especially those who live near to the main road. On top of that, the factory waste water is the main causes of water pollution because bad chemical is present in the waste water.Diffrently from others, the social impact of technological advancement have positive effect on peoples' life. People could be far away from each other with less time. Nowadays, the mobile phone and the internet are the most popular way to communicate with each other. For example, through the internet, person can talk to the family that in other country or even see the face of the each family member. Also, people can know what is happening around the world by the news that technology brings us every day. Social network such as Face book, Twitter, What'sApp and other are some example of source of information that people get to know on the social life on the internet. Social media change the social live to the highest society, as because people could know about the activities which are far away from his live and know about the rest of the world by different kind of the news and peoples' view point. Social media also give doctor an easier way to communicate with others even patient could know the information of the doctor online. Through social media and modern technology new society have been set up that exists on the internet. Modern technology have gained tremendous success because of many powerful innovations has been made in recent years. Having developed in a very short span of time, the business world has seen many changes in the way different aspect of the business is being performed, due to this technological advancement. Due to the progress of technology, many door's softwares have been introduced and used in many industries such as the use of mobile phone, the palm top and the compact discs. All these things has proven that from the invention of telephone and the industrial revolution, the progress of technology has changed the life of people in many ways. Innovations such as cars, the internet, the planets outer space, and satellites has given us new innovative scientific profession that shows in the creation of the work in the field of the science and new world where a person's thoughts thing him, not the material things. In the modern world, technology is developing fast and people live more long. Nowadays technology is as important in home as in industry because it makes many thing more convenient and easily. For example, micro-processor where the result can be found in most kitchen, games and other devices. As we can see is that just those small example have proven that over the year, demand and the use of the technology become a need and important in people's live. Foods are easy to prepare in short time, there is many different help that people are getting from the computer; people are ready to experience new thing and easy to find out something that they need in the computer. lastly, people could get the help in any where, any time with the technology fast development. Being a students in this era, there are many challenging that have to face every day of our life. Every students had to work hard in order to success and to get a good result. Lack of concentration in the class and feel bored after class are the common problems that faced by students. Well, in the modern society, students used computer and the internet to do their homework. Based on the studies shows that good performance and positive attitude to way of the students live are the effect of high use of the technology. Nowadays, many students have work part time job to rise money for study. Students are using the internet to work on the report and also used it for the research. Well, undoubtedly the special thing is that students also used the internet to find out the articles for the reading. With the advanced of technology, the student would foresee and easily to get the help through the computer as long as they are connected to the internet 24/7. On the other hand, people are working in the office we cannot ignore the benefit of technology because now the company's works are running in the technologies and the software. We can see that the most of the office work that we are experienced are totally run by the technology. Everyday, a computer and software have been updating help and progress in different way and create the efficient work and output as we expect from the company. In the modern era, everyday technology has been improvement and new technologies have been introduce to the society. It is hard to imagine how life was before the technological result time. But with the result of technology, people are ready to success in what ever work they are doing and just the way they want. The potential of technology is huge and it is continue to expanding which shows the positive effect on the technological progress on the society. Technology is changing the world in which we live and it should be show in the state of the economy as well. The economy is the relative well being of the whole in term of the economic for that. As we can see that, the progress of the technology is essential in all different type business, in labour market, in capital. And it always keep innovating and try to usher the new ways of creative destruction. By the technological period piece, before the industrial revolution, we can see there is no any change of economic pie through the big categories. But because of the technological progress and technological economics, the creation of factory have been increase the capital intensive and growth of the technological. As the more equipment and plant will be introduce, the demand of the labour and capital will be also increase which change the economic of the society from the technological recession. Also, the economic activities of the neighbourhood will non-stop growth which will be benefit for the business world. As for the impact on economy, the picture illustrate that the economy is much more capital intensive in a long term period and the technology will keep improving. High performance team is a team who achieve the goals and success by their own effective work, workload and internal development to the improvement. Also, high performance team and team who plays friend and have fun are two different teams which mean that high performance team are much more serious in the work and less time for them to have fun. However, from the high performance team research, it is approve that putting fun into work and also found that skilful fun is the main element that helps the team to maintain the successful level and commitment in term of the goal. Creativity in start up new business would be the benefit for the business and competition would becomes the challenges in the business world. Because of the high performance team, the project have been success and it is also due to the new and good innovations that bring to the new generation. Any business or industry, creativity new idea and new ways to solve the problem would change the strategy, the operation and the way of the planning to move turn. As we can see is that the knowledge and the ability of the individual would pass to other member, the experience of the working in a team and collective success will also gain. Among the six stages of the decision process, it is shows in the flowchart in the stage four which is the development of the alternative. There are tree ways which are brainstorming, the synetics and the lateral thoughts. Brainstorming is the open-ended thoughts that come in to the group and also generates the free-wheeling of the interaction. However, synectics is the creative thought of the group and mental creativity that help to realize the most perfect feeling in the group. lastly, lateral thoughts is a kind of the appreciate and properly used creativity in decision. What is from the charts tells to the other member have the space and time that can lead ideas. However, in the stage four, the lateral thoughts first while the development of the alternative is in the process. Team that don't work well are the reasons which turn to the failure and from the project where the output is much lower than the input. Team have to face many challenge from the disruptive list from the team work such as the team member from the pool of the partial idea, and too many possible choice of action, deny feelings, block the boredom and the pressure of the time and many others. lack of the team communication and collaboration, team member work in the separate way, duplication and time wasted in the wrong proper method and the fault of the group and pace of the idea that may the possible factors that lead to the ineffective in the team. In the process of the development of the alternative to choose the best alternative, it would be the benefit from the select and the manage in the decision. There are some way of the problem that the team may face in the team a consent the ways of the development of the alternative for the team. Through this technical report, the describe the certain kind of the high performance team, the way to make the team work, different kinds of the technological in team work. Also the description of the effect of the selection and the managing in the alternative. Creativity in decision process and the ways of the problem and the team may face is the report that might further explain and explore the key in success. In the process of the describe of the high performance team, the benefits of the building the team and the team work and make the team work, it is shows the important in the new ways of the team development and work. It is from the introduction that talk about the work force in the knowledge and the development assignment. Also the experience of working in team that help the individual career and the interest and the collective understanding. Last but not least, the collective success and it is from the introduction talk about the team working continuum in team development. Any way, from the introduction that shows how the work flow charts would be go through during the stages of decision process. Also the explain of the stage four the lateral thoughts, it is shows that the report describe the project overview and the project essences and three questions proposals in the choose of the project. Team work is an optimal way of the work. It is kind of the work that supports the work of the people. It is when people are values in the work place and value the difference in each other. Work teams are bring the high performance team is a great confident and success. Team work, as we all know is one of the main reasons for the success of many organizations. This concept of team work is significant not only for the employers but is equally important for the employees as well. For the success of the organization, it is essential for the employers to understand the strengths and weakness of each of the team member and assign work accordingly. Employee and employer communicate to each other, and play a strong role in the team work as well. As it is said that the team work that all people are doing is cooperative and the practices of the effective things of team. As we can see is we are moving towards the most exciting place to work. Team work definitively build the confident in each person to say what they are good in and help other in the work. Work with the team could most effective and the way of the carrying the things of work could be more efficient that work individual. It will create the improvement of the skill and knowledge, learning from each other and be open that give the lot of the idea and creativity in work the challenges. Because of the different experience and knowledge represent by the team member, creative has become much forceful in term of the possibility to the alternative and the flexibility. Team work has become an important part of the working culture as many workers has been program to work in team. It is from the critical, the common goal, the social interdependence's in work and the way of the approaches show in team work. These are the root that's goes though this technical report in the development of the high performance team. From the technical report which is team with different way in the team work, it is shows the methods that help to develop different way in the team work. Also it mainly talk about the keys in the team work and how the team members need to co-operate with each other in give the successful work. Keys in the high performance team development are commit to the common goal of the team, the definition of the communication and the levels of the give the team to the autonomy. First of all, in order to create and maintain the successful in the team work is to make sure that each of the team in the work have to under the common goal. Each person have to support the team work. Every one in the team have the confident in the team and work through out the effective of the team. Assign work to the member based on each person's strength and give the room to the autonomy that lead to the trust and the improvement in the continuous work that we do everyday because from the technical report shows that the freedom drive the high performance team to the successful completion of the task. As the development in the technology, many invention of the particular things has been discovered and the things that most have been envisioned in last 10 years has become the reality. Because in the modern technology, many elements and new ways of the technology have been intros in those as the mobile phone and some other quick way to the information. Creativity is the base of the knowledge of the future. That if we do not continue to the develop the way of new knowledge and new in experiences to the future. We find things, by using the technology in kind of meaningful perspectives and kind of by well enlightened people is that technology is a thing to be celebrated as a tool that can make the life better and easy to live every day. In that case, having to knowledge and good relationship in technology is the success to the contemporary society. A web services is a method of communication between two electric devices over the World Wide Web. In all the living things evolution is a process which basically seeks for the changes that take place in life. Some of these changes are either good or bad. In the other hand some are gradual while others are very fast. For instance, a small technological change in a particular section of the world may lead to a very big change in an entire society. There is so may different kind of the living things that our world is depended upon. But what kind of the good thing that a technology have been created to the new ways of the life? From the class note, technology is the making, modification, usage, and knowledge of tools, machine, technique in order to solve problem which continue in the modern society. Technology brings new ways of the life that people could not imagine of the passed. From the technologies, benefit and prosperity have been bring up to many different kind of the people in many ways. Technology have many different kind of the disciplines and knowledges that people have such as the computer, er electrical, mechanical to the art of the scientist. But what all of them have in common is that it bring the new way of the life. Without technologies many works would be impossible to people, such as the make the money as well as to support the people's living standard. There are two distinct teaching methods that relate to the class note on the view on writing. The continuing pedagogy believe that writing is a mode and goal of thereby shaping reality and that universities function to cultural a single sets of the academic writing. Also the intimate than other pedagogies that believe the writing might be natural because it is an expression of the should be the goal under a human intention and the context that also further the self developing of the life. Technology forecasting tries to predict the way of the technologies is going in the future. By the critical chain project management, it is a method of the planning and managing the project that put the main emphasis on the resources. And it is shown that the workforce have to be managing well from the manager and the emphasis redundancy on the certain of the key qualities and the indication of the critical path. The critical chain project management helps to minimize multi task and also to remove the inefficiency caused by the task by the project. Through the high performance team and the team work is important in term of the working culture as many workers has been program to work in team. Because of the different experience and knowledge represent by the team member, suggest and creativity has become much forceful in term of the possibility to the alternative and the flexibility. There are some stress and operation analysis that the concept of the depose, the meaning of the teachings and the test officious. Results show that the continuous and catastrophic kind of the model for the real time and the step it improving the testing of the time infusion whereas in the user give the several different class and kind of the failed test in the answering the conception question module. It should be further ways of promoting in the quality tutorial lead to decorate the use of the virtual learning because the transactions. Some work have been taken to the development and proposed the critical theories. To oversee the successful of the analytical team work and the team selection is deliberate and systematic in such the effective ways. And it is also treated the team work and the team work recruitment to be ongoing in the value of the high performance team. Also it is description of the major and secondary kind of the people management studies that are regularly course in general management syllabuses. Further evaluations on people management and the strategy thinking is shows that the recruitment increasingly prescribed the characteristics of the manager. It has been mentioned that the strategic activity is treacises from as they focused on the better and the recruitment because of has the long term recruitment. Last but non of the least, from the research report done by the team, it has been advice and provide in turn in absorption and the mechanism of the body of the terms existence. It is graceless in the demurring whether it is the most qualifies or most complete of the existing in the meaning of the plays or the teaching. From the idea of high performance team is not creating the management skill and in fact will work to the possible. Every team member should be dedicate and select the place to the work. There are three things will apply to the selection and managing of the alternative. One is give the people room in the works and provide the room to the autonomy, make sure that all people that mastered in the common goal and support the team work and last it provide the technology and the opportunity that lead the choose and the feeling of the work that contribute to the trust in the innovative in the work. And when from the report describe about the defination of the communicate and the freedom. The charts which illustrate to the stages of decision process and the flow and synectic and lateral thoughts. Well from the development of the alternative, it may the possible ways of the problem that the team may face in the team a consent. Through the high performance team we see that many ways to make the team work in the effective way with the result and the different knowledge and experiences are the benefit for the team that used in such kind of the work. It is assumption that we tend that put our faith and religion in human and the progress of the science in our age. There is apparent that if everybody have the opinions and turn to the consensus and knowledge because the solution is the problems of all thing well be forced on that forms the basic belief. It has from the strong because of the focusing that attempt to critical the results of the effects of knowledge on the policy and practice. Well it is reactive to the human of the ideas and technologies because it is more reactive and the focus on the concerned of the

2.1 Economic Impact

The economic impact of technological advancement has been an important focus in the academic literature. "The Office of Technology Assessment" stated that "technology-intensive businesses are responsible for approximately 40 million jobs and 60 percent of the nation's wages," demonstrating the significance of technology in the modern economy. The relationship between technology and employment has been a focal point of the research exploring the economic impact of technological advancement. By analyzing data measuring the use of technology in various industries against employment numbers, a study found that in the manufacturing industry, the use of industrial robots has a "positive and significant association with total factor productivity" but a "negative and significant association with employment." This implies that the rise of automation in manufacturing, a key sector of technology-intensive industries, has led to an overall increase in the efficiency of the industry while reducing the demand for labor, and hence jobs. The study also notes that, once technology has been fully integrated, the move to technology has displaced mid-wage jobs at the expense of creating more low-wage and less high-wage job opportunities.

2.2 Social Impact

The social impact of technological advancement was a subject of vivid discussions over the last decade. According to the study by the Chartered Institute of Personnel and Development (CIPD) (Kavanagh, 2018), investors believe that technological advancement benefits businesses and the economy by creating socio-economic relationships through improved productivity and the generation of novel services and products. However, some experts argue that the gains in productivity and material wealth have had a "social gradient" - that is, it helped the better-off more and often bypassed the least well-off (Wajcman, 2017). For example, the analysis of the European Working Conditions Survey data has shown that almost one in five workers have little or no influence on the order of tasks and on the speed of work and that every third surveyed worker has his work intensity determined by technology (Bechter et al., 2018). This leads to such problems as work intensification, decreased decision latitude and subordinative and harmful supervisory behaviour, often manifesting in a low socio-technical redesign of the work process, which, in turn, maintains low skill and job routinisation possibilities (Bechter et al., 2018). Moreover, the CIPD (Kavanagh, 2018) research found that only technological solutions to complex workplace issues are being implemented. Socio-technical solutions that complement worker needs and preferences are not being considered, and employers often opt for a technological fix to a non-technological problem - in a move that can actually damage the social fabric of the workplace through increased standardisation of tasks and decreased worker influence on work organisation (Kavanagh, 2018). Such standardisation of tasks and raised work intensity that are stimulated through technological advancement lead to a deficit in the attention focus on the social elements of the workplace, including informal communication and workplace relationships (Bechter et al., 2018). This undoubtedly triggers work-related mental health hazards, including burnout, depression and anxiety (Wessels, 2018).

2.3 Environmental Impact

This can be shown by an example played in the film called "The Day After Tomorrow", in which the world weather conditions were tremendously affected by the extreme climate change caused by the collapse of the northern polar ice caps. This real example can remind people to concern about the potential huge damage to the environment by technical advancement. Apart from the climate change, there are other types of pollutions generated by the production line of the newly technology-based industries. The most common one may be the water pollution. As industries are tend to set up their factories near the rivers, they could simply flush all the chemicals and destructive materials to the water directly after the process. This will certainly harm the aquatic lives, especially those small creatures which have high requirements to the water quality. On top of that, the overall food chain will also be affected. When the chemicals are absorbed by the smaller fish, the toxicity will gradually accumulate within the lives and it will certainly cause the reduction in the amount of species. Moreover, the air pollution also comes along with it. In order to make products with higher quality or in a shorter time by using different machines and equipment, factories choose to use the more advanced way of manufacturing which could produce an extremely large amount of certain notes and carbon. Numerical exterminates dizziness in the atmosphere increases at a very large speed. As a result, complaints will be generated more often from the workers and residents living nearby the factory as they have to bear the awful smell and there exists a high chance of getting respiratory problems. Based on the above analysis, it can be suggested that there is not an absolute point of view towards the impacts of technological advancement on the environment. It is possible to notice that, within different cases or scenarios, the influence on the world weather condition or the living standard of the human being always varies. However, it is undeniable that technology has the potential ability to damage the Earth as much as possible and the only reason for that is human beings do not use and manage the technology in the correct and planned way. We are now liable to find out and take the responsibility to prevent it from the destruction of our world environment caused by technological advancement.

2.4 Cultural Impact

One way in which technological advancement has impacted culture is through communication. The invention of the telephone made it convenient for people to talk with each other over long distances. Today, it is common to see people on the street, absorbed in the world that exists inside their phone. Social media platforms and messaging apps such as Facebook, Twitter, and Snapchat have enabled people to interact over long distances and in real life. With new technological breakthroughs shaping our society each and every day, it is important to be aware of the potential drawbacks. Online interactions can be perceived as less personal than physical interactions, purely because through a screen, anything is possible. In today's day and age, people are frequently making big life decisions based entirely on the data provided by these technological breakthroughs. An example would be what you choose to preoccupy your time and mind with each day – you may be influenced by what other people around you are doing, ultimately impacting your friendships and social life if you stay offline. Nowadays, people are spending a huge chunk of their time browsing the web and social media. This can lead to lower physical interactions and higher virtual interactions. When we change what we do with our time, we change who we are and, by extension, we change the kind of person we want to be. We must bear this in mind; although it has never been nor will it ever be necessary to burn down an iVerge, technologies are deserving of scrutiny and critique. With a better understanding of technology and its complexities, we can ensure that its potential negative effects are reduced.

3. Challenges and Ethical Considerations

Technological advancement has always been a driver of the economy. While it is true that technological progress creates opportunities for new and better paid jobs, it also leads to increased income inequality through the polarization of the labour market. Research has shown that low-skilled jobs are generally at a higher risk of automation, in addition to jobs that entail a routine task – for example, data input in the case of clerks. This then leaves workers searching for alternative employment and having to retrain, leading to social and economic dislocation. It can also increase the power of management over labour, through the intensification of working practices. A perfect example of this is the prevalence of zero-hours contracts in order to cope with unpredictable demand, particularly in industries such as retail and food. Contemporary debates around automation and job displacement are often large scale – a fast food chain, such as McDonald's, introduces touch screen technology in replacement of counter staff. However, we must also consider the impact this has for the individual worker – in this case, the retraining of counter staff and the intensification of work to fulfil orders. (Job Displacement, economicshelp.org) It is also of great concern the potential for technology to widen existing inequalities and create new ones. For example, it was found in Britain that citizens of a lower socio-economic status were more likely to report felt experiences of surveillance. This is a concept known as the 'digital poorhouse'; where the personal information of citizens of lower socio-economic status is 'warehoused' in large electronic databases, simplifying the surveillance of some of the most vulnerable members of society. As technological advancement shows no sign of abating, it means that in the future citizens may come to rely increasingly more on electronic forms of identity, such as social media profiles, further cementing the digital footprint of the 'poor' in society and creating a society that is even more sharply divided based on class. One may argue that the difference in the housing market between London and Wales is reasonably substantial however, the issue of data ownership and access rights are consistently present throughout the United Kingdom. This 'digital divide' becomes very apparent when identifying the demographic representation of people with internet access at home compared to those with no access at all. The age group with the highest proportion of no home internet access were those aged 75 and over, with 36% reporting to have no such access.

3.1 Job Displacement and Automation

In the mid-twentieth century, US automakers switched to a radical new system of production. Instead of assembling large vehicles from individual parts, companies began turning out cars on assembly lines. Thousands of workers performed the same tasks again and again, at breakneck speeds, doing this simple intensive work 50, 60, 70 or more hours a week, day and night. But these assembly workers grew wealthy because their labor created lots of value. They were an affluent, educated middle class at a time when only a quarter of Americans over 25 went to college. And because these workers were so productive, they could afford to pay the middle class wages required to buy the cars they were making. This virtuous circle enabled each generation to do better than the last. But today, technological advances are once again poised to utterly transform industry. Like the networking and digital technologies that have upended media, retailing, and financial services, the innovations remaking industry could bring enormous benefits in terms of higher productivity, national prosperity and improved quality of life. For instance, experts say that self-driving cars and trucks will eliminate a minimum of five hundred billion miles of driver travel a year while saving millions of people the time it takes to drive, as much as five hundred and ninety million hours a week. Yet advancing technologies such as robotics and artificial intelligence, and their deployment in the global economy, are likely to lead to even more radical economic disruptions than previous waves of technological advancement. First, these technologies increase productivity and facilitate unparalleled levels of efficiency for companies in industries across the economy. Second, the executive branch and Congress must provide educational, economic and regulatory strategies to encourage future American industries and businesses and to create local and national economic opportunity. Third, if technologies displace large numbers of workers over the next 1 to 5 years, immediate strategies might include first creating affordable skills and training programs for workers, including free education in community colleges and online education funded by either the federal or state governments. Second, expanding aid and scholarships for displaced workers to attend academic colleges and universities in order to retrain for long term, high quality employment. And third, increasing the availability of economic support for workers in industries and regions of the country that are most heavily impacted by job loss due to technological advantage.

3.2 Privacy and Data Security

Privacy law refers to the laws that deal with the regulation, storing, and using of personally identifiable information, and ensuring that data is stored in a manner that is in compliance with certain legal obligations. Many countries around the globe have enacted privacy laws; such laws are often designed to protect information privacy and to provide individuals with certain, specific privacy rights. Approaches to privacy can, broadly, be divided into two categories: specific laws that are designed to protect one aspect of privacy or another - such as the Electronic Communications Privacy Act, or the many data breach notification laws, which are intended to address privacy and security related to electronic data - and broader, more comprehensive legal protections, such as a nation's constitution. Some countries have no dedicated data protection laws or are in the process of enacting them. However, most countries recognize the importance of privacy rights for their citizens and have a treaty with the USA that allows the transfer of data and data processing across international borders. Such transfer and processing activities require adherence to certain privacy principles and the development of a "privacy shield" that complies with the treaty's standards. As of right now, public opinion and industry trends seem to be moving in the direction that greater extents of privacy in information management are a good thing and are fundamental to the evolution and continued function of modern society. For example, individuals around the globe are becoming increasingly privacy-savvy; that is, more and more people are aware of - and are advocating for - their rights and their needs vis-a-vis personal data privacy and information assurance. This movement has been bolstered by high-profile data breaches and data usage scandals, such as the Sony and Target breaches, and the Cambridge Analytica scandal. With respect to the Target and Sony breaches, this has led not only to immense class action lawsuits against the affected companies (the former paid $18.5M to settle a multi-state lawsuit) but to increased consumer awareness and a trend towards businesses being more accountable to their users. The Cambridge Analytica scandal has led to numerous lawsuits and investigations into Facebook, the company implicated in the scandal, and has resulted in a call for greater regulation and government oversight in the data markets.

3.3 Ethical Implications of Artificial Intelligence

In the area of technological exploration, it has become clear that I must study all the issues associated with new technologies, and not only to understand how a specific device or process works. New technologies may require me to learn completely new principles and techniques. My education and professional life now includes studying, teaching, and applying what some areas of science and engineering have learned about the best ways of developing useful and ethical technologies. This is because the most important everyday problems and opportunities in technology are "framed" by existing practices and beliefs. These new practices and beliefs may need to be developed, taught to others, and passed on to the next generation. There are several ways that people like me may learn to do something. Perhaps the most powerful way of learning is by reflecting on and critically evaluating what I have done. How is it relevant to practical intelligence? Every act of solving a problem (for example, how to produce a vacuum in a chemistry glass apparatus before proceeding with an experiment or how to frame an active material during a corrosion experiment) has a set of associated ends. I usually use that understanding to identify what device or method may be available to help solve the problem (so, for example, after a little experience, giving a 'quick fix' to a sticking suction cup on an aspirator is appropriate). The employment of techniques or devices is guided by how regularly successful they are and how important each success has been towards achieving each end that has come to be associated with the act. All of this will usually create a practice and give it a dynamic character.

3.4 Technological Divide and Access to Technology

To date, the benefits of technological development have not been shared equally among different sections of society because of the existence of what has been termed a 'technological divide', which may be defined as 'the gap that exists between those who have access to modern information and communication technology and those who do not'. Access to technology is important because it improves self-efficacy, supports problem-solving and critical thinking skills, and helps students to develop 21st-century skills. Technology also has the power to transform teaching by ushering in a new model of connected teaching. This model links teachers to their students and to professional content, resources, and systems to help them improve their own instruction and personalized learning. However, research has shown that for many teachers, the use of technology can be a problem because of the lack of resources and knowledge in how to use the technology. You can see the disadvantages of not having technology. The Impact of the Canada Research Chairs Program Research has been the driving force on how technology has been applied for both formative and summative assessments. It is through the research in both traditional and modern formative assessments such as student perceptions of effective teaching that common issues have been identified and tested with the use of technology for students, as pointed out by Beekes and Jardine. Also, technology has had a real impact on how the teachers, students, and administrators work. Students and teachers enjoy the technology. For example, instructors now design and create new instructional materials; students have the ability to participate in collaborative work, and students find that learning was more motivating and more satisfying.

4. Future of Technological Advancement

Emerging technologies, such as industrial robots, artificial intelligence, and biological and chemical engineering, are all new fields that are in the process of being introduced and are going to be critically important in the future. For example, according to the Massachusetts Institute of Technology, "many point to a second coming of artificial intelligence, in which machines will perform knowledge-based intelligent work, translating or giving advice, for example." This is important because many manual and routine tasks, such as packing boxes and assembly work, will become automated by robots and other new technologies. This will mean that many jobs traditionally done by people will be lost, although new jobs will be created in the field of robotics and computer programming, among others. However, these new technologies are not just leading to job losses; there are also many potential significant benefits. For example, Professor Rajkumar Roy, who is the director of manufacturing at Cranfield University, UK, argues that "emerging technologies in the factory environment offer game-changing potential to improve productivity through augmented intelligence and autonomy." This means that new technologies can help to improve manufacturing and also have the potential to regenerate factories and work that has been previously lost to other developing countries. This is important because it not only means that productivity will increase but also that factories will become cleaner and greener places to work. One example of this in action is the rise of smart factories, which use advanced manufacturing and materials technologies to benefit from the Internet of Things, data, and machine learning. Smart factories provide significant opportunities for improving the production process and flexibility, reducing the lead time, and increasing the efficiency of the supply chain, as well as providing better quality and greener production services. In fact, according to Siemens, one of Europe's largest industrial manufacturing companies, their smart factory in Amberg, Germany, "can produce more than 1,000 different customized products." This is important because it shows that technological advancement not only has the potential to create new jobs and industries but also significantly improve and change the ones that we are familiar with today, such as manufacturing and production. The focus on environmentally friendly technologies is also discussed, with a series of projects including the development of new energy storage technologies.

4.1 Emerging Technologies

Now we are living in a period of the most dramatic technological revolution in history and we are witnessing progress at a much faster rate. The term emerging technology is used to describe new developments that are expected to grow and have a significant impact in the coming years. It may be a new product, a new service, a new way of doing things or a new process or technology. There are many emerging technologies across the world. In health care, 3D printing technology is used to produce more durable and lighter tools for surgeons. Microchip implanted medicines continuously release fare amount of medication into the body. In simple it is a small technology when it is compared to others, but they all were going to develop. To empower the staff, left shift and share the information early. To increase the quality, service and value, the emerging technologies will speed up. In future, every industry will use the emerging technologies to increase productivity. The agriculture will use Global Positioning System in the fields where multiple actions will be performed at the same time. Banking goes to blockchain, the security will increase, Armenia, Belgium and Chile telecom are jointly entering Zimbabwe, it will be called Telecel Zimbabwe. Also the Video on Demand, Internet of Things, cloud solution, mobile money and mobile services are under emerging technology. The emerging technology in medicine is about those new tools and techniques that can help in the prevention, diagnosis and treatment of disease and helping maximize our chance population to healthier lives. People live in a digital world today. It is the fast growing, advanced technology and only thing it is changing the world. Today's infrastructure is available in the central and populous areas, but this new technology will spread all around Armenia as well. When a product or service goes through major pioneering changes, it can be called emerging. This technology comes from care and creativity, the developing. People believe someday their revolutions can fly forward and keep providing helpful, meaningful and new ideas for generations to improve. Emerging technology will enhance in many areas such as economy, agriculture, health care, security and so on, but step by step. There are many emerging technologies, the most pace of change is staggering, and it must be challenging to follow them. To address these disconnects and communicate in an effective way, the emerging technologies will continue to prioritize things and digital culture.

4.2 Potential Benefits and Risks

Firstly, it is recommended to read a text related to technological advancement in the modern world, which was published in 2012 by the National Academy of Engineering in the United States. The text, only briefly, emphasizes what are the potential benefits of technological advancement and the challenges that society has to face as a result of it. It is written that "one should expect his or her life to be both easier - with a higher quality and productivity through technological advancement - and more difficult - with significant improvements in global welfare and a growing concern for finding common solutions for problems that affect a vast number of people". After expressing his or her expectation about the positive aspects of technological advancements, the writer puts forth his or her main concerns. It is stated that the main challenge the world has to face, as a result of technological advancement, is that "as technology becomes increasingly complex and assumptions about its reliability are built into the design process, in addition to technology itself, the infrastructure becomes an important source of error". He or she continues to explain that "an infrastructure degraded by design complexity has complex interactions with planned and unplanned human actions and natural phenomena, and it constrains the ability to diagnose and recover from adverse events". He or she argues that if predicted changes in technology design and process management take place, the results are expected to be great by minimizing infrastructure errors; however, these would require a paradigm shift, which involves a major challenge: overcoming the stasis created by old theories, designs, education, and experience. With regards to the risks and challenges, it is written that "ensuring the long-term reliability of critical systems in the face of a rapid and significant evolution of technology - recognizing the potential systemic failures that may occur - is a profound engineering challenge". Also, the writer mentions the fact that "from the perspective of security and resilience, a fundamental challenge lies in ensuring that technical and social vulnerabilities are both recognized and addressed".

4.3 Ethical Frameworks for Future Technological Development

An interesting aspect of researching this section of technology is that many of the current forms of technology that we know of are not yet a thing of the past. This shows that the ethical framework would change as technology changes. One example is with robotic surgery. According to the John Hopkins Medical Institution, "Today, the most commonly used surgical robot is the da Vinci Surgical System, produced by Intuitive Surgical. The da Vinci System is just one example of recent advances in computer-enhanced technology." The institution also notes that this surgical system "is not a robot that can be programmed to do a wide variety of tasks. Instead, it is a master-slave system, meaning that it cannot be programmed to do a specific task that the surgeon has not thought of before." This is a huge ethical advance because it requires surgeons to be trained in the specific use of the system and also requires surgeons to work with the system so as best to help the patient. Also, according to an article on NCBI published by the U.S. National Library of Medicine, "Although the possibility of major functional morbidities after surgery may be reduced by the use of robotic assistance, there are ethical implications relating to the cost effectiveness and high initial and running costs." This would suggest that as ethical framework evolves, three questions can become more or less central: questions about liberty (i.e. would this reduce a human being's ability to make free choices about themselves?), questions about harm (i.e. how has this negatively impacted a person's well-being?) and questions about social justice (i.e. does this pose a threat to wider society or certain groups within society?). As technology itself evolves, so does the capability and potential for ethical frameworks. And that research into robotic surgery shows that the frameworks can change over time. Specifically, the article "Ethical Implications of Emerging Technologies" found in the "International Review of Information Ethics" further supports this idea, finding that "the central question which emerges in relation to ethical frameworks for research and the aseptic assembling of strategies and application of artificial bodies in biotechnology is that the existing legislative frameworks are rapidly overtaken by technological advances."

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How artificial intelligence is transforming the world

Subscribe to the center for technology innovation newsletter, darrell m. west and darrell m. west senior fellow - center for technology innovation , douglas dillon chair in governmental studies john r. allen john r. allen.

April 24, 2018

Artificial intelligence (AI) is a wide-ranging tool that enables people to rethink how we integrate information, analyze data, and use the resulting insights to improve decision making—and already it is transforming every walk of life. In this report, Darrell West and John Allen discuss AI’s application across a variety of sectors, address issues in its development, and offer recommendations for getting the most out of AI while still protecting important human values.

Table of Contents I. Qualities of artificial intelligence II. Applications in diverse sectors III. Policy, regulatory, and ethical issues IV. Recommendations V. Conclusion

• 49 min read

Most people are not very familiar with the concept of artificial intelligence (AI). As an illustration, when 1,500 senior business leaders in the United States in 2017 were asked about AI, only 17 percent said they were familiar with it. 1 A number of them were not sure what it was or how it would affect their particular companies. They understood there was considerable potential for altering business processes, but were not clear how AI could be deployed within their own organizations.

Despite its widespread lack of familiarity, AI is a technology that is transforming every walk of life. It is a wide-ranging tool that enables people to rethink how we integrate information, analyze data, and use the resulting insights to improve decisionmaking. Our hope through this comprehensive overview is to explain AI to an audience of policymakers, opinion leaders, and interested observers, and demonstrate how AI already is altering the world and raising important questions for society, the economy, and governance.

In this paper, we discuss novel applications in finance, national security, health care, criminal justice, transportation, and smart cities, and address issues such as data access problems, algorithmic bias, AI ethics and transparency, and legal liability for AI decisions. We contrast the regulatory approaches of the U.S. and European Union, and close by making a number of recommendations for getting the most out of AI while still protecting important human values. 2

In order to maximize AI benefits, we recommend nine steps for going forward:

• Encourage greater data access for researchers without compromising users’ personal privacy,
• invest more government funding in unclassified AI research,
• promote new models of digital education and AI workforce development so employees have the skills needed in the 21 st -century economy,
• create a federal AI advisory committee to make policy recommendations,
• engage with state and local officials so they enact effective policies,
• regulate broad AI principles rather than specific algorithms,
• take bias complaints seriously so AI does not replicate historic injustice, unfairness, or discrimination in data or algorithms,
• maintain mechanisms for human oversight and control, and
• penalize malicious AI behavior and promote cybersecurity.

Qualities of artificial intelligence

Although there is no uniformly agreed upon definition, AI generally is thought to refer to “machines that respond to stimulation consistent with traditional responses from humans, given the human capacity for contemplation, judgment and intention.” 3  According to researchers Shubhendu and Vijay, these software systems “make decisions which normally require [a] human level of expertise” and help people anticipate problems or deal with issues as they come up. 4 As such, they operate in an intentional, intelligent, and adaptive manner.

Intentionality

Artificial intelligence algorithms are designed to make decisions, often using real-time data. They are unlike passive machines that are capable only of mechanical or predetermined responses. Using sensors, digital data, or remote inputs, they combine information from a variety of different sources, analyze the material instantly, and act on the insights derived from those data. With massive improvements in storage systems, processing speeds, and analytic techniques, they are capable of tremendous sophistication in analysis and decisionmaking.

Artificial intelligence is already altering the world and raising important questions for society, the economy, and governance.

Intelligence

AI generally is undertaken in conjunction with machine learning and data analytics. 5 Machine learning takes data and looks for underlying trends. If it spots something that is relevant for a practical problem, software designers can take that knowledge and use it to analyze specific issues. All that is required are data that are sufficiently robust that algorithms can discern useful patterns. Data can come in the form of digital information, satellite imagery, visual information, text, or unstructured data.

Adaptability

AI systems have the ability to learn and adapt as they make decisions. In the transportation area, for example, semi-autonomous vehicles have tools that let drivers and vehicles know about upcoming congestion, potholes, highway construction, or other possible traffic impediments. Vehicles can take advantage of the experience of other vehicles on the road, without human involvement, and the entire corpus of their achieved “experience” is immediately and fully transferable to other similarly configured vehicles. Their advanced algorithms, sensors, and cameras incorporate experience in current operations, and use dashboards and visual displays to present information in real time so human drivers are able to make sense of ongoing traffic and vehicular conditions. And in the case of fully autonomous vehicles, advanced systems can completely control the car or truck, and make all the navigational decisions.

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Applications in diverse sectors

AI is not a futuristic vision, but rather something that is here today and being integrated with and deployed into a variety of sectors. This includes fields such as finance, national security, health care, criminal justice, transportation, and smart cities. There are numerous examples where AI already is making an impact on the world and augmenting human capabilities in significant ways. 6

One of the reasons for the growing role of AI is the tremendous opportunities for economic development that it presents. A project undertaken by PriceWaterhouseCoopers estimated that “artificial intelligence technologies could increase global GDP by $15.7 trillion, a full 14%, by 2030.” 7 That includes advances of $7 trillion in China, $3.7 trillion in North America, $1.8 trillion in Northern Europe, $1.2 trillion for Africa and Oceania, $0.9 trillion in the rest of Asia outside of China, $0.7 trillion in Southern Europe, and $0.5 trillion in Latin America. China is making rapid strides because it has set a national goal of investing $150 billion in AI and becoming the global leader in this area by 2030.

Meanwhile, a McKinsey Global Institute study of China found that “AI-led automation can give the Chinese economy a productivity injection that would add 0.8 to 1.4 percentage points to GDP growth annually, depending on the speed of adoption.” 8 Although its authors found that China currently lags the United States and the United Kingdom in AI deployment, the sheer size of its AI market gives that country tremendous opportunities for pilot testing and future development.

Investments in financial AI in the United States tripled between 2013 and 2014 to a total of $12.2 billion. 9 According to observers in that sector, “Decisions about loans are now being made by software that can take into account a variety of finely parsed data about a borrower, rather than just a credit score and a background check.” 10 In addition, there are so-called robo-advisers that “create personalized investment portfolios, obviating the need for stockbrokers and financial advisers.” 11 These advances are designed to take the emotion out of investing and undertake decisions based on analytical considerations, and make these choices in a matter of minutes.

A prominent example of this is taking place in stock exchanges, where high-frequency trading by machines has replaced much of human decisionmaking. People submit buy and sell orders, and computers match them in the blink of an eye without human intervention. Machines can spot trading inefficiencies or market differentials on a very small scale and execute trades that make money according to investor instructions. 12 Powered in some places by advanced computing, these tools have much greater capacities for storing information because of their emphasis not on a zero or a one, but on “quantum bits” that can store multiple values in each location. 13 That dramatically increases storage capacity and decreases processing times.

Fraud detection represents another way AI is helpful in financial systems. It sometimes is difficult to discern fraudulent activities in large organizations, but AI can identify abnormalities, outliers, or deviant cases requiring additional investigation. That helps managers find problems early in the cycle, before they reach dangerous levels. 14

National security

AI plays a substantial role in national defense. Through its Project Maven, the American military is deploying AI “to sift through the massive troves of data and video captured by surveillance and then alert human analysts of patterns or when there is abnormal or suspicious activity.” 15 According to Deputy Secretary of Defense Patrick Shanahan, the goal of emerging technologies in this area is “to meet our warfighters’ needs and to increase [the] speed and agility [of] technology development and procurement.” 16

Artificial intelligence will accelerate the traditional process of warfare so rapidly that a new term has been coined: hyperwar.

The big data analytics associated with AI will profoundly affect intelligence analysis, as massive amounts of data are sifted in near real time—if not eventually in real time—thereby providing commanders and their staffs a level of intelligence analysis and productivity heretofore unseen. Command and control will similarly be affected as human commanders delegate certain routine, and in special circumstances, key decisions to AI platforms, reducing dramatically the time associated with the decision and subsequent action. In the end, warfare is a time competitive process, where the side able to decide the fastest and move most quickly to execution will generally prevail. Indeed, artificially intelligent intelligence systems, tied to AI-assisted command and control systems, can move decision support and decisionmaking to a speed vastly superior to the speeds of the traditional means of waging war. So fast will be this process, especially if coupled to automatic decisions to launch artificially intelligent autonomous weapons systems capable of lethal outcomes, that a new term has been coined specifically to embrace the speed at which war will be waged: hyperwar.

While the ethical and legal debate is raging over whether America will ever wage war with artificially intelligent autonomous lethal systems, the Chinese and Russians are not nearly so mired in this debate, and we should anticipate our need to defend against these systems operating at hyperwar speeds. The challenge in the West of where to position “humans in the loop” in a hyperwar scenario will ultimately dictate the West’s capacity to be competitive in this new form of conflict. 17

Just as AI will profoundly affect the speed of warfare, the proliferation of zero day or zero second cyber threats as well as polymorphic malware will challenge even the most sophisticated signature-based cyber protection. This forces significant improvement to existing cyber defenses. Increasingly, vulnerable systems are migrating, and will need to shift to a layered approach to cybersecurity with cloud-based, cognitive AI platforms. This approach moves the community toward a “thinking” defensive capability that can defend networks through constant training on known threats. This capability includes DNA-level analysis of heretofore unknown code, with the possibility of recognizing and stopping inbound malicious code by recognizing a string component of the file. This is how certain key U.S.-based systems stopped the debilitating “WannaCry” and “Petya” viruses.

Preparing for hyperwar and defending critical cyber networks must become a high priority because China, Russia, North Korea, and other countries are putting substantial resources into AI. In 2017, China’s State Council issued a plan for the country to “build a domestic industry worth almost $150 billion” by 2030. 18 As an example of the possibilities, the Chinese search firm Baidu has pioneered a facial recognition application that finds missing people. In addition, cities such as Shenzhen are providing up to $1 million to support AI labs. That country hopes AI will provide security, combat terrorism, and improve speech recognition programs. 19 The dual-use nature of many AI algorithms will mean AI research focused on one sector of society can be rapidly modified for use in the security sector as well. 20

Health care

AI tools are helping designers improve computational sophistication in health care. For example, Merantix is a German company that applies deep learning to medical issues. It has an application in medical imaging that “detects lymph nodes in the human body in Computer Tomography (CT) images.” 21 According to its developers, the key is labeling the nodes and identifying small lesions or growths that could be problematic. Humans can do this, but radiologists charge $100 per hour and may be able to carefully read only four images an hour. If there were 10,000 images, the cost of this process would be $250,000, which is prohibitively expensive if done by humans.

What deep learning can do in this situation is train computers on data sets to learn what a normal-looking versus an irregular-appearing lymph node is. After doing that through imaging exercises and honing the accuracy of the labeling, radiological imaging specialists can apply this knowledge to actual patients and determine the extent to which someone is at risk of cancerous lymph nodes. Since only a few are likely to test positive, it is a matter of identifying the unhealthy versus healthy node.

AI has been applied to congestive heart failure as well, an illness that afflicts 10 percent of senior citizens and costs $35 billion each year in the United States. AI tools are helpful because they “predict in advance potential challenges ahead and allocate resources to patient education, sensing, and proactive interventions that keep patients out of the hospital.” 22

Criminal justice

AI is being deployed in the criminal justice area. The city of Chicago has developed an AI-driven “Strategic Subject List” that analyzes people who have been arrested for their risk of becoming future perpetrators. It ranks 400,000 people on a scale of 0 to 500, using items such as age, criminal activity, victimization, drug arrest records, and gang affiliation. In looking at the data, analysts found that youth is a strong predictor of violence, being a shooting victim is associated with becoming a future perpetrator, gang affiliation has little predictive value, and drug arrests are not significantly associated with future criminal activity. 23

Judicial experts claim AI programs reduce human bias in law enforcement and leads to a fairer sentencing system. R Street Institute Associate Caleb Watney writes:

Empirically grounded questions of predictive risk analysis play to the strengths of machine learning, automated reasoning and other forms of AI. One machine-learning policy simulation concluded that such programs could be used to cut crime up to 24.8 percent with no change in jailing rates, or reduce jail populations by up to 42 percent with no increase in crime rates. 24

However, critics worry that AI algorithms represent “a secret system to punish citizens for crimes they haven’t yet committed. The risk scores have been used numerous times to guide large-scale roundups.” 25 The fear is that such tools target people of color unfairly and have not helped Chicago reduce the murder wave that has plagued it in recent years.

Despite these concerns, other countries are moving ahead with rapid deployment in this area. In China, for example, companies already have “considerable resources and access to voices, faces and other biometric data in vast quantities, which would help them develop their technologies.” 26 New technologies make it possible to match images and voices with other types of information, and to use AI on these combined data sets to improve law enforcement and national security. Through its “Sharp Eyes” program, Chinese law enforcement is matching video images, social media activity, online purchases, travel records, and personal identity into a “police cloud.” This integrated database enables authorities to keep track of criminals, potential law-breakers, and terrorists. 27 Put differently, China has become the world’s leading AI-powered surveillance state.

Transportation

Transportation represents an area where AI and machine learning are producing major innovations. Research by Cameron Kerry and Jack Karsten of the Brookings Institution has found that over $80 billion was invested in autonomous vehicle technology between August 2014 and June 2017. Those investments include applications both for autonomous driving and the core technologies vital to that sector. 28

Autonomous vehicles—cars, trucks, buses, and drone delivery systems—use advanced technological capabilities. Those features include automated vehicle guidance and braking, lane-changing systems, the use of cameras and sensors for collision avoidance, the use of AI to analyze information in real time, and the use of high-performance computing and deep learning systems to adapt to new circumstances through detailed maps. 29

Light detection and ranging systems (LIDARs) and AI are key to navigation and collision avoidance. LIDAR systems combine light and radar instruments. They are mounted on the top of vehicles that use imaging in a 360-degree environment from a radar and light beams to measure the speed and distance of surrounding objects. Along with sensors placed on the front, sides, and back of the vehicle, these instruments provide information that keeps fast-moving cars and trucks in their own lane, helps them avoid other vehicles, applies brakes and steering when needed, and does so instantly so as to avoid accidents.

Advanced software enables cars to learn from the experiences of other vehicles on the road and adjust their guidance systems as weather, driving, or road conditions change. This means that software is the key—not the physical car or truck itself.

Since these cameras and sensors compile a huge amount of information and need to process it instantly to avoid the car in the next lane, autonomous vehicles require high-performance computing, advanced algorithms, and deep learning systems to adapt to new scenarios. This means that software is the key, not the physical car or truck itself. 30 Advanced software enables cars to learn from the experiences of other vehicles on the road and adjust their guidance systems as weather, driving, or road conditions change. 31

Ride-sharing companies are very interested in autonomous vehicles. They see advantages in terms of customer service and labor productivity. All of the major ride-sharing companies are exploring driverless cars. The surge of car-sharing and taxi services—such as Uber and Lyft in the United States, Daimler’s Mytaxi and Hailo service in Great Britain, and Didi Chuxing in China—demonstrate the opportunities of this transportation option. Uber recently signed an agreement to purchase 24,000 autonomous cars from Volvo for its ride-sharing service. 32

However, the ride-sharing firm suffered a setback in March 2018 when one of its autonomous vehicles in Arizona hit and killed a pedestrian. Uber and several auto manufacturers immediately suspended testing and launched investigations into what went wrong and how the fatality could have occurred. 33 Both industry and consumers want reassurance that the technology is safe and able to deliver on its stated promises. Unless there are persuasive answers, this accident could slow AI advancements in the transportation sector.

Smart cities

Metropolitan governments are using AI to improve urban service delivery. For example, according to Kevin Desouza, Rashmi Krishnamurthy, and Gregory Dawson:

The Cincinnati Fire Department is using data analytics to optimize medical emergency responses. The new analytics system recommends to the dispatcher an appropriate response to a medical emergency call—whether a patient can be treated on-site or needs to be taken to the hospital—by taking into account several factors, such as the type of call, location, weather, and similar calls. 34

Since it fields 80,000 requests each year, Cincinnati officials are deploying this technology to prioritize responses and determine the best ways to handle emergencies. They see AI as a way to deal with large volumes of data and figure out efficient ways of responding to public requests. Rather than address service issues in an ad hoc manner, authorities are trying to be proactive in how they provide urban services.

Cincinnati is not alone. A number of metropolitan areas are adopting smart city applications that use AI to improve service delivery, environmental planning, resource management, energy utilization, and crime prevention, among other things. For its smart cities index, the magazine Fast Company ranked American locales and found Seattle, Boston, San Francisco, Washington, D.C., and New York City as the top adopters. Seattle, for example, has embraced sustainability and is using AI to manage energy usage and resource management. Boston has launched a “City Hall To Go” that makes sure underserved communities receive needed public services. It also has deployed “cameras and inductive loops to manage traffic and acoustic sensors to identify gun shots.” San Francisco has certified 203 buildings as meeting LEED sustainability standards. 35

Through these and other means, metropolitan areas are leading the country in the deployment of AI solutions. Indeed, according to a National League of Cities report, 66 percent of American cities are investing in smart city technology. Among the top applications noted in the report are “smart meters for utilities, intelligent traffic signals, e-governance applications, Wi-Fi kiosks, and radio frequency identification sensors in pavement.” 36

Policy, regulatory, and ethical issues

These examples from a variety of sectors demonstrate how AI is transforming many walks of human existence. The increasing penetration of AI and autonomous devices into many aspects of life is altering basic operations and decisionmaking within organizations, and improving efficiency and response times.

At the same time, though, these developments raise important policy, regulatory, and ethical issues. For example, how should we promote data access? How do we guard against biased or unfair data used in algorithms? What types of ethical principles are introduced through software programming, and how transparent should designers be about their choices? What about questions of legal liability in cases where algorithms cause harm? 37

The increasing penetration of AI into many aspects of life is altering decisionmaking within organizations and improving efficiency. At the same time, though, these developments raise important policy, regulatory, and ethical issues.

Data access problems

The key to getting the most out of AI is having a “data-friendly ecosystem with unified standards and cross-platform sharing.” AI depends on data that can be analyzed in real time and brought to bear on concrete problems. Having data that are “accessible for exploration” in the research community is a prerequisite for successful AI development. 38

According to a McKinsey Global Institute study, nations that promote open data sources and data sharing are the ones most likely to see AI advances. In this regard, the United States has a substantial advantage over China. Global ratings on data openness show that U.S. ranks eighth overall in the world, compared to 93 for China. 39

But right now, the United States does not have a coherent national data strategy. There are few protocols for promoting research access or platforms that make it possible to gain new insights from proprietary data. It is not always clear who owns data or how much belongs in the public sphere. These uncertainties limit the innovation economy and act as a drag on academic research. In the following section, we outline ways to improve data access for researchers.

Biases in data and algorithms

In some instances, certain AI systems are thought to have enabled discriminatory or biased practices. 40 For example, Airbnb has been accused of having homeowners on its platform who discriminate against racial minorities. A research project undertaken by the Harvard Business School found that “Airbnb users with distinctly African American names were roughly 16 percent less likely to be accepted as guests than those with distinctly white names.” 41

Racial issues also come up with facial recognition software. Most such systems operate by comparing a person’s face to a range of faces in a large database. As pointed out by Joy Buolamwini of the Algorithmic Justice League, “If your facial recognition data contains mostly Caucasian faces, that’s what your program will learn to recognize.” 42 Unless the databases have access to diverse data, these programs perform poorly when attempting to recognize African-American or Asian-American features.

Many historical data sets reflect traditional values, which may or may not represent the preferences wanted in a current system. As Buolamwini notes, such an approach risks repeating inequities of the past:

The rise of automation and the increased reliance on algorithms for high-stakes decisions such as whether someone get insurance or not, your likelihood to default on a loan or somebody’s risk of recidivism means this is something that needs to be addressed. Even admissions decisions are increasingly automated—what school our children go to and what opportunities they have. We don’t have to bring the structural inequalities of the past into the future we create. 43

AI ethics and transparency

Algorithms embed ethical considerations and value choices into program decisions. As such, these systems raise questions concerning the criteria used in automated decisionmaking. Some people want to have a better understanding of how algorithms function and what choices are being made. 44

In the United States, many urban schools use algorithms for enrollment decisions based on a variety of considerations, such as parent preferences, neighborhood qualities, income level, and demographic background. According to Brookings researcher Jon Valant, the New Orleans–based Bricolage Academy “gives priority to economically disadvantaged applicants for up to 33 percent of available seats. In practice, though, most cities have opted for categories that prioritize siblings of current students, children of school employees, and families that live in school’s broad geographic area.” 45 Enrollment choices can be expected to be very different when considerations of this sort come into play.

Depending on how AI systems are set up, they can facilitate the redlining of mortgage applications, help people discriminate against individuals they don’t like, or help screen or build rosters of individuals based on unfair criteria. The types of considerations that go into programming decisions matter a lot in terms of how the systems operate and how they affect customers. 46

For these reasons, the EU is implementing the General Data Protection Regulation (GDPR) in May 2018. The rules specify that people have “the right to opt out of personally tailored ads” and “can contest ‘legal or similarly significant’ decisions made by algorithms and appeal for human intervention” in the form of an explanation of how the algorithm generated a particular outcome. Each guideline is designed to ensure the protection of personal data and provide individuals with information on how the “black box” operates. 47

Legal liability

There are questions concerning the legal liability of AI systems. If there are harms or infractions (or fatalities in the case of driverless cars), the operators of the algorithm likely will fall under product liability rules. A body of case law has shown that the situation’s facts and circumstances determine liability and influence the kind of penalties that are imposed. Those can range from civil fines to imprisonment for major harms. 48 The Uber-related fatality in Arizona will be an important test case for legal liability. The state actively recruited Uber to test its autonomous vehicles and gave the company considerable latitude in terms of road testing. It remains to be seen if there will be lawsuits in this case and who is sued: the human backup driver, the state of Arizona, the Phoenix suburb where the accident took place, Uber, software developers, or the auto manufacturer. Given the multiple people and organizations involved in the road testing, there are many legal questions to be resolved.

In non-transportation areas, digital platforms often have limited liability for what happens on their sites. For example, in the case of Airbnb, the firm “requires that people agree to waive their right to sue, or to join in any class-action lawsuit or class-action arbitration, to use the service.” By demanding that its users sacrifice basic rights, the company limits consumer protections and therefore curtails the ability of people to fight discrimination arising from unfair algorithms. 49 But whether the principle of neutral networks holds up in many sectors is yet to be determined on a widespread basis.

Recommendations

In order to balance innovation with basic human values, we propose a number of recommendations for moving forward with AI. This includes improving data access, increasing government investment in AI, promoting AI workforce development, creating a federal advisory committee, engaging with state and local officials to ensure they enact effective policies, regulating broad objectives as opposed to specific algorithms, taking bias seriously as an AI issue, maintaining mechanisms for human control and oversight, and penalizing malicious behavior and promoting cybersecurity.

Improving data access

The United States should develop a data strategy that promotes innovation and consumer protection. Right now, there are no uniform standards in terms of data access, data sharing, or data protection. Almost all the data are proprietary in nature and not shared very broadly with the research community, and this limits innovation and system design. AI requires data to test and improve its learning capacity. 50 Without structured and unstructured data sets, it will be nearly impossible to gain the full benefits of artificial intelligence.

In general, the research community needs better access to government and business data, although with appropriate safeguards to make sure researchers do not misuse data in the way Cambridge Analytica did with Facebook information. There is a variety of ways researchers could gain data access. One is through voluntary agreements with companies holding proprietary data. Facebook, for example, recently announced a partnership with Stanford economist Raj Chetty to use its social media data to explore inequality. 51 As part of the arrangement, researchers were required to undergo background checks and could only access data from secured sites in order to protect user privacy and security.

In the U.S., there are no uniform standards in terms of data access, data sharing, or data protection. Almost all the data are proprietary in nature and not shared very broadly with the research community, and this limits innovation and system design.

Google long has made available search results in aggregated form for researchers and the general public. Through its “Trends” site, scholars can analyze topics such as interest in Trump, views about democracy, and perspectives on the overall economy. 52 That helps people track movements in public interest and identify topics that galvanize the general public.

Twitter makes much of its tweets available to researchers through application programming interfaces, commonly referred to as APIs. These tools help people outside the company build application software and make use of data from its social media platform. They can study patterns of social media communications and see how people are commenting on or reacting to current events.

In some sectors where there is a discernible public benefit, governments can facilitate collaboration by building infrastructure that shares data. For example, the National Cancer Institute has pioneered a data-sharing protocol where certified researchers can query health data it has using de-identified information drawn from clinical data, claims information, and drug therapies. That enables researchers to evaluate efficacy and effectiveness, and make recommendations regarding the best medical approaches, without compromising the privacy of individual patients.

There could be public-private data partnerships that combine government and business data sets to improve system performance. For example, cities could integrate information from ride-sharing services with its own material on social service locations, bus lines, mass transit, and highway congestion to improve transportation. That would help metropolitan areas deal with traffic tie-ups and assist in highway and mass transit planning.

Some combination of these approaches would improve data access for researchers, the government, and the business community, without impinging on personal privacy. As noted by Ian Buck, the vice president of NVIDIA, “Data is the fuel that drives the AI engine. The federal government has access to vast sources of information. Opening access to that data will help us get insights that will transform the U.S. economy.” 53 Through its Data.gov portal, the federal government already has put over 230,000 data sets into the public domain, and this has propelled innovation and aided improvements in AI and data analytic technologies. 54 The private sector also needs to facilitate research data access so that society can achieve the full benefits of artificial intelligence.

Increase government investment in AI

According to Greg Brockman, the co-founder of OpenAI, the U.S. federal government invests only $1.1 billion in non-classified AI technology. 55 That is far lower than the amount being spent by China or other leading nations in this area of research. That shortfall is noteworthy because the economic payoffs of AI are substantial. In order to boost economic development and social innovation, federal officials need to increase investment in artificial intelligence and data analytics. Higher investment is likely to pay for itself many times over in economic and social benefits. 56

Promote digital education and workforce development

As AI applications accelerate across many sectors, it is vital that we reimagine our educational institutions for a world where AI will be ubiquitous and students need a different kind of training than they currently receive. Right now, many students do not receive instruction in the kinds of skills that will be needed in an AI-dominated landscape. For example, there currently are shortages of data scientists, computer scientists, engineers, coders, and platform developers. These are skills that are in short supply; unless our educational system generates more people with these capabilities, it will limit AI development.

For these reasons, both state and federal governments have been investing in AI human capital. For example, in 2017, the National Science Foundation funded over 6,500 graduate students in computer-related fields and has launched several new initiatives designed to encourage data and computer science at all levels from pre-K to higher and continuing education. 57 The goal is to build a larger pipeline of AI and data analytic personnel so that the United States can reap the full advantages of the knowledge revolution.

But there also needs to be substantial changes in the process of learning itself. It is not just technical skills that are needed in an AI world but skills of critical reasoning, collaboration, design, visual display of information, and independent thinking, among others. AI will reconfigure how society and the economy operate, and there needs to be “big picture” thinking on what this will mean for ethics, governance, and societal impact. People will need the ability to think broadly about many questions and integrate knowledge from a number of different areas.

One example of new ways to prepare students for a digital future is IBM’s Teacher Advisor program, utilizing Watson’s free online tools to help teachers bring the latest knowledge into the classroom. They enable instructors to develop new lesson plans in STEM and non-STEM fields, find relevant instructional videos, and help students get the most out of the classroom. 58 As such, they are precursors of new educational environments that need to be created.

Create a federal AI advisory committee

Federal officials need to think about how they deal with artificial intelligence. As noted previously, there are many issues ranging from the need for improved data access to addressing issues of bias and discrimination. It is vital that these and other concerns be considered so we gain the full benefits of this emerging technology.

In order to move forward in this area, several members of Congress have introduced the “Future of Artificial Intelligence Act,” a bill designed to establish broad policy and legal principles for AI. It proposes the secretary of commerce create a federal advisory committee on the development and implementation of artificial intelligence. The legislation provides a mechanism for the federal government to get advice on ways to promote a “climate of investment and innovation to ensure the global competitiveness of the United States,” “optimize the development of artificial intelligence to address the potential growth, restructuring, or other changes in the United States workforce,” “support the unbiased development and application of artificial intelligence,” and “protect the privacy rights of individuals.” 59

Among the specific questions the committee is asked to address include the following: competitiveness, workforce impact, education, ethics training, data sharing, international cooperation, accountability, machine learning bias, rural impact, government efficiency, investment climate, job impact, bias, and consumer impact. The committee is directed to submit a report to Congress and the administration 540 days after enactment regarding any legislative or administrative action needed on AI.

This legislation is a step in the right direction, although the field is moving so rapidly that we would recommend shortening the reporting timeline from 540 days to 180 days. Waiting nearly two years for a committee report will certainly result in missed opportunities and a lack of action on important issues. Given rapid advances in the field, having a much quicker turnaround time on the committee analysis would be quite beneficial.

Engage with state and local officials

States and localities also are taking action on AI. For example, the New York City Council unanimously passed a bill that directed the mayor to form a taskforce that would “monitor the fairness and validity of algorithms used by municipal agencies.” 60 The city employs algorithms to “determine if a lower bail will be assigned to an indigent defendant, where firehouses are established, student placement for public schools, assessing teacher performance, identifying Medicaid fraud and determine where crime will happen next.” 61

According to the legislation’s developers, city officials want to know how these algorithms work and make sure there is sufficient AI transparency and accountability. In addition, there is concern regarding the fairness and biases of AI algorithms, so the taskforce has been directed to analyze these issues and make recommendations regarding future usage. It is scheduled to report back to the mayor on a range of AI policy, legal, and regulatory issues by late 2019.

Some observers already are worrying that the taskforce won’t go far enough in holding algorithms accountable. For example, Julia Powles of Cornell Tech and New York University argues that the bill originally required companies to make the AI source code available to the public for inspection, and that there be simulations of its decisionmaking using actual data. After criticism of those provisions, however, former Councilman James Vacca dropped the requirements in favor of a task force studying these issues. He and other city officials were concerned that publication of proprietary information on algorithms would slow innovation and make it difficult to find AI vendors who would work with the city. 62 It remains to be seen how this local task force will balance issues of innovation, privacy, and transparency.

Regulate broad objectives more than specific algorithms

The European Union has taken a restrictive stance on these issues of data collection and analysis. 63 It has rules limiting the ability of companies from collecting data on road conditions and mapping street views. Because many of these countries worry that people’s personal information in unencrypted Wi-Fi networks are swept up in overall data collection, the EU has fined technology firms, demanded copies of data, and placed limits on the material collected. 64 This has made it more difficult for technology companies operating there to develop the high-definition maps required for autonomous vehicles.

The GDPR being implemented in Europe place severe restrictions on the use of artificial intelligence and machine learning. According to published guidelines, “Regulations prohibit any automated decision that ‘significantly affects’ EU citizens. This includes techniques that evaluates a person’s ‘performance at work, economic situation, health, personal preferences, interests, reliability, behavior, location, or movements.’” 65 In addition, these new rules give citizens the right to review how digital services made specific algorithmic choices affecting people.

By taking a restrictive stance on issues of data collection and analysis, the European Union is putting its manufacturers and software designers at a significant disadvantage to the rest of the world.

If interpreted stringently, these rules will make it difficult for European software designers (and American designers who work with European counterparts) to incorporate artificial intelligence and high-definition mapping in autonomous vehicles. Central to navigation in these cars and trucks is tracking location and movements. Without high-definition maps containing geo-coded data and the deep learning that makes use of this information, fully autonomous driving will stagnate in Europe. Through this and other data protection actions, the European Union is putting its manufacturers and software designers at a significant disadvantage to the rest of the world.

It makes more sense to think about the broad objectives desired in AI and enact policies that advance them, as opposed to governments trying to crack open the “black boxes” and see exactly how specific algorithms operate. Regulating individual algorithms will limit innovation and make it difficult for companies to make use of artificial intelligence.

Take biases seriously

Bias and discrimination are serious issues for AI. There already have been a number of cases of unfair treatment linked to historic data, and steps need to be undertaken to make sure that does not become prevalent in artificial intelligence. Existing statutes governing discrimination in the physical economy need to be extended to digital platforms. That will help protect consumers and build confidence in these systems as a whole.

For these advances to be widely adopted, more transparency is needed in how AI systems operate. Andrew Burt of Immuta argues, “The key problem confronting predictive analytics is really transparency. We’re in a world where data science operations are taking on increasingly important tasks, and the only thing holding them back is going to be how well the data scientists who train the models can explain what it is their models are doing.” 66

Maintaining mechanisms for human oversight and control

Some individuals have argued that there needs to be avenues for humans to exercise oversight and control of AI systems. For example, Allen Institute for Artificial Intelligence CEO Oren Etzioni argues there should be rules for regulating these systems. First, he says, AI must be governed by all the laws that already have been developed for human behavior, including regulations concerning “cyberbullying, stock manipulation or terrorist threats,” as well as “entrap[ping] people into committing crimes.” Second, he believes that these systems should disclose they are automated systems and not human beings. Third, he states, “An A.I. system cannot retain or disclose confidential information without explicit approval from the source of that information.” 67 His rationale is that these tools store so much data that people have to be cognizant of the privacy risks posed by AI.

In the same vein, the IEEE Global Initiative has ethical guidelines for AI and autonomous systems. Its experts suggest that these models be programmed with consideration for widely accepted human norms and rules for behavior. AI algorithms need to take into effect the importance of these norms, how norm conflict can be resolved, and ways these systems can be transparent about norm resolution. Software designs should be programmed for “nondeception” and “honesty,” according to ethics experts. When failures occur, there must be mitigation mechanisms to deal with the consequences. In particular, AI must be sensitive to problems such as bias, discrimination, and fairness. 68

A group of machine learning experts claim it is possible to automate ethical decisionmaking. Using the trolley problem as a moral dilemma, they ask the following question: If an autonomous car goes out of control, should it be programmed to kill its own passengers or the pedestrians who are crossing the street? They devised a “voting-based system” that asked 1.3 million people to assess alternative scenarios, summarized the overall choices, and applied the overall perspective of these individuals to a range of vehicular possibilities. That allowed them to automate ethical decisionmaking in AI algorithms, taking public preferences into account. 69 This procedure, of course, does not reduce the tragedy involved in any kind of fatality, such as seen in the Uber case, but it provides a mechanism to help AI developers incorporate ethical considerations in their planning.

Penalize malicious behavior and promote cybersecurity

As with any emerging technology, it is important to discourage malicious treatment designed to trick software or use it for undesirable ends. 70 This is especially important given the dual-use aspects of AI, where the same tool can be used for beneficial or malicious purposes. The malevolent use of AI exposes individuals and organizations to unnecessary risks and undermines the virtues of the emerging technology. This includes behaviors such as hacking, manipulating algorithms, compromising privacy and confidentiality, or stealing identities. Efforts to hijack AI in order to solicit confidential information should be seriously penalized as a way to deter such actions. 71

In a rapidly changing world with many entities having advanced computing capabilities, there needs to be serious attention devoted to cybersecurity. Countries have to be careful to safeguard their own systems and keep other nations from damaging their security. 72 According to the U.S. Department of Homeland Security, a major American bank receives around 11 million calls a week at its service center. In order to protect its telephony from denial of service attacks, it uses a “machine learning-based policy engine [that] blocks more than 120,000 calls per month based on voice firewall policies including harassing callers, robocalls and potential fraudulent calls.” 73 This represents a way in which machine learning can help defend technology systems from malevolent attacks.

To summarize, the world is on the cusp of revolutionizing many sectors through artificial intelligence and data analytics. There already are significant deployments in finance, national security, health care, criminal justice, transportation, and smart cities that have altered decisionmaking, business models, risk mitigation, and system performance. These developments are generating substantial economic and social benefits.

The world is on the cusp of revolutionizing many sectors through artificial intelligence, but the way AI systems are developed need to be better understood due to the major implications these technologies will have for society as a whole.

Yet the manner in which AI systems unfold has major implications for society as a whole. It matters how policy issues are addressed, ethical conflicts are reconciled, legal realities are resolved, and how much transparency is required in AI and data analytic solutions. 74 Human choices about software development affect the way in which decisions are made and the manner in which they are integrated into organizational routines. Exactly how these processes are executed need to be better understood because they will have substantial impact on the general public soon, and for the foreseeable future. AI may well be a revolution in human affairs, and become the single most influential human innovation in history.

Note: We appreciate the research assistance of Grace Gilberg, Jack Karsten, Hillary Schaub, and Kristjan Tomasson on this project.

The Brookings Institution is a nonprofit organization devoted to independent research and policy solutions. Its mission is to conduct high-quality, independent research and, based on that research, to provide innovative, practical recommendations for policymakers and the public. The conclusions and recommendations of any Brookings publication are solely those of its author(s), and do not reflect the views of the Institution, its management, or its other scholars.

Support for this publication was generously provided by Amazon. Brookings recognizes that the value it provides is in its absolute commitment to quality, independence, and impact. Activities supported by its donors reflect this commitment. 

John R. Allen is a member of the Board of Advisors of Amida Technology and on the Board of Directors of Spark Cognition. Both companies work in fields discussed in this piece.

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• Ibid., p. 7.
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• “Joy Buolamwini,” Bloomberg Businessweek , July 3, 2017, p. 80.
• Mark Purdy and Paul Daugherty, “Why Artificial Intelligence is the Future of Growth,” Accenture, 2016.
• Jon Valant, “Integrating Charter Schools and Choice-Based Education Systems,” Brown Center Chalkboard blog, Brookings Institution, June 23, 2017.
• Tucker, “‘A White Mask Worked Better.’”
• Cliff Kuang, “Can A.I. Be Taught to Explain Itself?” New York Times Magazine , November 21, 2017.
• Yale Law School Information Society Project, “Governing Machine Learning,” September 2017.
• Katie Benner, “Airbnb Vows to Fight Racism, But Its Users Can’t Sue to Prompt Fairness,” New York Times , June 19, 2016.
• Executive Office of the President, “Artificial Intelligence, Automation, and the Economy” and “Preparing for the Future of Artificial Intelligence.”
• Nancy Scolar, “Facebook’s Next Project: American Inequality,” Politico , February 19, 2018.
• Darrell M. West, “What Internet Search Data Reveals about Donald Trump’s First Year in Office,” Brookings Institution policy report, January 17, 2018.
• Ian Buck, “Testimony before the House Committee on Oversight and Government Reform Subcommittee on Information Technology,” February 14, 2018.
• Keith Nakasone, “Testimony before the House Committee on Oversight and Government Reform Subcommittee on Information Technology,” March 7, 2018.
• Greg Brockman, “The Dawn of Artificial Intelligence,” Testimony before U.S. Senate Subcommittee on Space, Science, and Competitiveness, November 30, 2016.
• Amir Khosrowshahi, “Testimony before the House Committee on Oversight and Government Reform Subcommittee on Information Technology,” February 14, 2018.
• James Kurose, “Testimony before the House Committee on Oversight and Government Reform Subcommittee on Information Technology,” March 7, 2018.
• Stephen Noonoo, “Teachers Can Now Use IBM’s Watson to Search for Free Lesson Plans,” EdSurge , September 13, 2017.
• Congress.gov, “H.R. 4625 FUTURE of Artificial Intelligence Act of 2017,” December 12, 2017.
• Elizabeth Zima, “Could New York City’s AI Transparency Bill Be a Model for the Country?” Government Technology , January 4, 2018.
• Julia Powles, “New York City’s Bold, Flawed Attempt to Make Algorithms Accountable,” New Yorker , December 20, 2017.
• Sheera Frenkel, “Tech Giants Brace for Europe’s New Data Privacy Rules,” New York Times , January 28, 2018.
• Claire Miller and Kevin O’Brien, “Germany’s Complicated Relationship with Google Street View,” New York Times , April 23, 2013.
• Cade Metz, “Artificial Intelligence is Setting Up the Internet for a Huge Clash with Europe,” Wired , July 11, 2016.
• Eric Siegel, “Predictive Analytics Interview Series: Andrew Burt,” Predictive Analytics Times , June 14, 2017.
• Oren Etzioni, “How to Regulate Artificial Intelligence,” New York Times , September 1, 2017.
• “Ethical Considerations in Artificial Intelligence and Autonomous Systems,” unpublished paper. IEEE Global Initiative, 2018.
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• Miles Brundage, et al., “The Malicious Use of Artificial Intelligence,” University of Oxford unpublished paper, February 2018.
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The societal impacts of technological change can be seen in many domains, from messenger RNA vaccines and automation to drones and climate change. The pace of that technological change can affect its impact, and how quickly a technology improves in performance can be an indicator of its future importance. For decision-makers like investors, entrepreneurs, and policymakers, predicting which technologies are fast improving (and which are overhyped) can mean the difference between success and failure.

New research from MIT aims to assist in the prediction of technology performance improvement using U.S. patents as a dataset. The study describes 97 percent of the U.S. patent system as a set of 1,757 discrete technology domains, and quantitatively assesses each domain for its improvement potential.

“The rate of improvement can only be empirically estimated when substantial performance measurements are made over long time periods,” says Anuraag Singh SM ’20, lead author of the paper. “In some large technological fields, including software and clinical medicine, such measures have rarely, if ever, been made.”

A previous MIT study provided empirical measures for 30 technological domains, but the patent sets identified for those technologies cover less than 15 percent of the patents in the U.S. patent system. The major purpose of this new study is to provide predictions of the performance improvement rates for the thousands of domains not accessed by empirical measurement. To accomplish this, the researchers developed a method using a new probability-based algorithm, machine learning, natural language processing, and patent network analytics.

Overlap and centrality

A technology domain, as the researchers define it, consists of sets of artifacts fulfilling a specific function using a specific branch of scientific knowledge. To find the patents that best represent a domain, the team built on previous research conducted by co-author Chris Magee, a professor of the practice of engineering systems within the Institute for Data, Systems, and Society (IDSS). Magee and his colleagues found that by looking for patent overlap between the U.S. and international patent-classification systems, they could quickly identify patents that best represent a technology. The researchers ultimately created a correspondence of all patents within the U.S. patent system to a set of 1,757 technology domains.

To estimate performance improvement, Singh employed a method refined by co-authors Magee and Giorgio Triulzi, a researcher with the Sociotechnical Systems Research Center (SSRC) within IDSS and an assistant professor at Universidad de los Andes in Colombia. Their method is based on the average “centrality” of patents in the patent citation network. Centrality refers to multiple criteria for determining the ranking or importance of nodes within a network.

“Our method provides predictions of performance improvement rates for nearly all definable technologies for the first time,” says Singh.

Those rates vary — from a low of 2 percent per year for the “Mechanical skin treatment — Hair removal and wrinkles” domain to a high of 216 percent per year for the “Dynamic information exchange and support systems integrating multiple channels” domain. The researchers found that most technologies improve slowly; more than 80 percent of technologies improve at less than 25 percent per year. Notably, the number of patents in a technological area was not a strong indicator of a higher improvement rate.

“Fast-improving domains are concentrated in a few technological areas,” says Magee. “The domains that show improvement rates greater than the predicted rate for integrated chips — 42 percent, from Moore’s law — are predominantly based upon software and algorithms.”

TechNext Inc.

The researchers built an online interactive system where domains corresponding to technology-related keywords can be found along with their improvement rates. Users can input a keyword describing a technology and the system returns a prediction of improvement for the technological domain, an automated measure of the quality of the match between the keyword and the domain, and patent sets so that the reader can judge the semantic quality of the match.

Moving forward, the researchers have founded a new MIT spinoff called TechNext Inc. to further refine this technology and use it to help leaders make better decisions, from budgets to investment priorities to technology policy. Like any inventors, Magee and his colleagues want to protect their intellectual property rights. To that end, they have applied for a patent for their novel system and its unique methodology.

“Technologies that improve faster win the market,” says Singh. “Our search system enables technology managers, investors, policymakers, and entrepreneurs to quickly look up predictions of improvement rates for specific technologies.”

Adds Magee: “Our goal is to bring greater accuracy, precision, and repeatability to the as-yet fuzzy art of technology forecasting.”

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• Technology Essay

Essay on Technology

The word "technology" and its uses have immensely changed since the 20th century, and with time, it has continued to evolve ever since. We are living in a world driven by technology. The advancement of technology has played an important role in the development of human civilization, along with cultural changes. Technology provides innovative ways of doing work through various smart and innovative means. 

Electronic appliances, gadgets, faster modes of communication, and transport have added to the comfort factor in our lives. It has helped in improving the productivity of individuals and different business enterprises. Technology has brought a revolution in many operational fields. It has undoubtedly made a very important contribution to the progress that mankind has made over the years.

The Advancement of Technology:

Technology has reduced the effort and time and increased the efficiency of the production requirements in every field. It has made our lives easy, comfortable, healthy, and enjoyable. It has brought a revolution in transport and communication. The advancement of technology, along with science, has helped us to become self-reliant in all spheres of life. With the innovation of a particular technology, it becomes part of society and integral to human lives after a point in time.

Technology is Our Part of Life:

Technology has changed our day-to-day lives. Technology has brought the world closer and better connected. Those days have passed when only the rich could afford such luxuries. Because of the rise of globalisation and liberalisation, all luxuries are now within the reach of the average person. Today, an average middle-class family can afford a mobile phone, a television, a washing machine, a refrigerator, a computer, the Internet, etc. At the touch of a switch, a man can witness any event that is happening in far-off places.  

Benefits of Technology in All Fields: 

We cannot escape technology; it has improved the quality of life and brought about revolutions in various fields of modern-day society, be it communication, transportation, education, healthcare, and many more. Let us learn about it.

Technology in Communication:

With the advent of technology in communication, which includes telephones, fax machines, cellular phones, the Internet, multimedia, and email, communication has become much faster and easier. It has transformed and influenced relationships in many ways. We no longer need to rely on sending physical letters and waiting for several days for a response. Technology has made communication so simple that you can connect with anyone from anywhere by calling them via mobile phone or messaging them using different messaging apps that are easy to download.

Innovation in communication technology has had an immense influence on social life. Human socialising has become easier by using social networking sites, dating, and even matrimonial services available on mobile applications and websites.

Today, the Internet is used for shopping, paying utility bills, credit card bills, admission fees, e-commerce, and online banking. In the world of marketing, many companies are marketing and selling their products and creating brands over the internet. 

In the field of travel, cities, towns, states, and countries are using the web to post detailed tourist and event information. Travellers across the globe can easily find information on tourism, sightseeing, places to stay, weather, maps, timings for events, transportation schedules, and buy tickets to various tourist spots and destinations.

Technology in the Office or Workplace:

Technology has increased efficiency and flexibility in the workspace. Technology has made it easy to work remotely, which has increased the productivity of the employees. External and internal communication has become faster through emails and apps. Automation has saved time, and there is also a reduction in redundancy in tasks. Robots are now being used to manufacture products that consistently deliver the same product without defect until the robot itself fails. Artificial Intelligence and Machine Learning technology are innovations that are being deployed across industries to reap benefits.

Technology has wiped out the manual way of storing files. Now files are stored in the cloud, which can be accessed at any time and from anywhere. With technology, companies can make quick decisions, act faster towards solutions, and remain adaptable. Technology has optimised the usage of resources and connected businesses worldwide. For example, if the customer is based in America, he can have the services delivered from India. They can communicate with each other in an instant. Every company uses business technology like virtual meeting tools, corporate social networks, tablets, and smart customer relationship management applications that accelerate the fast movement of data and information.

Technology in Education:

Technology is making the education industry improve over time. With technology, students and parents have a variety of learning tools at their fingertips. Teachers can coordinate with classrooms across the world and share their ideas and resources online. Students can get immediate access to an abundance of good information on the Internet. Teachers and students can access plenty of resources available on the web and utilise them for their project work, research, etc. Online learning has changed our perception of education. 

The COVID-19 pandemic brought a paradigm shift using technology where school-going kids continued their studies from home and schools facilitated imparting education by their teachers online from home. Students have learned and used 21st-century skills and tools, like virtual classrooms, AR (Augmented Reality), robots, etc. All these have increased communication and collaboration significantly. 

Technology in Banking:

Technology and banking are now inseparable. Technology has boosted digital transformation in how the banking industry works and has vastly improved banking services for their customers across the globe.

Technology has made banking operations very sophisticated and has reduced errors to almost nil, which were somewhat prevalent with manual human activities. Banks are adopting Artificial Intelligence (AI) to increase their efficiency and profits. With the emergence of Internet banking, self-service tools have replaced the traditional methods of banking. 

You can now access your money, handle transactions like paying bills, money transfers, and online purchases from merchants, and monitor your bank statements anytime and from anywhere in the world. Technology has made banking more secure and safe. You do not need to carry cash in your pocket or wallet; the payments can be made digitally using e-wallets. Mobile banking, banking apps, and cybersecurity are changing the face of the banking industry.

Manufacturing and Production Industry Automation:

At present, manufacturing industries are using all the latest technologies, ranging from big data analytics to artificial intelligence. Big data, ARVR (Augmented Reality and Virtual Reality), and IoT (Internet of Things) are the biggest manufacturing industry players. Automation has increased the level of productivity in various fields. It has reduced labour costs, increased efficiency, and reduced the cost of production.

For example, 3D printing is used to design and develop prototypes in the automobile industry. Repetitive work is being done easily with the help of robots without any waste of time. This has also reduced the cost of the products. 

Technology in the Healthcare Industry:

Technological advancements in the healthcare industry have not only improved our personal quality of life and longevity; they have also improved the lives of many medical professionals and students who are training to become medical experts. It has allowed much faster access to the medical records of each patient. 

The Internet has drastically transformed patients' and doctors’ relationships. Everyone can stay up to date on the latest medical discoveries, share treatment information, and offer one another support when dealing with medical issues. Modern technology has allowed us to contact doctors from the comfort of our homes. There are many sites and apps through which we can contact doctors and get medical help. 

Breakthrough innovations in surgery, artificial organs, brain implants, and networked sensors are examples of transformative developments in the healthcare industry. Hospitals use different tools and applications to perform their administrative tasks, using digital marketing to promote their services.

Technology in Agriculture:

Today, farmers work very differently than they would have decades ago. Data analytics and robotics have built a productive food system. Digital innovations are being used for plant breeding and harvesting equipment. Software and mobile devices are helping farmers harvest better. With various data and information available to farmers, they can make better-informed decisions, for example, tracking the amount of carbon stored in soil and helping with climate change.

Disadvantages of Technology:

People have become dependent on various gadgets and machines, resulting in a lack of physical activity and tempting people to lead an increasingly sedentary lifestyle. Even though technology has increased the productivity of individuals, organisations, and the nation, it has not increased the efficiency of machines. Machines cannot plan and think beyond the instructions that are fed into their system. Technology alone is not enough for progress and prosperity. Management is required, and management is a human act. Technology is largely dependent on human intervention. 

Computers and smartphones have led to an increase in social isolation. Young children are spending more time surfing the internet, playing games, and ignoring their real lives. Usage of technology is also resulting in job losses and distracting students from learning. Technology has been a reason for the production of weapons of destruction.

Dependency on technology is also increasing privacy concerns and cyber crimes, giving way to hackers.

FAQs on Technology Essay

1. What is technology?

Technology refers to innovative ways of doing work through various smart means. The advancement of technology has played an important role in the development of human civilization. It has helped in improving the productivity of individuals and businesses.

2. How has technology changed the face of banking?

Technology has made banking operations very sophisticated. With the emergence of Internet banking, self-service tools have replaced the traditional methods of banking. You can now access your money, handle transactions, and monitor your bank statements anytime and from anywhere in the world. Technology has made banking more secure and safe.

3. How has technology brought a revolution in the medical field?

Patients and doctors keep each other up to date on the most recent medical discoveries, share treatment information, and offer each other support when dealing with medical issues. It has allowed much faster access to the medical records of each patient. Modern technology has allowed us to contact doctors from the comfort of our homes. There are many websites and mobile apps through which we can contact doctors and get medical help.

4. Are we dependent on technology?

Yes, today, we are becoming increasingly dependent on technology. Computers, smartphones, and modern technology have helped humanity achieve success and progress. However, in hindsight, people need to continuously build a healthy lifestyle, sorting out personal problems that arise due to technological advancements in different aspects of human life.

Modern Technology’s Impact on Society Essay

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Introduction

Disadvantages and advantages of technology.

Modern technology has changed the world beyond recognition. Thanks to technology in the twentieth and twenty-first centuries, advances have been made that have revolutionized our lives. Modern man can hardly imagine his life without machines. Every day, new devices either appear, or existing ones are improved. Technology has made the world a better place, bringing people additional conveniences and opportunities for healthy living through advances in science. I believe that the changes that technology has brought to our lives are incredibly positive in many areas.

One of the fields where computing and the Web have introduced improvements is education. Machines can keep large volumes of information in a tiny space, reducing entire library shelves of literature to a single CD-ROM of content (Garsten & Wulff, 2020). The Web also acts as a huge learning tool, linking together data sites and enabling inquisitive individuals to seek out just about any subject conceivable. A single personal computer can hold hundreds of instructional programs, visual and audio tutorials, and provide learners with exposure to an immense quantity of content. In the classroom, virtual whiteboards are replacing conventional whiteboards, allowing teachers to provide interactive content for students and play instructional movies without the need for a projector.

Advanced technology has also dramatically and favorably changed the medical care sector. Developments in diagnostic instruments allow doctors to detect hidden diseases, improving the likelihood of successful therapy and saving lives. Advances in drugs and vaccines have been extremely influential, nearly eradicating diseases such as measles, diphtheria, and smallpox, which once caused massive epidemics (Garsten & Wulff, 2020). Modern medicine allows patients to treat chronic diseases that were once debilitating and life-threatening, such as diabetes and hypertension. Technological advances in medicine have helped improve the lives of people around the world. In addition, the latest technology has dramatically increased the productivity of various techniques.

The computers’ capability to resolve complicated mathematical calculations enables them to accelerate any problem that involves metrics or other calculations. Simulating physical processes on a computer can save time and money in any production situation, giving engineers the ability to simulate any design. Modern technology in transportation allows large distances to be traveled quickly. Electric trains, airplanes, cars, and even rockets are used for this purpose (Garsten & Wulff, 2020). In this way, technology brings positive change for people who love to travel.

Despite all the positive changes, there are also disadvantages to the active development of technology. For example, more and more people are becoming dependent on the computer, TV, or cell phone. They ignore their household chores, studies, or work and spend all their time in front of a laptop or TV screen (Garsten & Wulff, 2020). Because of this, people may become inactive and less willing to work, hoping that technology will do everything for them.

In conclusion, I believe that despite some of the disadvantages, the advantages of gadgets are much more significant. Modern technology saves time and allows people to enjoy life. Moreover, new technologies in medicine also contribute to a longer life expectancy of the population and the cure of diseases that were previously beyond the reach of doctors. In addition to medicine, technology has brought significant positive changes to the fields of communication, education, and engineering. Therefore, I believe that the positive impact of technological progress on human lives cannot be denied.

Garsten, C., & Wulff, H. (2020). New technologies at work: People, screens, and social virtuality . Routledge. Web.

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Technological Change

Technological change underpins many of the developments we've seen in health, agriculture, energy, and global development.

By: Max Roser , Hannah Ritchie and Edouard Mathieu

Almost every development we cover on Our World in Data is underpinned by technological change.

Medical innovations contributed to the decline in child mortality and the improvement in life expectancy . Thanks to the advances in agricultural technologies, higher crop yields and less undernourishment became possible. The long-term decline of global poverty was primarily driven by increased productivity from technological change. Access to energy , electricity, sanitation , and clean water has transformed the lives of billions. Transport, telephones, and the Internet have allowed us to collaborate on problems at a global level.

Emerging technologies are often expensive and, therefore, initially limited to society's richest. A key part of technological progress is making these life-changing and often life-saving innovations affordable for everyone.

Technology has improved our lives in many ways, but these developments are not always positive. Many of humanity’s largest threats — such as nuclear weapons and potentially artificial intelligence — result from technological advances. To mitigate these risks, good governance can be as important as the technology itself.

On this page, you can find our data, visualizations, and writing on the most fundamental technological changes that have shaped our world.

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Key articles on technological change.

Technology over the long run: zoom out to see how dramatically the world can change within a lifetime

The brief history of artificial intelligence: the world has changed fast — what might be next?

Artificial intelligence is transforming our world — it is on all of us to make sure that it goes well

The price of batteries has declined by 97% in the last three decades

Hannah Ritchie

Artificial Intelligence (AI) and Communication Technologies

AI timelines: What do experts in artificial intelligence expect for the future?

Artificial intelligence has advanced despite having few resources dedicated to its development – now investments have increased substantially

The importance of social networks for innovation and productivity

Esteban Ortiz-Ospina

The rise of social media

Energy and agricultural technologies.

Why did renewables become so cheap so fast?

How many people does synthetic fertilizer feed?

Yields vs. land use: how the Green Revolution enabled us to feed a growing population

The world now produces more seafood from fish farms than wild catch

Theory of technological change.

What is Moore's Law?

Max Roser, Hannah Ritchie and Edouard Mathieu

Learning curves: What does it mean for a technology to follow Wright’s Law?

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Industrial Revolution and Technology

Whether it was mechanical inventions or new ways of doing old things, innovations powered the Industrial Revolution.

Social Studies, World History

Steam Engine Queens Mill

The use of steam-powered machines in cotton production pushed Britain’s economic development from 1750 to 1850. Built more than 100 years ago, this steam engine still powers the Queens Mill textile factory in Burnley, England, United Kingdom.

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It has been said that the Industrial Revolution was the most profound revolution in human history, because of its sweeping impact on people’s daily lives. The term “industrial revolution” is a succinct catchphrase to describe a historical period, starting in 18th-century Great Britain, where the pace of change appeared to speed up. This acceleration in the processes of technical innovation brought about an array of new tools and machines. It also involved more subtle practical improvements in various fields affecting labor, production, and resource use. The word “technology” (which derives from the Greek word techne , meaning art or craft) encompasses both of these dimensions of innovation. The technological revolution, and that sense of ever-quickening change, began much earlier than the 18th century and has continued all the way to the present day. Perhaps what was most unique about the Industrial Revolution was its merger of technology with industry. Key inventions and innovations served to shape virtually every existing sector of human activity along industrial lines, while also creating many new industries. The following are some key examples of the forces driving change. Agriculture Western European farming methods had been improving gradually over the centuries. Several factors came together in 18th-century Britain to bring about a substantial increase in agricultural productivity. These included new types of equipment, such as the seed drill developed by Jethro Tull around 1701. Progress was also made in crop rotation and land use, soil health, development of new crop varieties, and animal husbandry . The result was a sustained increase in yields, capable of feeding a rapidly growing population with improved nutrition. The combination of factors also brought about a shift toward large-scale commercial farming, a trend that continued into the 19th century and later. Poorer peasants had a harder time making ends meet through traditional subsistence farming. The enclosure movement, which converted common-use pasture land into private property, contributed to this trend toward market-oriented agriculture. A great many rural workers and families were forced by circumstance to migrate to the cities to become industrial laborers. Energy Deforestation in England had led to a shortage of wood for lumber and fuel starting in the 16th century. The country’s transition to coal as a principal energy source was more or less complete by the end of the 17th century. The mining and distribution of coal set in motion some of the dynamics that led to Britain’s industrialization. The coal-fired steam engine was in many respects the decisive technology of the Industrial Revolution. Steam power was first applied to pump water out of coal mines. For centuries, windmills had been employed in the Netherlands for the roughly similar operation of draining low-lying flood plains. Wind was, and is, a readily available and renewable energy source, but its irregularity was considered a drawback. Water power was a more popular energy source for grinding grain and other types of mill work in most of preindustrial Europe. By the last quarter of the 18th century, however, thanks to the work of the Scottish engineer James Watt and his business partner Matthew Boulton, steam engines achieved a high level of efficiency and versatility in their design. They swiftly became the standard power supply for British, and, later, European industry. The steam engine turned the wheels of mechanized factory production. Its emergence freed manufacturers from the need to locate their factories on or near sources of water power. Large enterprises began to concentrate in rapidly growing industrial cities. Metallurgy In this time-honored craft, Britain’s wood shortage necessitated a switch from wood charcoal to coke, a coal product, in the smelting process. The substitute fuel eventually proved highly beneficial for iron production. Experimentation led to some other advances in metallurgical methods during the 18th century. For example, a certain type of furnace that separated the coal and kept it from contaminating the metal, and a process of “puddling” or stirring the molten iron, both made it possible to produce larger amounts of wrought iron. Wrought iron is more malleable than cast iron and therefore more suitable for fabricating machinery and other heavy industrial applications. Textiles The production of fabrics, especially cotton, was fundamental to Britain’s economic development between 1750 and 1850. Those are the years historians commonly use to bracket the Industrial Revolution. In this period, the organization of cotton production shifted from a small-scale cottage industry, in which rural families performed spinning and weaving tasks in their homes, to a large, mechanized, factory-based industry. The boom in productivity began with a few technical devices, including the spinning jenny, spinning mule, and power loom. First human, then water, and finally steam power were applied to operate power looms, carding machines, and other specialized equipment. Another well-known innovation was the cotton gin, invented in the United States in 1793. This device spurred an increase in cotton cultivation and export from U.S. slave states, a key British supplier. Chemicals This industry arose partly in response to the demand for improved bleaching solutions for cotton and other manufactured textiles. Other chemical research was motivated by the quest for artificial dyes, explosives, solvents , fertilizers, and medicines, including pharmaceuticals. In the second half of the 19th century, Germany became the world’s leader in industrial chemistry. Transportation Concurrent with the increased output of agricultural produce and manufactured goods arose the need for more efficient means of delivering these products to market. The first efforts toward this end in Europe involved constructing improved overland roads. Canals were dug in both Europe and North America to create maritime corridors between existing waterways. Steam engines were recognized as useful in locomotion, resulting in the emergence of the steamboat in the early 19th century. High-pressure steam engines also powered railroad locomotives, which operated in Britain after 1825. Railways spread rapidly across Europe and North America, extending to Asia in the latter half of the 19th century. Railroads became one of the world’s leading industries as they expanded the frontiers of industrial society.

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• Review Article
• Open access
• Published: 02 September 2024

Circulating tumor cells: from new biological insights to clinical practice

• Xuyu Gu 1   na1 ,
• Shiyou Wei   ORCID: orcid.org/0000-0002-1783-0372 2   na1 &

Signal Transduction and Targeted Therapy volume  9 , Article number:  226 ( 2024 ) Cite this article

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• Cancer metabolism

The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.

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Epigenomic analysis reveals a unique DNA methylation program of metastasis-competent circulating tumor cells in colorectal cancer

Circulating tumor cells: biology and clinical significance

Liquid biopsy: one cell at a time

Introduction.

The progression of cancer from a localized tumor to a widespread metastatic disease is a complex and multifaceted process, making it cancer patients’ leading cause of death. 1 The driving force behind this process is CTCs, which break from the primary tumor site and spread through the bloodstream to colonize other organs. 2 The study of CTCs has garnered considerable attention as it opens new avenues for understanding the intricacies of metastasis, offering potential markers for early detection and targets for therapeutic intervention. 3

Recent technological advancements in genomics and molecular biology have significantly enhanced our capability to scrutinize the biological mechanisms underpinning CTC dissemination. 4 Among the myriad of molecular processes implicated in this journey, DNA methylation emerges as a pivotal regulatory mechanism influencing gene expression and chromosome stability. 5 Cellular differentiation, growth, and adaptation to environmental changes all depend on DNA methylation, a reversible epigenetic alteration that adds methyl groups to the DNA molecule. 6 For their roles in the development and propagation of cancer, changes in DNA methylation patterns are becoming more and more recognized. 7

Hypomethylation across the entire genome, alongside hypermethylation of specific gene loci, has been implicated in the disruption of genomic integrity and the silencing of tumor suppressor genes, respectively. 8 , 9 These epigenetic changes are fundamental to the transformation of normal cells into malignant ones, affecting their ability to proliferate, evade immune detection, and metastasize. 10 This comprehensive review delves into the mechanisms of CTC formation, highlighting processes such as EMT, immune system evasion, and the colonization of distant tissues, all of which are critical to the metastatic cascade. Furthermore, this review aims to dissect the role of DNA methylation modifications within CTCs, examining how these alterations influence the aforementioned stages of CTC dissemination. After comprehending the epigenetic landscape of CTCs, researchers can find new targets for therapeutic intervention as well as biomarkers for cancer diagnosis and prognosis. The modulation of DNA methylation in CTCs, in particular, presents a promising path for the development of targeted therapies intended to prevent the spread of cancer.

Biology of CTCs

CTCs enter the peripheral circulation from primary or metastatic lesions either spontaneously or as a result of therapeutic manipulation. 11 The notion of CTCs was initially introduced by Ashworth in 1969, and these cells can be categorized into three groups: epithelial, mesenchymal, and hybrid. 12 , 13 , 14 , 15 While most CTCs can be eliminated by the host immune system, a subset of highly active and metastatic CTCs may evade immune clearance, ultimately resulting in the establishment of microscopic cancer foci, tumor recurrence, and metastasis. 16 , 17 , 18 , 19 , 20 , 21 Thus, CTCs are regarded as a plausible origin of fatal metastatic disease in individuals (Fig. 1 ).

Route and location of CTCs Metastasis. Circulating tumor cells (CTCs) are the fundamental constituents of liquid biopsy, functioning as the cornerstones of this approach. a These neoplastic cells are shed naturally from primary or metastatic tumors and circulate within the bloodstream, b serving as the “seeds” of tumors that can potentially result in fatal metastasis of various sites. The figure was created with BioRender.com

However, there are several obstacles that CTCs must overcome in order to successfully detach from the primary tumor tissue, including: 1) Adhesion: Extracellular matrix (ECM) and surrounding cells in the tissue of the primary tumor are both firmly adhered to by cancer cells, which are typically highly sticky. CTCs must overcome these adhesion forces in order to detach and enter the lymphatic or bloodstream system. 2) Invasion: Cancer cells must also be able to invade the neighboring tissue to reach the lymphatic or blood vessels. This requires the cells to degrade the ECM and surrounding tissues. 3) Shear stress: Once in the bloodstream or lymphatic system, CTCs are subjected to significant shear stress due to the movement of fluid. This can cause mechanical damage to the cells and can also trigger apoptosis (cell death). 4) Immune system surveillance: The immune system is constantly surveilling the bloodstream and lymphatic system for foreign or abnormal cells. CTCs must avoid being detected by the immune system in order to survive and potentially form secondary tumors. Overall, the process of CTC detachment and dissemination is complex and involves many different factors. Understanding these obstacles and how CTCs overcome them is a crucial area of research on the biology of cancer and may lead to new therapies for preventing or treating cancer metastasis.

Molecular markers of CTCs

CTCs have been found in a wide range of cancer types using a comprehensive panel of molecular markers. Table 1 provides a summary of CTC-associated markers utilized in different cancers. 22 , 23 The leading marker for CTCs is epithelial cell adhesion molecule (EpCAM), a “universal” epithelial marker for tumors, since the majority of tumors originate in epithelial tissues. 24 Different cancer types 25 express EpCAM differently, and EpCAM-based CTC detection systems are widely employed for tumors with significant EpCAM expression, like prostate and breast cancers. Numerous studies have demonstrated that CTCs in prostate and breast cancers are EpCAM-positive, indicating their prognostic value in the disease’s early and metastatic stages. 26 , 27 Other epithelial-derived cancers, including pancreatic, 28 colorectal, 29 and hepatocellular cancers, 30 also exhibit significant detection rates of EpCAM-positive CTCs. Similar to early distant metastases, the presence of these EpCAM-positive CTCs is associated with poorer patient survival. 29 , 31 , 32 However, there are limitations to using EpCAM as a CTC marker. Tumors that are low-expression or EpCAM-negative, including neurogenic cancers, are unable to be treated with this method. CTCs can undergo EMT, a process during which epithelial markers, including EpCAM, are downregulated. The rate of EpCAM-positive CTC detection is affected by this downregulation. Numerous studies have shown the clinical usefulness of EpCAM-positive CTCs, despite uncertainties about the efficacy of EpCAM-based technology for detecting all CTCs. 33 Positive EpCAM CTCs make up a significant subset of all CTCs, indicating that they could serve as a trustworthy biomarker for cancer prognosis and therapy efficacy when necessary. EpCAM-positive CTCs are likely to miss critical biological information associated with EpCAM-negative CTCs, leading to an underestimation of the actual number of CTCs within the population. This phenomenon has been observed in certain types of cancer such as NSCLC (NSCLC), the number of EpCAM-negative CTCs is significantly higher than that of EpCAM-positive CTCs. 34 However, the usage of both mesenchymal and epithelial cells, along with marker-independent detection techniques, can enhance the suboptimal isolation of CTCs by EpCAM-based technologies. For example, the use of fluorescent-magnetic nanoparticles with a dual-antibody interface that targets both N-cadherin and EpCAM in breast cancer has accelerated the identification of CTCs and increased the efficiency of CTC isolation. 35 , 36 The identification of both epithelial and non-conventional CTCs, which lacked leukocyte and epithelial markers, enhanced the CTC positivity rate in a single-cell assay for CTC detection in biliary tract cancer. 37

Molecular changes accompany the EMT in cancer cells. Among these are the downregulation of epithelial indicators like ZO-1, claudins, and occludins and the upregulation of mesenchymal markers like Vimentin, N-cadherin, fibroblast-specific protein 1, and fibronectin. 38 EMT is regulated by EMT-related transcription factors, mainly from the TWIST, ZEB, and SNAIL families. 39 All these EMT-related molecules have the potential to be utilized in targeting methods for EMT-associated CTCs. Many EMT-related molecules, however, are nuclear or cytoplasmic proteins, limiting their application in current membrane-based CTC detection techniques. The usage of proteins like E-cadherin, Vimentin, and TWIST has been common in the past because of their detectability in traditional CTC detection methods, including as flow cytometry sorting, immunostaining, and fluorescence in situ hybridization (FISH) staining. 40 Nevertheless, the advent of single-cell CTC sequencing technologies 41 holds the promise of more comprehensively revealing the EMT status of CTCs, encompassing all EMT-related molecular alterations at the RNA level.

Numerous studies have proposed that either differentiated progenitor cells or somatic stem cells may be the source of cancer stem cells (CSCs) with tumor initiating capacities. Evidence suggests that this specific subpopulation of cancer cells may be responsible for relapse and metastasis. 42 If the majority of cancer cells are unable to form new tumors and only the rarest CSCs may travel to cause metastatic disease, therefore the main goal of CTC research is to identify and eliminate this circulating-CSC population. After identifying and isolating CSCs within CTCs, it would be possible to combat residual cancer more effectively. Two hypotheses can be taken into consideration to clarify the origin of circulating CSCs. First, cancerous somatic stem cells EMT and exit the main tumor into the circulation. These cells are known as mesenchymal CSCs. Second, these cells can be the result of fully differentiated cancer cells that have undergone EMT pathways to acquire migratory properties. 43 Regardless of the pathway, the end result is the dispersal of CSCs, which move in the direction of niches via intermediary cells that display a combination of mesenchymal, epithelial, and stemness characteristics. This could explain the diversity of surface markers and/or transcription factors observed in tumor-initiating cells within CTCs. The heterogeneity of CTCs, originating from either EMT in CSCs or differentiated cancer cells, underscores the challenge of selecting significant identification markers. This complexity is further compounded by the specific organ of tumor origin. During EMT, cancer cells acquire stemness characteristics, transforming into mesenchymal stem cancer cells. The MET, which is a reverse process, transforms them into epithelial stem cancer cells. ALDH1 expression, initially observed in 1–2% of normal breast epithelial cells, was first documented in breast cancer tissue by Ginestier et al. 44 Barriere et al. found in a clinical study for early breast cancer diagnosis that blood samples from patients with non-metastatic breast cancer had a stemness CTC population. Out of 130 patients, 17 had ALDH1 markers and 49 were CTC-positive. 45 CD44, a cell surface glycoprotein implicated in metastasis and cell migration, 46 characterizes a subpopulation of breast CSCs capable of intravasating into the bloodstream, identified by the CD44 + /CD24 low/– /Lin – markers. 47 In colorectal cancer, CSCs expressing CD44v6 are associated with metastatic potential. 48 Additionally, CSCs have decreased levels of certain glycosphingolipids that are important for cell growth and motility, such as Fuc-(n) Lc4Cer and Gb3Cer, while elevated levels of GD2, GD3, GM2, and GD1a are seen. These gangliosides have the potential to function as markers of CTC stemness. Specifically, GD2 is associated with the CD44high CD24low phenotype linked to CSCs, and GD3 similarly indicates stemness features, although GD1a remains a putative marker. 49 , 50 Recent research has also linked the CSCs phenotype to high ABCG2 transporter expression levels. This transporter is responsible for removing a variety of xenobiotics, including chemotherapy drugs. This chemoresistance implies that ABCG2 expression and stemness are closely associated. It has been found that CSCs from lung, pancreatic, and retinoblastoma tumors exhibit high levels of ABCG2. 51 , 52 Additional biomarkers have been found to be markers for CTCs in a variety of cancers, each with unique therapeutic implications. These include human epidermal growth factor receptor-2 (HER-2) 53 , 54 ; estrogen receptor 55 , 56 , 57 ; prostate-specific membrane antigen 58 , 59 ; folate receptor 60 , 61 ; and survivin. 62 Table 1 provides specifics on these CTC markers. The majority of these markers match the unique molecular markers of the primary tumor. However, the expression of specific markers in CTCs often differs from that of the primary tumor. For example, there is about a 15% 63 discrepancy in HER-2 gene amplification between primary breast tumors and CTCs, indicating that genetic instability is most likely the cause of clonal selection or acquisition. CTC detection technologies are dependent on a number of melanoma cell adhesion molecules, which are highly specific molecular markers for melanoma and include HMW-MAA, 62 , 64 MART-1, 65 , 66 CD146, 67 , 68 and MAGE A. 66 , 67 , 69 , 70 , 71 Melanoma is a kind of skin cancer that starts in melanocytes. The diverse range of CTC markers underscores the heterogeneity of CTCs across various cancer types. Even within a single patient, CTCs display spatio-temporal heterogeneity, possibly attributable to spatially distinct microenvironments within the bloodstream and temporal variations in response to therapy. As such, characterizing the whole population of CTCs using the few molecular markers that are currently accessible is difficult. Furthermore, CTC markers vary over the course of cancer treatment and at different stages of the disease.

The biological progress of CTCs development

Epithelial cells typically undergo anoikis, a form of programmed cell death, upon detachment from their surrounding environment. This characteristic makes metastatic seeding generally inefficient. 72 , 73 , 74 This raises an important question: what characteristics allow CTCs to metastasize successfully? Enhanced survival and tumor-seeding ability appear to be restricted to a small subset of cells initiating tumors or metastases with stem-like properties. 75 EMT has been proposed as an essential factor for metastasis since it increases both invasive potential and contact-independent survival (i.e., resistance to anoikis). 75 , 76 , 77 Preclinical studies have shown that EMT transcription factors, like TWIST and SNAIL, enhance motility and invasiveness in vitro while suppressing cell-cell adhesion. 78 , 79 Silencing SNAIL and TWIST, however, can reduce metastasis in vivo but does not totally prevent it, raising doubts about the absolute requirement of EMT-related transcriptional regulators in the metastatic process. 80 , 81 Interestingly, it has been found that EMT can inhibit the effective seeding of metastatic tumors by deleting E-cadherin or modifying TWIST expression in several EMT lineage tracing models. 80 , 82 The observed plasticity of the epithelium-to-mesenchymal transition raises the possibility that this change is fluid and transitional rather than binary and irreversible, acting more as a catalyst for metastasis than as a direct cause. 83 , 84 Consequently, CTCs have been seen to exhibit an intermediate degree of EMT, which is linked to their adaptability, stem cell-like qualities, poor response to therapy, and progression of the disease. 76 , 84 , 85 There have been multiple hybrid states found at the invasive boundary of patient tumor tissues from common carcinoma types and xenografts. 84 , 86 , 87 Their functional role in invasion, invasion, and metastatic colonization requires further studies.

There may be concurrent existence of metastasis pathways that are both plasticity-dependent and plasticity-independent. 88 The discovery of collectively moving, highly metastatic clusters of cell contact-dependent CTCs, which were first reported several decades ago, offers a significant refutation of the idea that EMT is necessary for metastasis. 89 , 90 Metastatic colonies are polyclonal, 91 , 92 , 93 , 94 and subclones interact synergistically, 95 , 96 suggesting that heterogeneous CTC clusters 97 , 98 as well as solitary CTCs are involved in cancer propagation. Despite making up a small portion of all CTC events in peripheral circulation, multiple studies have demonstrated that CTC clusters have up to a 100-fold higher potential for metastasis than individual CTCs. 82 , 97 , 98 , 99 Intratumor hypoxia is shown to upregulate genes producing cell adhesion proteins in patient samples and mice models, which promotes collective CTC cluster shedding. 98 Homotypic clustering has been shown to improve a number of cellular characteristics, such as the overexpression of stem-like traits 100 , 101 via the hypomethylation of binding sites for transcription factors OCT4, SOX2, and NANOG 102 and the methylation of metastasis suppressor genes. 5 Clustering can also be augmented by circulating galectin 3 or cancer-associated MUC1, 100 homotypic ICAM interactions, 103 or CD44 interacting with PAK2. 98 This clustering can also enhance survival and self-renewal capacity through CDK6 or increased size or number of desmosomes and hemidesmosomes. 97 , 104 CD44 was among the first markers discovered to detect breast cancer cells with elevated tumor-initiating capacity in solid tumors. 47 Later, it was demonstrated that CD44, along with MET, epithelial EpCAM, and CD47, could identify subpopulations of breast cancer that were highly metastatic. 76 Importantly, CD44 expression should not be employed as a CTC marker alone because it is widely expressed in the hematopoietic cell compartment. 105 Previously thought to be specific to stem-like cells, CK14 expression is more common in CTC clusters than in individual CTCs and is required for distant metastasis. 106 EpCAM – , HER2 + , EGFR + , heparanase (HPSE) + , and NOTCH1 + are stem-like phenotypic signatures in CTCs that have been shown to provide competence for brain and lung metastasis. 104

Heterotypic clusters, which include platelets, myeloid cells, and cancer-associated fibroblasts (CAFs), as well as homotypic clusters formed by CTCs, can potentially form between CTCs or other cell types. 107 , 108 , 109 , 110 , 111 The rapid interaction of CTCs with platelets in circulation 112 enhances plasticity and metastasis-initiating capacity 107 through mechanisms like RhoA–MYPT1–PP1-mediated YAP1 signaling 113 and increased vascular permeability via platelet-derived ATP–P2Y2 interaction. 114 The glycoprotein A additionally, protecting against T cell-mediated clearance and NK cell-mediated clearance, respectively, are repetitions predominant (GARP)–TGFβ axis 115 and platelet-derived major histocompatibility complex class I. 116 Barbara Maria Szczerba et al. demonstrated that neutrophils also participate in forming heterotypic CTC clusters. 117 Neutrophils are drawn to CTCs by chemotaxis that is dependent on CXCL5 and CXCL7 111 and connects with them via adhesion mediated by vascular cell adhesion molecule 1 (VCAM1), which enhances their potential for proliferation and metastasis. 111 Through the formation of neutrophil extracellular traps or the secretion of matrix metalloproteinases and IL-1β, neutrophils facilitate adhesion and extravasation. 108 In addition, neutrophils protect CTCs from immune surveillance 118 , 119 ; macrophages and myeloid-derived suppressor cells in CTC clusters also provide this protection. 118 , 120 It has been demonstrated that heterotypic adherens junctions, mediated by N-cadherin in stromal CAFs and E-cadherin in invasive cancer cells, promote collective invasion. Here, CAFs serve as invasive and migrating leader cells, 110 , 119 facilitating metastasis by allowing tumors to “bring their own soil”. 121 Mathematical models indicate that the form of clusters influences CTC behavior during circulation in addition to the biological consequences of clustering. Compact clusters usually flow closer to the endothelium wall compared to linear clusters. 122 However, clusters move in a “single chain” structure as they pass through narrow capillaries. 109 , 123 , 124 , 125 The metastatic potential of CTCs is significantly impacted by the phenotypic plasticity and clustering differences, which highlights potential strategies for inhibiting the metastatic process.

Furthermore, the dynamics of CTC propagation are becoming recognized as an equally important component for the dissemination of tumor cells. 111 , 126 Chronotherapy has been used to study and evaluate the clinical application of the circadian rhythm’s function in tumor onset 127 , 128 and growth dynamics. 129 , 130 This therapeutic approach seeks to optimize therapy timing in order to increase the effectiveness of antitumor drugs. 131 , 132 However, it has only recently been established how circadian rhythm impacts CTC release and the dissemination of metastatic disease. 111 , 126 The way that CTCs are currently detected frequently assumes that peripheral blood counts remain stable throughout the day, which may lead to inconsistent results and make it more difficult to use CTCs as a liquid biopsy analyte in clinical settings. Fluorescence in vivo flow cytometry studies in orthotopic mice models of human prostate cancer have suggested circadian rhythmicity. 133 The temporal dynamics of CTC intravasation, demonstrating significant circadian rhythm-based variations both in breast cancer patients and in mouse models. CTC counts are highest during sleep because to these variations, which are caused by rhythmic changes in hormone levels, such as melatonin. 128

The role and mechanism of CTC in drug resistance

The manifestation of an EMT phenotype in CTCs has been associated with therapeutic resistance and tumor relapse. For example, in patients with metastatic colorectal cancer, overexpression of CSV and plastin 3 in EMT-positive CTCs has been associated with drug resistance. 134 CTC survival is improved by the acquisition of stem cell characteristics during EMT, which promotes enhanced migratory and invasive abilities as well as resistance to therapy. Tumor relapse following targeted therapy can be driven by CTCs with stem cell features, 135 such as in colorectal cancer, 136 where drug-resistant CTCs may act as metastasis-initiating cells, driving tumors to become more aggressive as a result of anticancer drugs’ selection pressure. Targeted therapy-induced tumor relapse in melanoma patients has been linked to phenotypic switching of CTCs to a less differentiated state. 137 Therapies resistance in breast, prostate, pancreatic, and NSCLC have also been linked to phenotypic switching. 138 Therapeutic resistance mechanisms seen in primary tumor cells include target mutation or inactivation, improved genomic DNA repair, faster drug efflux, upregulation of markers associated with quiescence, downregulation of markers associated with proliferative activity, and inhibition of the formation of oxygen radicals, 139 are also evident in CTCs. Tumor cells can separate from the original tumor and circulate in the blood as clusters of tiny cells, challenging the idea that CTCs with EMT and/or stem cell phenotypes are the sole type that initiates metastasis (i.e., groups of >2 CTCs and up to large micro-emboli). 97 Metastatic potential and drug resistance may be influenced by CTC clusters. The absence of proliferation in CTC clusters, as indicated by Ki67 staining, has been linked to their resistance to cytotoxic therapies. 140 Significantly reduced overall survival following systemic therapy is observed in PDAC patients who harbor a high number of CTC clusters (more than 30 clusters per 2 mL of blood). 141 Expanding CTCs from patients into cell lines or xenografts may reveal insights into their therapeutic resistance and present an opportunity for targeted therapy. 142 However, high CTC numbers and several months of establishment make CTC-derived cell lines or xenografts impractical for clinical use. Furthermore, prolonged passage of CTCs in culture is likely to induce irreversible adaptation and clonal expansion. 143

Stem cell and EMT markers exhibit frequent overexpression in CTCs of metastatic breast cancer. 144 Recently, within breast tumors, a subpopulation displaying a stem cell-like phenotype characterized by CD44 positivity and CD24 negativity has been delineated. 47 This subpopulation potentially disseminates into the bloodstream, evading therapeutic measures, 145 and demonstrates an expression profile associated with metastatic recurrence. 146 The modulation of HER2 signaling has been reported to augment cancer stem cell reservoir, potentially necessary for its maintenance; a significant association between HER2-like tumors and stem cells has been observed. 147 A breast cancer stem cell-like phenotype, exhibiting higher resistance to treatment and reduced proliferation in circulation, is suggested by preliminary evidence. 148 ALDH1, a marker indicative of both normal and neoplastic breast stem cells, 144 has been found to be overexpressed in 70% of CTCs, correlating with therapy resistance. A substantial proportion of CTCs display detectable levels of at least one EMT marker such as TWIST, AKT2, and PI3Kalpha, in addition to ALDH1, thereby delineating a highly tumorigenic subset of EMT-associated breast CSCs. 44 This subset of CTCs has clinical value since it predicts drug resistance and a poor result for patients with metastatic cancer. 44 Notably, ALDH1 and EMT markers were discernible even prior to CTC detection in circulation, as evidenced by their positivity in RT-PCR for transcripts such as HER2, MUC1, and EpCAM. 44 Consistently, stem cell-like phenotypes, particularly CD44 + CD24 −/low and ALDH1 high CD24 −/low , have been found in 35.2% and 17.7% of CTCs, respectively. 63 Among ALDH1-highly positive CTCs, the subset expressing CD44 + CD2 4−/low exhibits heightened tumorigenic potential. 149 Though ALDH1-positive cells constitute just 5% of cells in tumors expressing ALDH1, ALDH1 positivity is associated with a high histological grade and poor clinical outcomes. 149

According to the cancer stem cell model, putative cancer stem cells 44 are necessary for tumor growth and drug resistance, and their existence should be associated with a worsened prognosis, 149 albeit data on this matter are still inconsistent. 44 , 150 , 151 Because of their capacity to self-renew and resistance to chemotherapeutic drugs, eradicating these cells during therapy poses challenges. Notably, patients’ chances of responding to chemotherapy are poorer when their CTCs are ALDH1-positive. 44 It has recently been shown that CTCs express one or more multidrug resistance-related proteins (MRPs) in 86% of metastatic breast cancer patients, with patients exhibiting positive MRP-positive CTCs having considerably shorter progression-free intervals. 57 , 144 , 152 , 153 Further investigations are warranted to elucidate the association between the presence of CD44 + CD24 − or ALDH1 high CD24 −/low CTCs and clinical trajectory as well as disease progression.

CTC isolation and identification

For CTCs to be used as a liquid biopsy analyte in clinical settings, it is essential to adopt impartial, affordable, quick, and effective capture technologies that can reliably isolate adequate numbers of CTCs. In order to facilitate the development of data necessary for precise patient stratification and therapeutic decision-making, these capture approaches must also be compatible with functional assays and cutting-edge sequencing technologies. For probing the biology and vulnerabilities of metastatic cancer at the molecular and functional levels, CTCs provide a wide variety of scope when they are isolated in a viable state. CTCs have a unique role as a liquid biopsy analyte because they can represent aggressive subclones with greater metastatic potential. There is conjecture that their molecular and phenotypic analysis may provide more pertinent insight than traditional tissue biopsies (which involve the random subclone isolation) 154 , 155 or other circulating analytes like circulating tumor DNA (which mainly identify dying subclones). However, further exploration is warranted. The ease of access provided by minimally invasive blood draws may allow for regular, long-term assessments of the effectiveness of treatment interventions, which may also make early cancer detection or recurrence possible. 156 As a result, CTCs become an optimal biomarker repository for personalized therapy and real-time clinical applications. However, it is still challenging to obtain CTCs because of their paucity, and effective CTC enrichment is required for reliable downstream analysis and applications.

In the previous ten years, numerous technical progress has been made to improve CTC analysis and detection 157 , 158 by utilizing distinct characteristics and phenotypes of CTCs. These developments can be broadly categorized into antigen-dependent and antigen-independent techniques. The most widely used strategies currently in use help to promote positive selection by using antigens that are expressed on CTCs and minimally expressed on other circulating cells. This strategy is frequently combined with CD45-based negative selection to reduce the number of hematopoietic cells and enhance discrimination. It is notable that the CellSearch system (Menarini Silicon Biosystems, Italy) and AdnaTest CTC Select (QIAGEN, Germany), which have been approved by the US Food and Drug Administration (FDA), utilize immunomagnetic selection based on EpCAM expression. 159 , 160 To increase sensitivity and specificity, respectively, more markers are used, such as pan-CK and CD45. For CTC capture, antibody-coated magnetic beads are used in the Magnetic-Activated Cell Separation (MACS) method (Miltenyi Biotec, Germany). 85 Additionally, the Geometrically Enhanced Differential Immunocapture method combines microfluidics with different antibodies according to the kind of tumor (tumor includes, for instance, HER2 in breast cancer and PSMA in prostate cancer) and positive for cytokeratin for counting. 161

Physical characteristics including size, charge, density, or elasticity are used by antigen-agnostic detection systems to enrich CTCs. Detection of CTCs based on physical properties is facilitated by several methods, including density gradient centrifugation, filter-based devices, capture surfaces, and microfluidic systems. Notable examples of microfluidic systems are ISET (Rarecells Diagnostics, France), Smart Biosurface Slides, CTC-iChip (TellBio, USA), and the FDA-approved Parsortix (ANGLE, UK). 162 , 163 To improve sensitivity and specificity even more, multimodality techniques are being developed. For example, Isoflux (Fluxion Biosciences, USA) combines immunomagnetic beads, 164 with flow control, and the Cyttel system (CYTTEL Biosciences, China) is an image-based detection tool that identifies CTCs by combining immunohistochemistry, fluorescence in situ hybridization, and centrifugation in that order. With the use of the microfluidic platforms Parsortix and CTC-iChip, marker-based positive and negative selection (such as EGFR, HER2, CD45, and EpCAM) can be combined with imaging and micromanipulation to identify pure CTC subsets. 5 , 111 , 162 , 165

Novel in vivo CTC detection tools have emerged to address the challenge of low CTC levels in peripheral blood samples. CTCs can be directly extracted from the bloodstream using methods such as intravascular CTC-catching guidewires coated with EpCAM-directed antibodies, as exemplified by the CellCollector device from GILUPI in Germany. 166 When combined with antigen-dependent selection, cytopheresis facilitates the enrichment of cell fractions from vast blood volumes and offers promise for the isolation of CTCs. 167 The adoption of this approach into routine clinical practice may pose challenges due to its lengthy and invasive nature, alongside potential vascular health issues in heavily treated cancer patients. Studies comparing different methods of accessing the vasculature shows that patients with early-stage NSCLC have higher CTC counts in tumor-draining vessels than in peripheral locations. 156 , 168 For early-stage cancer patients undergoing surgery, this concept provides an attractive opportunity for liquid biopsy. Despite its significance, it remains impractical to use these findings to routine CTC evaluation or to patients with advanced illness who do not undergo surgery.

Advances in capture methods have enabled thorough molecular and functional studies of CTCs at both bulk and single-cell levels, epigenomic, exploring genomic, proteomic, transcriptomic, and functional properties. This has extended research on these cells beyond mere counting to comprehensive analysis. Since these advances have been extensively reviewed, we will focus primarily on aspects related to cell multi-omics and the functional evaluation of CTCs. 2 , 157 , 169 , 170 For instance, assessing drug responses alongside single-cell examination of individual CTCs and CTC clusters can uncover biological dependencies and potential targets for therapy. 5 CTC proteins and secreted factors are being characterized using microfluidic platforms that employ single-cell resolution mass spectrometry and bead-based immunoassays. 171 , 172 , 173 A key barrier to ex vivo CTC cultures’ clinical applicability is their low success rates, despite the fact that experimental proof-of-principle studies 174 , 175 have demonstrated their efficacy. Although the feasibility and therapeutic relevance of CTC capture and downstream analysis have been shown, most of the above approaches are not currently used as routine. Existing CTC technologies face limitations that necessitate resolution for robust integration into clinical settings. These issues encompass the necessity for a more profound comprehension of epitope expression and plasticity, along with challenges associated with cell loss caused by variations in size and deformability, low purity of CTCs, device blockage, the need for substantial blood volumes, time limitations, and difficulties with automation. Additional challenges include the need to improve functional assays, such as enhancing culture methods and developing CTC-derived xenografts, and ensuring robust validation of molecular analyses. This involves addressing issues like stochastic variations, limited sequencing coverage, biases in amplification, high error rates, and variability in bioinformatics approaches. 2 If these challenges are overcome, CTCs may become prominent sources of comprehensive biomarkers that are minimally invasive and personalized.

Metastasis of CTCs

Stephen Paget first proposed the “seed theory” or the soil and seed hypothesis of metastasis in 1889. 176 According to the hypothesis, cancer cells (seeds) have a selective affinity for certain organs (soil) and that the capacity of cancer cells to establish colonies in distant locations is determined not only by the characteristics of the cells themselves but also by the specific microenvironment of the secondary site. According to the seed theory, cancer cells must go through a sequence of steps in order to successfully metastasize to a distant site. encompass the cancer cells’ ability to invade the nearby tissue, penetrate the bloodstream or lymphatic system, survive while circulating, extravasate into the secondary site, and establish a new colony of cancer cells.

Initiation of metastasis

According to the “seed theory”, metastasis typically entails two distinct steps. The first step entails a tumor cell’s detachment from its original site and subsequent circulation through the bloodstream or lymphatic system to a distant location. The second step involves the successful colonization of the tumor cell in the distant site, which requires the cancer cell to be able to proliferate and establish a secondary tumor. 177 CTCs are crucial for the process of tumor metastasis, and it is believed that a specific subgroup of CTCs found in patient blood is what initiates the metastatic cascade. 76 During the early stages of cancer, cellular properties like adhesion and stroma formation act as physical obstacles that impede distant metastasis. To overcome these barriers, carcinoma cells must boost their motility within the stroma and gain access to the bloodstream through either active or passive entry mediated by either the EMT or non-EMT pathways. CTCs that are viable in the bloodstream have the potential to arrest at various locations, including the secondary metastatic sites, or new distant locations. 178 , 179 , 180 , 181 Upon arrest, these CTCs have the potential to undergo MET, which can facilitate extravasation and allow the cells to either enter a dormant state or colonize and engraft at the site (Fig. 2 ). CTCs with stem-like properties, demonstrating increased resistance to anoikis and invasive potential, are identified as crucial for successful metastatic dissemination due to their phenotypic heterogeneity. 182 Notably, CTC clusters, characterized by polyclonality and enhanced metastatic potential, exhibit superior survival in circulation compared to individual CTCs. 183 These clusters are formed through homotypic interactions among tumor cells or heterotypic interactions involving other cell types such as platelets or myeloid cells. 184 The formation of these clusters not only boosts the proliferation and survival of CTCs in the bloodstream but also enhances their metastatic efficiency by aiding in immune evasion and seeding competency at distant sites (Fig. 3 ). Key factors like intratumor hypoxia and platelet interactions are implicated in promoting CTC cluster formation and the initiation of metastasis. 185

Schematic representation of EMT-associated mechanisms supporting CTC survival and early metastasis. a CTCs are liberated into the bloodstream by means of epithelial-mesenchymal transition (EMT)-related mechanisms, including individual cell or collective migration, intravasation, as well as passive processes such as the detachment of isolated tumor cells or clumps through damaged blood vessels. Certain individual or clustered CTCs have the ability to survive in the bloodstream and form metastases in secondary organs. This is due to their possession of characteristics that are elevated in EMT-induced cells, and that facilitate their survival in the bloodstream and establishment of metastases. Specifically, b the Fas/FasL signaling pathway plays a crucial role in tumorigenesis, where impairment in cancer cells can lead to resistance to apoptosis and contribute to tumor progression and CTCs generation, c EMT progression is regulated by signaling pathways such as integrin and TGF-β that can cooperate to induce downstream responses to promote CTCs survival and anti-apoptosis properties. The figure was created with BioRender.com

Mechanisms of CTCs cluster generation and the potential CTC subpopulations survival in the blood circulation. CTCs that undergo EMT express Tissue Factor (TF), which significantly contributes to platelet activation. These coagulation-dependent mechanisms initiate the formation of a fibrin/platelet-rich cocoon around tumor cells, believed to offer protection from shear stress, anoikis, and immune attack. The formation of the aforementioned cocoon is crucial for CTC seeding and early establishment. Additionally, neutrophils have been observed to physically interact with tumor cells and platelets, thereby promoting tumor cell survival and proliferation. Furthermore, neutrophils aid in the adhesion of CTCs to the vascular wall. Neutrophils, through their capacity to capture tumor cells in Neutrophil Extracellular Traps (NETs)—structures that also facilitate coagulation events - aid in the formation of a protective and anchoring scaffold that supports CTC survival. This process facilitates the arrest of CTCs in capillaries and early phases of metastatic establishment. The coagulation- and neutrophil-dependent shielding mechanisms described above safeguard CTCs from immune destruction. Furthermore, CTCs, especially those that undergo EMT, possess an increased ability to evade immune surveillance. One mechanism that contributes to this is the expression of immune checkpoint proteins such as PD-L1, which likely enhances their resistance to cytotoxic immune cells. After a possible period of dormancy, CTCs can eventually resume growth and initiate secondary tumors. The figure was created with BioRender.com

EMT of CTCs

Through a process called EMT, tumor cells can acquire on mesenchymal characteristics like enhanced motility and invasiveness. 186 , 187 , 188 The dynamic and intricate process of EMT in cancer cells involves changes in gene expression and the activation of various signaling pathways. During the early stages of EMT, cancer cells undergo a transformation in which they lose their epithelial traits, such as intercellular adhesion and polarity, and gain mesenchymal characteristics to acquire an invasive phenotype. 189 , 190 Alongside this, a number of genes show changed expression, including those related to ECM remodeling, cytoskeletal organization, and cell adhesion. 191 , 192 , 193 As the EMT process progresses, cancer cells may undergo additional changes, such as the activation of stemness, which can lead to tumor heterogeneity and treatment resistance. EMT can also facilitate the formation of metastases, as mesenchymal-like cancer cells are better able to invade neighboring tissues and enter the bloodstream or lymphatic system. 194 , 195 The progression of EMT in cancer cells is influenced by various factors such as signaling pathways (TGF-β, WNT, and NOTCH, etc.) including the TME, such as hypoxia and inflammation. 38 , 196 Furthermore, EMT is regulated by a number of transcription factors, such as Twist, Slug, and Snail, which have the ability to either activate or inhibit the expression of genes connected to EMT. 197 , 198 , 199 In general, EMT in cancer cells is a dynamic and complex process that is orchestrated by multiple signaling pathways and transcription factors. Understanding the mechanisms that drive EMT in cancer cells may provide new ideas for the management of cancer.

Initiation of EMT

Several signaling pathways, such as TGF-β, WNT, and NOTCH signaling, initiate the process of EMT. These pathways trigger transcription factors, such as Twist, Snail, Slug, and zinc finger E-box binding homeobox 1 (ZEB1), that promote mesenchymal genes and suppress epithelial genes. 200 , 201 , 202 By reducing cell-cell interaction, EMT-related transcription factors including Snail and TWIST promote motility and invasiveness in vitro. Nevertheless, knockdown of these factors could only partially limit metastasis in vivo, which challenges the necessity of them for the metastatic process. 80 , 81 Interestingly, loss of E-cadherin or TWIST modulation was found to prevent the successful metastatic seeding of in several EMT lineage tracing models. 82 Many studies have investigated several genes associated with EMT in CTCs. Among the commonly studied EMT target genes, Vimentin is often included. 203 , 204 , 205 Vimentin, primarily expressed in mesenchymal cells as a type III intermediate filament, is a well-known indicator of EMT and is frequently studied in relation to CTCs. Moreover, it has been associated with tumor metastasis, including promoting CTC survival and tumor cell migration. 206 , 207 EMT has been observed to affect the expression of a variety of epithelial adhesion molecules, thereby modifying intercellular interactions. A typical example is the modulation of adhesion molecules, which involves suppression of E-cadherin and up-regulation of N-cadherin. This change in expression has been linked to the EMT process, 208 , 209 and both E-cadherin and N-cadherin, molecules that modulate cell-cell interactions and whose expression is altered in EMTs, are often evaluated in CTCs. The adhesion molecule EpCAM, previously utilized in CTC studies for enrichment purposes, is another EMT target gene that is frequently investigated in CTC research. 210 , 211

Disassembly of cell–cell junctions

EMT begins with the disruption of tight junctions, adherens junctions, and desmosomes, which hold epithelial cells together. 111 , 212 , 213 In order for tumor cells to separate from the main tumor and infiltrate nearby tissues, this step entails the breakdown of the intercellular adhesion molecules that hold epithelial cells together. One key player in the disassembly of cell-cell junctions during EMT is Snail. 214 Snail suppresses the E-cadherin expression, which is a key component of adherens junctions that hold epithelial cells together. By recruiting co-repressors such histone deacetylases (HDACs) and chromatin remodeling factors, snail is able to repress this gene by attaching to E-box elements in the E-cadherin promoter region. 63 , 215 This results in the E-cadherin silencing and the subsequent loss of cell-cell adhesion. Other transcription factors such as ZEB1 and Slug also exerts crucial functions in the disassembly of cell-cell junctions during EMT. Slug represses E-cadherin expression by binding with its promoter and recruiting HDACs and other co-repressors. ZEB1 upregulates mesenchymal genes including Vimentin and fibronectin while suppressing the expression of E-cadherin, further supporting the mesenchymal phenotype of cancer cells. 216 , 217 A role for signaling pathways in the disassembly of cell-cell junctions during EMT has also been studied in previous research. For instance, it is known that the TGF-β pathway induces EMT in different forms of cancer by increasing the expression of associated transcription factors that inhibit E-cadherin. 218 , 219 The Notch and Wnt pathways have also correlated with EMT and cell-cell junction disassembly in different cancer types. 114 , 220 , 221 In conclusion, the disassembly of cell-cell junctions is a complex process that entails the dysregulation of multiple signaling pathways and transcriptional networks. The development of novel therapies for the control and prevention of metastatic cancer may result from improving our understanding of the molecular mechanisms underlying this process.

Remodeling of the ECM

During EMT, cancer cells undergo changes that allow them to break down the ECM and invade surrounding tissues. 191 Several studies have investigated the molecular mechanisms underlying this process in various cancer types. One of the key players in ECM remodeling during EMT is the matrix metalloproteinases (MMPs). MMPs are a class of zinc-dependent endopeptidases that can degrade collagens, laminins, and proteoglycans, among various ECM components. 222 , 223 , 224 MMPs are upregulated during EMT in numerous cancer types, and their expression is manipulated by a number of signaling pathways and transcription factors, including Twist and Snail. 225 , 226 Other proteases have also been implicated in ECM remodeling during EMT, including urokinase-type plasminogen activator (uPA) and its receptor. 227 , 228 uPA is an enzyme belonging to the class of serine proteases that can activate plasminogen, leading to the degradation of ECM components. 229 uPA expression is upregulated during EMT in various cancer types, and its expression is governed by various transcription factors such as Snail and ZEB1. 230 , 231 The remodeling of the ECM during EMT also involves changes in the expression and activity of integrins, a group of transmembrane receptors that regulate cell-ECM interactions. A variety of signaling pathways and transcription factors, such as TGF-β and Snail, orchestrate the upregulation of integrin expression during EMT in various cancer types. 232 Integrins can promote the invasiveness of cancer cells by activating downstream pathways such as phosphatidylinositol 3-kinase (PI3K) and focal adhesion kinase. 233 , 234 Studies have also shown the involvement of non-coding RNAs (nc), including long nc RNAs (lncRNAs) and microRNAs (miRNAs), in ECM remodeling during EMT. For example, miR-29b has been shown to inhibit the expression of MMP2 and MMP9, leading to the suppressed ECM degradation and inhibited EMT in lung cancer cells. Similarly, the lncRNA MALAT1 has been demonstrated to trigger ECM remodeling and EMT in bladder cancer cells by manipulating the expression of MMP2 and uPA. 235 , 236 , 237

Non-EMT with CTCs

Recent studies utilizing transgenic mouse models has indicated that invasion and metastasis may happen without the involvement of EMT. These findings support the concept that the initiation of metastasis may not necessarily require EMT. 80 , 81 The deletion of EMT-related transcription in transgenic mouse models suggests that EMT inhibition does not affect the development of systemic metastasis. 81 Moreover, it has been reported by Godinho et al. that cancer cell invasion can also be triggered by centrosome amplification. This occurs through the disruption of cell-cell adhesion and an increase in actin polymerization dependent on Arp2/3. 238 Moreover, passive infiltration, which is caused by external forces such as mechanical stress and tumor growth, can lead to the genesis of “accidental” CTCs in the bloodstream. 239 , 240 The disseminated cancer cells that arise from invasion not mediated by EMT can reside either as individual cells or clusters and maintain their epithelial phenotype. 80 , 239

CTC clusters pose a higher risk for cancer metastasis compared to individual CTCs, and they also have unique properties that make them resistant to chemotherapy and immune surveillance. Though the mechanism of CTC cluster formation remains elusive, several studies have shed light on the process. A study by Aceto et al. investigated the role of E-cadherin, a cell adhesion molecule, in CTC cluster formation. They found that E-cadherin was downregulated in single CTCs, but it was upregulated in CTC clusters. Furthermore, they showed that blocking E-cadherin expression prevented CTC cluster formation, suggesting that E-cadherin plays a crucial role in CTC cluster formation. 241 , 242 Gasic et al. was one of the first to suggest that platelets might be involved in CTC cluster formation. 84 They found that platelets accumulated around CTCs in the bloodstream, and they speculated that platelets might facilitate CTC cluster formation. More recent studies have confirmed this hypothesis. For instance, a study by Haemmerl found that platelets promoted CTC cluster formation by activating the TGF-β signaling pathway, which upregulates EMT genes and downregulates cell adhesion molecules. 243 , 244 The role of integrin in CTC cluster formation. They found that CTCs overexpressed several integrins, including integrin α5β1, which promoted CTC cluster formation by facilitating cell-cell adhesion. 245 , 246 The role of chemokines, a group of signaling proteins that recruit immune cells to the location of inflammation or infection, in CTC cluster formation. CTCs secreted several chemokines, including CXCL1 and CXCL2, which promoted CTC cluster formation by attracting neutrophils, a type of immune cell, to the site of CTCs. 247 , 248 The role of hypoxia, a condition of low oxygen levels, in CTC cluster formation. Hypoxia upregulated the expression of a transcription factor called HIF-1α, which promoted CTC cluster formation by upregulating EMT genes and downregulating cell adhesion molecules. The role of physical forces, such as shear stress and hydrodynamic forces, in CTC cluster formation. CTCs were more likely to form clusters in areas of low shear stress and high hydrodynamic forces, such as in the corners of blood vessels. 249 , 250 , 251 In summary, CTC cluster formation is a multifactorial and complex process that entails multiple biological and physical factors. Despite our incomplete comprehension of the mechanism of CTC cluster formation, technological advancements have facilitated a more precise and comprehensive examination of CTCs and CTC clusters, offering new potential for understanding and treating metastatic cancer.

When epithelial cells detach from their surrounding tissue, they usually undergo programmed cell death known as anoikis, which limits the efficacy of metastatic seeding. 72 , 73 , 74 However, a small proportion of tumor- or metastasis-initiating cells with stem-like characteristics have been found to have an enhanced ability to survive and seed tumors. 47 , 75 , 85 EMT is considered as a prerequisite for metastatic dissemination, as it enhances contact-independent survival and invasive potential. 78 , 79 This indicates that EMT may function as a modulator rather than a promoter of metastasis. Meanwhile, a moderate level of EMT has been observed in CTCs, which links to stem-like properties, plasticity, reduced response to treatment and disease development. 76 , 85 On the invasive edge of xenografts and patient tumor tissues of common carcinoma types, intermediate EMT stages have been seen. 84 , 86 , 87 However, further investigation is needed to determine their functions in invasion, and metastatic dissemination.

The investigation of EMT within the context of CTCs is a field that is rapidly evolving, with numerous essential factors being explored. Commonly examined within CTCs are EMT-associated genes such as Vimentin, adhesion molecules, and core transcription factors. The analysis of signaling pathways triggered by membrane receptors and Receptor Tyrosine Kinases (RTKs) is a common practice in CTC studies, as these pathways, such as EGFR, TGF-β, Notch, c-Met, and Wnt, are crucial in the regulation of EMT. The investigation of Axl, an RTK associated with EMT, is gaining momentum in CTC studies, given that clinical trials are currently evaluating commercial inhibitors for Axl. It is noteworthy that EMT is associated with cancer-stem cells, and the majority of EMT-related markers examined in CTCs affect CTC survival and the ability to metastasize. Numerous studies have provided evidence of the heterogeneity of EMT-associated molecules present in the CTC population and have identified hybrid epithelial/mesenchymal (E/M) phenotypes in lung cancer. Table 2 highlights these findings.

Intravasation of CTCs

Intravasation, which involves the entry of cancer cells into the bloodstream, can occur through either active or passive mechanisms. The exact mechanism utilized by the tumor cells depends on various factors, including the tumor types, the micro-environment, and the integrity of the blood vessels. 252 Active intravasation occurs when tumor cells or clusters actively migrate into the bloodstream through EMT. Passive intravasation, on the other hand, happens when single cells or groups of cells separate from the main promise and enter the bloodstream as a result of broken tumor blood vessels brought on by tumor growth or treatment. 181 After entering the bloodstream, CTCs are subjected to various obstacles that can threaten their survival, including shear stress caused by blood flow, anoikis, all of which can potentially lead to their elimination. 253 Tumor cells can gain access to the bloodstream through either a blood vessel or a lymphatic vessel, which can be influenced by several factors such as accessibility, physical constraints, and the existence of active mechanisms that lure cells to specific types of vessels. 254 , 255 Additionally, tumor cells can utilize lymphatic vessels as a pathway to enter the bloodstream since these vessels ultimately empty into the major thoracic duct. 254 , 256 Although lymphatic vessels can aid in the entry of certain cancer cells into the blood circulatory system, current evidence is limited, and cancer cells may encounter dead ends in lymphatic deposits. This observation highlights the degree of concurrent dissemination from the primary tumor. 75 , 257 , 258 Alternatively, cancer cells are likely to spread primarily through the bloodstream for distant metastasis. In this process, lymphatic fluid passes through a sequence of lymph nodes, which frequently serve as the primary sites of metastasis. 252 , 259

Colonization of CTCs

The colonization of tumor cells is the final step of the metastasis process and involves the establishment of tumor cells in a distant organ. 232 , 260 , 261 The colonization process is complex and involves several steps that are regulated by multiple signaling pathways and molecular networks. This process requires the re-activation of epithelial factors and the suppression of mesenchymal ones, a process known as MET. Several studies have investigated the molecular mechanisms underlying this process in various cancer types. One of the key players in the colonization of tumor cells is p63, which is a member of the p53 group of tumor suppressors. P63 is upregulated during MET in a variety of cancer types and is essential for the maintenance of epithelial stem cells. 262 P63 promotes the reactivation of epithelial genes like E-cadherin and cytokeratins, while suppressing mesenchymal genes like Vimentin and fibronectin. 263 Twist and Snail have also been implicated in the regulation of MET and the colonization of tumor cells. Twist is upregulated during EMT and downregulated during MET. 264 Twist improves the mesenchymal phenotype of tumor cells by suppressing E-cadherin expression and increasing N-cadherin and fibronectin expression. 265 Snail, on the other hand, promotes EMT and invasion by inhibiting E-cadherin expression, but its role in MET and colonization is less clear. Several signaling pathways also participated in the regulation of MET and tumor cell the colonization. 266 , 267 The TGF-β pathway, for example, can induce EMT in various cancer types but can also promote MET and colonization by activating the expression of p63 and other epithelial genes. 268 Other signaling pathways, such as Notch, Hedgehog, and Wnt, have also been implicated in the regulation of MET and colonization in various cancer types. 269 , 270 During metastasis, CTCs and the target organ microenvironment engage in a critical dialog that determines the fate of metastatic colonization. This interaction encompasses various components such as ECM proteins, immune cells, and soluble factors, which collectively influence the survival, dormancy, and growth of CTCs. Key processes include the EMT, which CTCs undergo to establish new tumors, and the evasion of immune surveillance. The microenvironment’s role extends to either supporting CTC colonization through the provision of growth factors or hindering it by presenting physical barriers and immune challenges. 271 , 272

The CTCs under immune system surveillance

The mechanism by which CTCs overcome immune system surveillance is not completely understood, but there are several possible ways in which they may evade detection by the immune system. One explanation is that CTCs suppress or mask the expression of surface antigens that immune cells often recognize as abnormal or foreign. This can make the CTCs less visible to the immune system and allow them to escape detection. Another possibility is that CTCs produce factors that suppress or inhibit the immune response, such as cytokines or chemokines that recruit immune cells to the tumor microenvironment but then suppress their function. For example, studies have shown that CTCs can produce the cytokine TGF-β, which can suppress the activity of T cells and other immune cells (Fig. 4 ). Finally, CTCs may be able to evade immune surveillance by mimicking normal cells or using other mechanisms to avoid detection. For example, some CTCs may express proteins or molecules that are normally present in healthy cells, leading to a challenge for the immune system in differentiating them from healthy cells. 273 , 274

Immune-escape mechanisms of CTCs in the peripheral blood. The diagram depicts the various mechanisms employed by CTCs to circumvent the immune system and the interactions that take place between CTCs and immune cells in the peripheral blood. The interaction between circulating tumor cells (CTCs) and natural killer (NK) cells is a prominent area of investigation, given that CTCs secrete LDH5 and shed the MICA/MICB ligand via ADAM10, which inhibits recognition and elimination of CTCs through NK cell-mediated lysis. The diagram portrays three mechanisms employed by CTCs to evade recognition by NK cells and T cells through MHC I molecules. These strategies include masking MHC I recognition by TCR via cytokeratins (CK8, CD18, and CK19) bound to the cell surface, gaining a “pseudo-normal” phenotype through membrane transfer from platelets to CTCs, and reducing or eliminating MHC I expression altogether. The interaction between CTCs and natural killer (NK) cells is a key area of focus, as the release of LDH5 and shedding of MICA/MICB ligands by ADAM10 from CTCs prevents their recognition and elimination via NK cell-mediated lysis. Additionally, LDH5 enhances NKG2D ligand expression on circulating monocytes, which in turn reduces NKG2D expression on NK cells. Furthermore, the diagram illustrates other strategies employed by CTCs to evade the immune system, such as the upregulation of the inhibitory immune checkpoint molecule PD-L1, expression of the “don’t eat me” signaling receptor CD47 and altered expression of apoptotic proteins FAS and/or FASL. The figure was created with BioRender.com

Immune evasion through antigen loss

CTCs can downregulate or lose expression of antigens normally recognized by the immune system, making them less visible to immune cells. MHC class I molecules, for example, are required for T cell recognition, and their expression is downregulated by certain CTCs. For example, in 2012, researchers found that the expression of EpCAM, a common antigen used for CTC detection, was downregulated in CTCs from breast cancer patients who had received chemotherapy. 275 , 276 Similarly, a study reported that CTCs from breast patients who received anti-HER-2 therapy reduced their expression of HER-2, another common antigen. 277 , 278 , 279

CTCs secreted immunosuppressive factors

CTCs have the ability to secrete immunosuppressive factors including TGF-β and IL-10, which can inhibit immune cell activation and function and create an immunosuppressive milieu that shields CTCs from immune attack. A previous work demonstrated that CTCs from breast cancer patients secrete high levels of TGF-β, which can and promote tumor growth and metastasis because of immune cell inactivation. 280 , 281 , 282 Similarly, another study showed that CTCs from melanoma patients release IL-1, which has the ability inhibit T cell activation and proliferation, a crucial part of the immune system’s defense against cancer. 103 , 283 , 284 Besides, Zhao et al. reported that CTCs from lung cancer patients secrete CCL2, which can attract immune-suppressive cells to the tumor microenvironment, thereby suppressing the immune response. Then, a clinical trial demonstrated that CTCs from prostate cancer patients secrete GAL-3, which can induce the apoptosis of tumor-killing immune cells, thereby blocking the immune response against cancer. 285 , 286 , 287 In order to promote angiogenesis and suppress the immune response, CTCs from breast cancer patient have also been reported to secrete VEGF. 288 , 289 , 290 Also, CTCs from colorectal cancer patients secreted PGE2 and led to immune suppression and tumor progression as well. 291 , 292 Moreover, CTCs from melanoma patients secrete IL-10, which can inhibit the proliferation and promote tumor growth and metastasis by activating T cells. 293 , 294 A study showed that CTCs from lung cancer patients expressed high levels of programmed cell death ligand 1(PD-L1), which inhibited the activity of immune cells and promoted immune evasion. 295 , 296 , 297 , 298

Immunological checkpoint (IC) proteins

CTCs have the ability to express IC proteins, such as PD-L1, which bind to the receptors on immune cells to prevent the immune cells from activating and functioning. This can prevent immune cells from attacking CTCs and allow them to escape immune surveillance. CTCs from patients with advanced colorectal, breast, or prostate cancer exhibit IC proteins such PD-L1 and CTLA-4, which can promote immune evasion and support in tumor growth, according to Krebs MG. 297 , 298 , 299 Maheswaran et al. demonstrated that CTCs from lung cancer patients express PD-L1 and other IC proteins, and that PD-L1 expression is linked to poor prognosis. 300 , 301 Gkountela et al. reported that CTCs from breast cancer patients express PD-L1, which is linked to resistance to chemotherapy. 302 Zhang W et al. showed that CTCs from gastric cancer patients express PD-L1 and TIM-3, which is associated with advanced stage and poor prognosis. 303 Sanmamed et al. demonstrated that CTCs from melanoma patients express PD-L1 and other IC proteins, and that PD-L1 expression leads to treatment resistance and poor outcome. 304 Similar results have been observed in patients with breast cancer. 305 Another study revealed that CTCs from lung cancer patients who received IC inhibitor therapy have downregulated PD-L1 expression. 306 , 307 , 308 The dual inhibition strategy of blocking PD-L1 and CD47 on CTCs has been found to significantly enhance the effectiveness of IC therapy. By enabling the immune system to more efficiently target and eliminate CTCs, this approach holds promise for reducing the risk of tumor recurrence and metastasis. Preclinical models have demonstrated that this combination therapy is more effective, indicating its potential for successful clinical application in cancer treatment. 309

Production of extracellular vesicles

By promoting the detachment of CTCs from the original site, extracellular vesicles (EVs) play a vital role in the metastatic process. EVs enhance the shedding of CTCs and protect them in circulation, thereby influencing their metastatic direction. The detachment of CTCs from the main site is facilitated by EVs, which also contribute to EMT and ECM remodeling, promote angiogenesis, and improve vascular permeability. In addition, EVs protect CTCs by activating platelets, inducing immunosuppression, and determining the organotropism of metastasis, thus influencing the colonization of CTCs in distant organs. 310 EVs released by CTCs can interact with immune cells and modulate their function, creating an environment that favors CTC survival and growth. Armstrong AJ showed that CTCs from prostate cancer patients produce extracellular vesicles that can suppress the immune response by suppressing the T cell and NK cell activity. 311 , 312 , 313 Keklikoglou demonstrated that CTCs from breast cancer patients produce extracellular vesicles that can promote immune evasion by inducing the differentiation of monocytes into immunosuppressive macrophages. 314 , 315 , 316 Whiteside TL et al. discussed the role of extracellular vesicles produced by CTCs and other tumor cells in promoting immune suppression and tumor progression. 317 Peinado H et al. showed that CTCs from breast cancer patients produce extracellular vesicles that can promote metastasis by modifying the microenvironment at distant sites and suppressing the immune response. 318 Liu C et al. demonstrated that extracellular vesicles produced by CTCs from lung cancer patients can induce immunosuppression by blocking the activity of NK and T cells. 319 Melo SA et al. showed that CTCs from pancreatic cancer patients produce extracellular vesicles that can promote immune evasion by inducing the differentiation of monocytes into immunosuppressive macrophages. 320 Lu J et al. demonstrated that extracellular vesicles produced by CTCs from lung cancer patients can induce immunosuppression. 321 , 322 Hoshino et al. showed that CTCs from melanoma patients produce extracellular vesicles that can promote immune evasion by inhibiting the activity of tumor-killing immune cells, and that targeting these vesicles can enhance the effectiveness of immunotherapy. 323

Formation of immune-resistant micro-metastases

CTCs can establish small metastatic lesions that are immune-resistant. These lesions can create a reservoir of CTCs that can escape immune surveillance and facilitate further metastatic spread. ICAM1 is essential for the development of CTC clusters and their trans-endothelial migration in lung metastases of BRCA. It has been found to facilitate metastasis more effectively in clusters as opposed to single cells, thereby contributing to a decrease in overall survival rates. In lung metastases of patient-derived xenografts of TNBC, the expression of ICAM1 is noticeably elevated. The inhibition of ICAM1 has been shown to impede the lung colonization of TNBC cells by disrupting the formation of tumor cell clusters, suggesting that ICAM1 could serve as a promising therapeutic target for inhibiting metastasis initiation in TNBC. 100 Janssen LME showed that CTCs can form immune-resistant micro-metastases by secreting extracellular vesicles that modulate the immune response and create a favorable microenvironment for metastatic growth. 324 Krebs et al. demonstrated that CTCs can form micro-metastases that are resistant to chemotherapy and immune surveillance in breast cancer patients. 325 Focusing on the formation of osimertinib-resistant micro-metastases following treatment, a study described an orthotopic model of lung cancer. This model provides a platform for analyzing resistance mechanisms and evaluating new therapeutic strategies against metastases of NSCLC. 326 Kallergi et al. showed that CTCs can form micro-metastases that are resistant to chemotherapy and immune surveillance in breast cancer patients, and that targeting the immune system can improve treatment outcomes. 326 Aceto N et al. showed that CTCs can form micro-metastases that are resistant to chemotherapy and immune surveillance in breast cancer patients, and that targeting the immune system can improve treatment outcomes. 327 Bidard FC et al. demonstrated that CTCs can form micro-metastases that are resistant to chemotherapy and immune surveillance in breast cancer patients, and that targeting the immune system can improve treatment outcomes. 328

Platelets coordinate with CTCs

It has been indicated that the lifespan of certain CTCs is brief, as a majority of them are undetectable within 24 h after primary tumor excision. 329 Research reported that the interaction of CTCs with other blood components, particularly platelets, significantly affects their survival and potential for metastasis. 329 CTCs shortly after entering the bloodstream, are known to create a thrombus rich in platelets around them, serving as a protective shield against shear stress and immune response. Furthermore, this thrombus promotes the attachment of CTCs to the endothelial lining of blood vessels, enabling extravasation. 121 , 309 , 330 Upon entering the bloodstream, CTCs can form a shield of platelets through the action of platelet tissue factor. The formation of a thrombus rich in platelets can offer protection to CTCs against shear stress and immune system attacks, while also aiding in the attachment of tumor cells to the blood vessel wall and extravasation. Moreover, studies have shown that activated platelets can transfer the MHC to CTCs, enabling them to evade immune surveillance by mimicking host cells. 117 , 331 In addition, platelets have been shown to reduce the recognition and elimination of tumor cells by NK cells. Platelets can release soluble factors that impair the cytotoxicity of NK cells and promote the expansion of regulatory T cells, which further interfere with the immune responses. Platelets can also inhibit the recognition and destruction of tumor cells by immune cells, as they express molecules that interact with receptors on immune cells and prevent their activation. One such molecule is CD47, which can bind to SIRPα on macrophages and inhibit their engulfment of tumor cells. These mechanisms collectively enhance the survival and dissemination of CTCs. 117 , 243

Moreover, the transfer of MHC molecules by platelets is a mechanism by which CTCs can evade immune surveillance. 117 , 332 Platelets have the ability to impede the identification and destruction of neoplastic cells by NK cells. 18 , 322 , 333 The invasiveness and metastasis of CTCs can be enhanced by platelets, which release TGFβ and promote the EMT in these cells. This phenomenon has been demonstrated in previous research. 107 , 334 CTCs have been found to interact with different types of leukocytes such as, monocytes, and macrophages, which can enhance the survival of CTCs and facilitate their interaction with endothelial cells, leading to extravasation. 21 , 107

Role of epigenetic modifications in deciphering the properties of CTCs

Recent research has highlighted that significant epigenetic alterations in normal cells can lead to the acquisition of a malignant phenotype. 335 Epigenetics involves the investigation of inheritable alterations in gene expression that occur without modifications to the DNA sequence itself. 336 A number of epigenetic modifications, including histone acetylation and methylation patterns, microRNA-mediated gene regulation, hypomethylation of oncogenes, hypermethylation of tumor suppressor genes, and others, greatly contribute to the progression of cancer. 337 Understanding the intratumor heterogeneity and gaining insight into tumor-specific epigenetic markers linked to metastasis may be facilitated by mapping the epigenetic landscape of CTCs. This approach may also identify subpopulations of CTCs capable of metastatic dissemination. The main areas of epigenetic research that apply to this scenario are gene regulation and DNA methylation.

DNA methylation

DNA methylation is the addition of methyl groups to DNA’s cytosine residues, and it is essential for regulating gene expression. DNA methylation patterns that deviate from the normal or expected patterns have been linked to various health conditions, including cancer. Several studies have shown that CTCs have distinct DNA methylation profiles compared to primary tumors, which could be useful in detecting early-stage cancer, predicting cancer prognosis, and developing targeted therapies. 338 , 339

CTCs exhibit unique DNA methylation patterns that differ from primary tumor. 339 For instance, in breast cancer patients, CTCs had increased DNA methylation levels compared to primary tumors. 121 They identified several differentially methylated genes that were specific to CTCs, including the FBLN1, FBN2, and IGFBP6 genes. A prognostic factor for cancer may be the DNA methylation status of CTCs, as these genes have been linked to the progression and metastasis of cancer. Similarly, in prostate cancer, CTCs had unique DNA methylation patterns compared to primary tumors. 340 They identified several differentially methylated genes, including the FOXA2, HOXA9, and PTEN genes. These genes are involved in cancer progression, invasiveness, and metastasis. Additionally, they discovered a correlation between the DNA methylation status of CTCs and patient survival, suggesting that this biomarker may have applications in the prediction of cancer prognosis. Moreover, DNA methylation patterns of CTCs can also differ based on the origin of the tumor. For instance, a study by Xu et al. compared DNA methylation profiles of CTCs separated from lung cancer and pancreatic cancer patients. 341 They found that CTCs from lung cancer patients exhibited higher DNA methylation levels compared to CTCs from PAAD patients. Furthermore, they identified differentially methylated genes specific to each cancer type, such as the RASSF1A gene in lung cancer CTCs and the TGFBI gene in pancreatic cancer CTCs. This evidence support that the DNA methylation pattern of CTCs could be used to distinguish between different cancer types and aid in personalized cancer treatment. 342

In addition, DNA methylation patterns of CTCs can also be influenced by treatment. DNA methylation patterns of CTCs changed after chemotherapy in breast cancer patients. 343 They identified several genes, including the CDH1 and ZEB1 genes, which had differentially methylated CpG sites before and after chemotherapy. These results imply that monitoring alterations in the DNA methylation patterns of CTCs could be utilized to evaluate the effectiveness of cancer treatments.

Further research is required to unravel the gene methylation landscape of CTCs and how these methylation changes contribute to CTC-mediated metastasis. Such studies can reveal the tumor-specific epigenetic characteristics related to metastasis and the heterogeneity of tumor populations. 344 , 345 Gkountela et al. analyzed the DNA methylation patterns of CTCs from BRCA patients and tumor xenograft models in NSG mice and discovered numerous differentially methylated regions (DMRs) in CTCs. 5 , 346 CTCs showed lower DNA methylation levels of genes such as JUN, MIXL1, SHOX2, and MEF2C, which are often enriched in various types of cancer. CTC clustering was associated with low methylation levels of TFBSs that regulate and proliferation- and stemness-related genes, such as OCT4, MANOG, SOX2, and SIN3A. 17 , 97 , 347 This was accompanied by hypermethylation and H3K27me3 repression of target gene promoters and bodies of PRC2 targets, including SUZ12 and EED, collectively increasing the hematogenous metastatic potential of CTC clusters. 348 , 349 In a study comparing the DNA methylation of CTCs from cancer patients and normal blood controls, abnormal methylation changes were found in multiple genes, and were associated with resistance to sunitinib. This ample evidence suggests that abnormal gene methylation in CTCs may play a crucial role in their clustering and promote distant metastatic ability (Table 3 ).

Aberrant DNA methylation leading to mutation and inactivation of oncogenes or tumor suppressor genes

TSGs play a critical role in orchestrating cellular processes and maintaining genomic stability. Their mutations can cause excessive cell proliferation, which can contribute to the development of tumors. They are also in responsible for causing apoptosis, repairing DNA damage, and regulating cell division. One example of a TSG is hMLH1, which is involved in DNA mismatch repair. 350 Studies have shown that hMLH1 gene mutations and Microsatellite Instability are positively correlated with hMLH1 promoter hypermethylation. The Knudson hypothesis proposes that mutations in both alleles are necessary to inactivate TSGs, and epigenetic modifications, such as the silencing of one allele through promoter hypermethylation, can satisfy this requirement. 351

Some patients showed evidence of epigenetic silencing of the MGMT gene by promoter hypermethylation, which was connected to a higher frequency of activating mutations in KRAS, a proto-oncogene frequently mutated in colorectal cancer. It has been indicated that hypermethylation of the MGMT promoter may contribute to the development of colorectal cancer by promoting KRAS mutations through the inactivation of a DNA repair gene. A study of 244 patients with colorectal cancer analyzed the effects of epigenetic alterations on proto-oncogenes by examining the MGMT gene. The study found that the promoter hypermethylation-mediated MGMT inactivation was linked with a rise in guanine-to-adenine mutations in K-Ras oncogenes. The MGMT gene expression helps to prevent such transitions in the Ras genes. 352 The aforementioned discoveries underscore the essential function of epigenetic modifications in stimulating proto-oncogenes and consequently, advancing the growth and advancement of cancer. A study revealed that lung cancer CTCs demonstrate a distinctive DNA methylation pattern in comparison to primary tumors and normal tissues. This signature is characterized by a substantial reduction in CTC DNA methylation overall, indicating a process of gradual demethylation that progresses from primary tumors to normal tissues and ultimately to CTCs. This underscores the dynamic epigenetic alterations linked to cancer metastasis and spread. Notably, this demethylation phenomenon is observed throughout various genomic regions, encompassing promoters, gene bodies, introns, and intergenic regions. There is a noticeable decrease in methylation at CpG-poor promoters in CTCs when contrasted with primary tumors. 338 We have summarized the different mechanisms of DNA methylation modifications in CTCs to promote metastasis in Fig. 5 .

Different DNA methylation modifications operating in CTCs to promote metastasis. The process by which methylation promotes detachment and invasiveness of CTCs is intricate and involves both hypermethylation and hypomethylation of various genes. a Specifically, hypermethylation of tumor suppressor genes (TSGs) and metastasis-associated genes (MSGs) triggers the detachment of CTCs and contributes to their enhanced proliferative capacity. CTC clusters exhibit distinct DNA methylation profiles compared to single CTCs, featuring hypomethylation of binding sites for transcription factors like OCT4, NANOG, SOX2, and SIN3A, b which are stemness-related transcription factors play crucial roles in the pluripotency network of induced pluripotent stem cells (iPSCs). The figure was created with BioRender.com

Hypomethylation regulation of CTC clusters and increases metastatic potential

The sustained proliferation and self-renewal capacities of embryonic stem cells require the maintenance of stemness and proliferation properties. 353 It has been indicated that stemness-related genes may be entailed in the dissemination of cancer cells. However, the precise mechanisms underlying the ability of CTCs to disseminate and form metastases are not yet fully elucidated, and their survival in the bloodstream is critical for this process. A research study on breast cancer patients aimed to examine the metastasis of CTCs by investigating their ability to form clusters. In the study, single CTCs and CTC clusters from patients with progressing breast cancer were isolated using Parsortix microfluidic technology. Subsequently, whole-genome bisulfite sequencing was conducted on single-cell resolution matched CTCs, which were selected from eight out of a total of 43 analyzed samples (19%). The sequencing outcomes revealed that clusters had hypomethylation of stemness-related genes, specifically SOX2, NANOG, and SIN3A, compared to sing CTCs. This observation facilitated the identification of potential therapeutic targets that might diminish the metastatic potential of the CTC clusters. Specifically, the researchers identified the alteration of methylation patterns in the promoter of the related genes by a Na + /K + ATPase inhibitor led to the separation of the clusters and the reduced tumor metastasis in mice. 5

A study identified DMRs between CTCs and primary lung cancer samples, revealing a significant number of hypomethylated DMRs in CTCs. This trend towards decreased DNA methylation at aberrantly methylated loci in CTCs suggests a potential mechanism underlying their unique characteristics. A potential function in regulating crucial physiological processes such cell proliferation, differentiation, and apoptosis was discovered in the hypomethylated regions of CTCs, which were found to be highly enriched for transcription factor binding sites (TFBSs). Consequently, the evidence supports the idea that hypomethylation in CTCs may play a crucial role in the formation of CTC clusters and enhance their metastatic potential by influencing gene expression related to EMT and other pathways critical for cancer progression. 338 The significance of this study lies in its use of genome-wide sequencing-based methylation profiling for CTCs, making it the first of its kind. This emphasizes the importance of generating comprehensive methylation patterns for CTCs in the context of broader biological research. The incorporation of advanced technology in this research signifies a significant advancement in the current understanding of metastasis and the recognition of novel drug targets.

Hypermethylation regulation the invasiveness of CTCs

The process of detachment of CTCs from their primary tumors and their subsequent migration to distant organs is a pivotal event in the progression of metastasis. To facilitate this process, the cells require the ability to detach and enhance their plasticity, allowing them to penetrate through capillaries and settle in different organs. The mechanism that plays a crucial role in this process is known as EMT, which endows the cells with increased invasiveness and motility. 354 Utilizing peripheral blood samples from 52 patients with metastatic colorectal cancer, the researchers extracted CTCs and examined the methylation patterns of two crucial EMT genes, Vimentin and SFRP2, to investigate the function of EMT in CTC invasiveness. The findings of the study indicated that the selected genes were heavily methylated in the isolated CTCs as compared with the healthy tissue samples. The study demonstrated that the Vimentin gene was suppressed by DNA methylation, causing a disruption in the formation of the cytoskeleton, and consequently promoting increased plasticity and invasiveness of the cells. In contrast, the study revealed that the suppression of the SFRP2 gene by methylation activated the Wnt signaling pathway, which led to increased invasiveness of the CTCs. 355 In another study, researchers evaluated the methylation status of E-cadherin, an EMT suppressor gene that is responsible for preserving the epithelial phenotype. The methylation pattern was assessed in CTCs obtained from six individuals diagnosed with metastatic prostate cancer. The findings indicated that E-cadherin was highly methylated in the CTCs from the cancer patients. Furthermore, the study presented an association between E-cadherin hypermethylation and an increased invasiveness of CTCs. 356 The role of EMT in CTCs is crucial for their adaptability and survival in the bloodstream during the early stages of metastatic colonization, as highlighted in a recent review. Therefore, a comprehensive analysis of EMT in CTCs is essential for informing personalized medicine strategies that target specific aspects of this biological process. 178 The research conducted by Zavridou et al. offers compelling evidence for the effectiveness of the size-based method in addressing the heterogeneity of CTCs. 357

DNA methylation and CTCs immune escape

The dysregulation of DNMTs and TET enzymes can profoundly influence gene expression and contribute to transcriptional silencing or activation in various pathologies, such as cancer. 358 Studies have provided evidence indicating that the dysregulation of TET enzymes and DNMTs can have significant impacts on gene expression, leading to transcriptional activation or silencing in several pathological states, including cancer. Studies have shown that breast cancer and colorectal cancer patients exhibit increased expression of TET enzymes and decreased expression of DNMTs in both their tumor tissues and circulation, which correlates with DNA hypomethylation and upregulation of IC molecules or their ligands 359 , 360 (Fig. 6 ).

DNA methylation regulation in CTCs related Immunity. DNA methylation play key roles in adaptive immune response, including dendritic cell development and T cell priming and activation. a Recent studies revealed the contributions of chromatin remodeling responding to cytotoxic attack in tumor cells and exhaustion phenotype in tumor infiltrating CD8 + T cells. b CTLA-4 DNA hypermethylation significantly correlated with a poor response to treatment, highlighting the potential of CTLA-4 methylation as a predictive biomarker for therapy outcomes. c In tumor cells, DNA modifications affects production of tumor antigens, silencing of anti-tumor cytokines, and induction of the PD-L1 checkpoint. d In NK cells, the methylation status of killer Ig-like receptors (KIR) CpG islands is crucial for maintaining clonal KIR expression and modulating NK cell recognition and lysis of abnormal cells. The figure was created with BioRender.com

Furthermore, it has been demonstrated that restoring normal DNA methylation patterns can enhance the therapeutic efficacy of various cancer treatments. Specifically, the use of epigenetic modifiers that target DNA methylation in combination with chemotherapy, radiotherapy, and immunotherapy has shown increased treatment effect on preclinical models and early clinical trials of several cancers, including breast, prostate, and colon cancer. 361 , 362 , 363 Based on the outcomes of diverse preclinical models and preliminary clinical trials, it appears that epigenetic modulators aimed at DNA methylation may have the ability to function as adjunctive therapy to conventional cancer treatments. Nevertheless, further large-scale clinical trials are required to verify these findings and establish the optimal combination of treatments for different cancer types. To sum up, there is a correlation between abnormal DNA methylation patterns in cancer cells and immune evasion, tumorigenesis, and resistance to cancer treatments. Therefore, DNA methylation patterns may be a crucial target in cancer therapy, and reinstating regular DNA methylation patterns could be a promising strategy to enhance the therapeutic efficacy and overcome resistance mechanisms.

The evidence provided by these studies suggests that the control of ICs and IC ligand expression in cancer patients, particularly in breast and colorectal cancers, is critically influenced by DNA methylation. According to the study, significant upregulation of ICs, including PD-L1 and TIGIT, as well as other ICs/IC ligands in both circulation and tumor tissues, can be attributed to DNA hypomethylation. The significance of DNA methylation in predicting the effectiveness of immunotherapeutic treatments is highlighted by the correlation between overall hypomethylation and inadequate clinical responses. Based on these findings, therapeutic manipulation of DNA methylation has the potential to serve as an effective strategy for enhancing the outcomes of immunotherapies. However, further investigation is demanded to fully understand the mechanism by which DNA methylation impacts the expression of ICs and to develop efficient therapeutic approaches that target these epigenetic alterations. 364

DNA methylation alterations have been linked to the expression of several immunomodulatory genes in breast and colorectal cancer tissues. A study demonstrated that the hypomethylation of CpG islands led to the upregulation of PD-1, CTLA-4, and TIM-3 in breast cancer. 359 Moreover, the study observed complete hypomethylation of LAG-3 gene promoter regions in both breast tumor tissues and their corresponding normal tissue. This suggests that DNA methylation is not entailed in the elevation of these genes in breast cancer. 359 According to another study, DNA hypomethylation is responsible for the overexpression of CTLA-4 and TIGIT in human colorectal cancer tissues. 360 By contrast, in colorectal tumor tissues, the PD-1, PD-L1, galectin-9, and TIM-3 overexpression was not found to be associated with DNA methylation, according to the study. 360 Marwitz et al. reported that the PD-1 and CTLA-4 upregulation in tumor tissues of patients with lung cancer is attributed to DNA hypomethylation. 365 However, the study did not find any relationship between the elevated PD-L1 expression and DNA methylation in the tumor tissues. 365 Conversely, DNA hypomethylation was discovered to be the underlying cause of the upregulation of PD-L1 expression in HNSCC tumor tissues. 366 In a study by Goltz et al., the promoter methylation of PD-L1 was predictive of favorable prognosis in several cancer types, including colorectal cancer, HNSCC, and acute myeloid leukemia. 367 , 368 DNA hypomethylation was identified as the cause of the increased expression of CTLA-4, PD-1, PD-L1, and PD-L2 in patients with lower-grade gliomas, according to a study by Rover et al. Overall, these findings support that DNA hypomethylation is entailed in the upregulation of IC molecules and ligands in different types of cancers, although the specific genes that are regulated by DNA methylation may vary across different cancer types.

DNA methylation of CTCs cluster formation

Recent research has suggested that there may be a relationship between CTC cluster formation and DNA methylation. One study found that DNA methylation changes in CTCs may contribute to the CTC cluster formation, and that these changes may be associated with increased metastatic potential. Specifically, the researchers found that methylation changes in genes associated with cell adhesion and motility were more frequent in CTC clusters than in single CTCs. Jang et al. investigates the DNA methylation status of CTCs in gastric cancer patients and its correlation with CTC cluster formation. 369 The authors find that DNA methylation alterations in CTCs are associated with increased cluster formation and suggest that targeting these alterations may be a potential therapeutic approach. 370 , 371 , 372 Gkountela et al. demonstrates that CTC clustering induces DNA methylation changes that promote metastatic seeding. The authors claim that targeting these epigenetic changes may be a potential therapeutic strategy for preventing metastasis. 373 , 374 Zhang et al. demonstrate that DNA methylation changes in CTCs are involved in their ability to form brain metastases in breast cancer patients. The authors suggest that targeting these epigenetic alterations may represent a potential strategy for preventing brain metastases. 376 Huang et al. investigates the correlation between DNA methylation in CTCs and their ability to resist EGFR inhibitors in lung adenocarcinoma patients. 253 The findings of the authors indicate that targeting DNA methylation abnormalities in CTCs may enhance treatment response, as these variations are linked to higher resistance to EGFR inhibitors. 375 , 376 Overall, while the relationship between CTC cluster formation and DNA methylation is still not fully understood, the current evidence suggests that changes in DNA methylation may be involved in the progression of metastatic cancer.

Histone modification

Histones are essential components of the dynamic architecture of chromatin. The octameric core of these proteins is formed by the assembly of two copies of each histone variation, including H3, H4, H2A, and H2B. This structure serves as a pool around which a DNA sequence consisting of 146 base pairs coils elaborately. 377 The globular structures of histones are enriched in basic amino acids like arginine and lysine in their tails, which serve as excellent locations for a wide range of covalent posttranslational modifications (PTMs). The chromatin landscape is altered by these chemical modifications, which also generate docking sites for proteins that control chromatin functionality. 378 These modifications also modify the interaction between histones and DNA. 379 Extensive studies has shown phosphorylation, methylation, and acetylation as the central histone modifications. All of these PTMs, however, add to the complexity of the regulation of gene expression by expanding the histone code. These additional PTMs include crotonylation, lactylation, citrullination, ubiquitination, and adenosine diphosphate (ADP)-ribosylation. 380 Enzymes known as “writers”, “readers”, and “erasers”, whose dysregulation is usually linked to cancer, meticulously control this dynamic epigenetic gene landscape. 381 Decoding the histone modification patterns presents a challenge since, even in identical cellular contexts, same configurations can produce divergent biological responses. 378 Abnormalities in this molecular communication have the potential to cause oncogenic transformation, 382 alter gene regulatory networks, and upset cellular equilibrium. Understanding this molecular dialog is critical for both understanding and fighting the molecular bases of CTC metastasis. It is also fundamental to elucidating cellular physiology.

Dysregulation in the landscape of histone modifications on TSG and oncogenes

By regulating transcriptional activity, histone alterations play a critical role in the initiation and proliferation of tumors. This often results in the upregulation of oncogenes and the downregulation of tumor suppressor genes. The erratic patterns of H3K27me3, which have a substantial influence on genomic stability, are a notable example of this dysregulation385. 383 The enhancer of EZH2 gene, which encodes the methyltransferase responsible for the specific histone modification H3K27me3, can be influenced by recurring mutations that may alter the levels of this modification. 384 The transcriptional landscape undergoes a significant reconfiguration during tumorigenesis. After being found to be tumor suppressors in a variety of cancers, 385 CBP/p300 has lately come to light as essential regulators of transcriptional activation mediated by enhancers and super-enhancers, especially with regard to important oncogenes. 386 , 387 In ALL, binding sites for the MYB transcription factor are created upstream of the TAL1 oncogene by heterozygous somatic mutations. This MYB interaction attracts CBP, resulting in the formation of a super-enhancer that promotes cell transformation and leukemogenic expression by driving the overexpression of TAL1. 388 Similar to this, p300 has been associated with a substantial reprogramming of super-enhancers in HCC, which results in the upregulation of critical oncogenes such MYC, MYCN, and CCND1, which promotes cancer cell proliferation both in vitro and in vivo. 389

Due to their important role in tumorigenesis, chromatin remodeling complexes (CRCs), especially the SWI/SNF family, are crucial in the DNA damage response (DDR). More than 20% of cancers have mutations in the SWI/SNF complex genes, highlighting the significance of these genes in the genesis of cancer. 390 Gene mutations can be caused by environmental factors such as UV light and gamma radiation that damage DNA. Prompt damage detection, repair signaling, repair factor mobilization, and cellular fate direction towards apoptosis or senescence are done by the DDR machinery. The historical background of DDR deficits in carcinogenesis is well established, having begun with the finding of chromosomal abnormalities in genes and continuing through the revelation that inadequate telomere maintenance catalyzes genomic instability and the detection of important tumor-suppressive functions of DDR components. 391 , 392 , 393 The SWI/SNF complexes affect DNA repair pathways by increasing nucleosome mobility through ATPase activity, which facilitates DDR. There are several roles that SWI/SNF subunits play in DDR. Some directly recruit DDR proteins, whereas others alter the chromatin architecture at DNA damage sites. 394 , 395 , 396 The PBAF and cBAF complexes are associated with DNA repair processes such as homologous recombination (HR) and non-homologous end joining. 337 , 397 To be more precise, DNA lesions are attracted by SMARCA4 and the cBAF-exclusive ARID1A, which help in double-strand break resolution and repair. 398 Poly-ADP ribose polymerase 1 (PARP1) and SMARCA4 have been shown to collaborate at damage sites, promoting chromatin remodeling to lower nucleosome density and assisting in the repair process. 396 SMARCA4 and ARID1A deficiencies are linked to mitotic abnormalities and erratic chromosomal segregation, suggesting that these proteins also play roles in DNA decatenation and telomere cohesion. 399 DDR also involves PBRM1, a component of PBAF. It is involved in centromeric cohesion maintenance, which is essential for genomic integrity, and transcriptional suppression at double-strand breaks to speed DNA lesion repair. 400 CHD1L plays a key role in the regulation of checkpoint control following DNA damage. It facilitates the movement of nucleosomes, which is promoted by PARP1, and also regulates checkpoint activities. 401 A lack of CHD1L impairs the accessibility of chromatin and the recruitment of repair factors, resulting in increased sensitivity to PARP. 402 The multifaceted involvement of cancer highlights their pivotal role in maintaining genomic integrity and preventing cancer. Understanding these complex interactions and mechanisms not only elucidates cellular physiology but also provides insights into potential therapeutic targets for cancer treatment.

Topologically Associating Domains (TADs) borders breaking down in the oncogenic landscape represent a fundamental abnormality. These disruptions are often caused by structural variations or damaged CCCTC-binding factor (CTCF) interaction due to changes in DNA methylation. 403 The proto-oncogene TAL1 is activated by microdeletions that obliterate TAD boundaries in T-ALL. 403 Broken genomic insulation in gliomas and gastrointestinal stromal tumors interferes with CTCF anchoring at loop structures. Like with PDGFRA and FGF4, this results in oncogene activation and ectopic enhancer-promoter crosstalk. 404 , 405 An explanation for the observed correlation between increased CCNE1 expression in gastric cancer primary tumors and CCNE1 rearrangement in response to changed TAD borders and interactions has been found. 406 Because the promoter-enhancer looping dynamics are dysregulated, this rearrangement promotes oncogenicity. An example of such a dynamic is the interaction between the MYC gene and the lncRNA PVT1 promoter. The PVT1 promoter blocks the promoter-enhancer looping of MYC, which in healthy cells decreases MYC expression competitively. On the other hand, malignant transformation often silences the PVT1 promoter by structural or epigenetic changes, re-establishing MYC’s enhancer-gene interaction and quickening tumorigenesis. 407 The loss of a single CTCF allele, which has been linked to oncogenic drivers in cancers including breast and endometrial, has supported CTCF’s role as a tumor suppressor through numerous genetic aberrations. 408 , 409 , 410 Prostate, ovarian, and breast cancers 411 frequently have hemizygous deletions of CTCF, while kidney and endometrial cancers with an allelic loss of CTCF are linked to lower patient survival. 412 , 413 Since hypermethylation of CpG islands is associated with a decrease in CTCF binding, this tumor-suppressing mechanism may entail the regulation of DNA methylation patterns. On top of that, PD-L1 upregulation is associated with CTCF deficiency, which allows cancer cells to evade immune monitoring. 414

Histone H3 and H4 acetylation patterns have become characteristic indicators of cancer cells, and dysregulation in the histone modification landscape is becoming more and more associated with metastasis. Histone acetylation states in cancer are impacted by metabolic reprogramming, which modifies the absolute amounts of acetyl-CoA and the ratio of acetyl-CoA to coenzyme A. Because of its role in acetyl-CoA gene rating through the ligation of acetate and CoA, ACSS2 can cause HIF-2 to become acetylated, which inhibits EMT under hypoxic conditions in HCC. 415 Overexpression of ACSS2, which promotes acetylation of H3K27 in the ATG5 promoter region, is used to achieve reduced breast cancer cell proliferation, migration, and invasion. This, in turn, ensures the maintenance of autophagic flow. 416 ACOT12, also referred as cytoplasmic acetyl-CoA hydrolase, is a predominant liver enzyme that selectively hydrolyzes the thioester bond of acetyl-CoA, gene rating acetate and CoA. 417 Reduced levels of ACOT12 in HCC lead to increased levels of acetyl-CoA, which in turn promotes the acetylation of H3K9 and H3K56. This acetylation process facilitates the EMT mediated by TWIST2. 418 , 419

Acetyl groups are transferred from acetyl-CoA to lysine residues by histone acetyltransferases (HATs). This process helps neutralize the positive charge on histones, thereby loosening the interaction between histones and DNA. As a result, genes become more accessible to transcription factors, facilitating gene expression. 420 GCN5, the initial identified HAT, controls a diverse array of biological processes including cellular proliferation, gene expression, and metabolism. It has also been demonstrated to play a role in the growth and metastasis of cancer cells. 421 GCN5 is recruited to the Runx2 promoter to sustain H3K27ac levels, which leads to the upregulation of Runx2 and promotes lung metastasis in osteosarcoma. 422 The biological function of HDACs in cancer is well-established. HDACs have the ability to both promote and inhibit tumor metastasis. Specific types, mainly through facilitating the downregulation of E-cadherin, have been linked to the proliferation and potential for metastasis of a variety of cancers. These include HDAC1, HDAC2, HDAC4, HDAC5, and HDAC6. 423 , 424 Simultaneously, HDAC8 has been identified as a new TGF-β pathway regulator. It works by transcriptionally suppressing SIRT7 via specific chromatin remodeling. Lung cancer metastasis is accelerated by this HDAC8 activity, which functions as a cofactor to the SMAD3/4 complex and triggers the activation of TGF-β signaling. 425 Histone H3K27 can be maintained in a deacetylated state by recruiting HDAC1 to the promoter of the DUSP2 gene. This results in DUSP2 being silenced and elevated MMP2 levels, promoting metastasis of nasopharyngeal metastesis. 426 In colorectal cancer, HDAC11 suppresses metastasis by downregulating MMP3 expression. This occurs through the reduction of histone H3K9 acetylation at the MMP promoter. 427 On the progression and metastasis of breast cancer, HDAC11 may have divergent effects. The survival and proliferation of tumors within the lymph nodes can be enhanced by increased HDAC11 expression, whereas a migratory phenotype is promoted by reduced HDAC11 expression, which significantly increases migration from the lymph nodes to distant organs. 428

Dysregulation in the landscape of histone modifications in CTCs immune escape

CTCs employ various strategies to evade immune surveillance by cytotoxic T cells. These mechanisms include suppressing T-cell activation, altering the expression of MHC-I at both transcriptional and posttranscriptional levels, reducing the levels of TAAs, and overexpressing IC molecules such as PD-L1 and GAL-9. 429 Downregulation of MHC-I molecules hinders CD8 + T-cell activation against TAAs presented by CTCs. The WNT/β-catenin signaling pathway regulates STT3, which glycosylates and stabilizes PD-L1, leading to increased PD-L1 levels on CTCs and facilitating evasion from cytotoxic T-cell immune surveillance. 430

In hypoxic conditions within the TME, PD-L1 and VEGF expression is elevated in CTCs. VEGF promotes the expression of TIM-3, the T-cell inhibitory receptor. Interaction between overexpressed PD-L1 and Gal-9 on CTCs with their corresponding receptors (e.g., PD-1 and TIM-3) on T cells suppresses T-cell proliferation, reduces cytokine production, induces T-cell exhaustion, and ultimately enables CTC evasion from cytotoxic T-cell activity. 429 , 431 Mature dendritic cells (DCs) are pivotal in initiating T-cell-mediated immune responses by presenting TAAs and expressing costimulatory molecules. 432 However, CTCs employ diverse mechanisms to inhibit DC-mediated antitumor responses, including the release of TGF-β. Specifically, CTCs hinder the recruitment of CD103+ DCs to tumors, 433 impair their maturation, promote differentiation into immunosuppressive regulatory DCs, 434 and induce the development of PD-1+ DCs that deactivate CD8 + T cells. 435 Through its negative regulation of DCs, macrophages, and T cells expressing their receptors, CD200, an increased immune checkpoint in CLL, BRCA, NSCLC, and COAD, develops immunological tolerance. 436 The interaction between TAMs and CTCs promotes CTC survival and the establishment of an immunosuppressive TME. 437 Numerous cells, including fibroblasts, endothelial cells, and immune cells, make up the CTC niche within the TME. These cells are enriched with factors like periostin (OSF-2, an osteoblast-specific factor), TGF-β, and colony-stimulating factor 1. 438 These factors drive the polarization of macrophages towards an immunosuppressive M2 or TAM phenotype. 439 TAM-secreted molecules like WNT, TGF-β, and VEGF promote cancer stemness, create an immunosuppressive TME, facilitate EMT, and support cancer metastasis. 440 Additionally, TAMs enhance PD-L1 expression on CTCs and PD-1 on T cells, thus dampening T-cell-mediated cytotoxicity. 441

MDSCs play a pivotal role in the TME by secreting cytokines and chemokines that foster an immunosuppressive niche, thereby impairing the efficacy of immunotherapy. 442 Granulocyte-macrophage colony-stimulating factors are released by CTCs via the mTOR signaling pathway, promoting MDSC infiltration into tumors. 443 Within the TME, MDSCs release IL-6 and nitric oxide, which epigenetically upregulate CTCs markers such as EpCAM, while also facilitating the activation of Tregs through TGF-β release. 444 , 445 By interacting with the immunosuppressive TME, Tregs, an immunosuppressive T-cell fraction, promote CTC immune evasion, suppressing the effects of cancer immunotherapy. CTC-derived TGF-β facilitates Treg infiltration into tumors, correlating with poorer survival rates. 446 Additionally, CTCs upregulate CCL1 expression through epigenetic mechanisms that decrease H3K27me3 levels at the CCL1 promoter, enhancing Treg recruitment to the TME. 447 Moreover, CTCs evade T-cell-induced apoptosis by inducing the differentiation of uncommitted CD4 + T cells into Tregs. 448 Specifically, Tregs in the hypoxic TME release VEGF, promoting CTCs stemness, angiogenesis, and EMT. 449 , 450 Natural killer (NK) cells express receptors like NKG2D, FASL, and TRAIL, which selectively target and eliminate MHC-I-negative CTCs. 451 NK cell-mediated cytotoxicity has been observed in MHC-I-negative colon and ovarian CTCs expressing NKG2DL and ligands for activating receptors NKp30 and NKp44. 452 However, CTCs from some ovarian and renal carcinoma patients upregulate MHC-I molecules, reducing susceptibility to NK cell-mediated lysis. 444 , 445 Interestingly, latent competent cancer cells expressing SOX2/SOX9 induce dormant CTCs (or latency-competent cancer cells) that downregulate NKG2DL through a unique mechanism involving WNT inhibitor DKK1, thereby evading NK cell-mediated immunity. 446 Epigenetic modifications, such as H3K27 acetylation, are enforced by CBP and p300 in the regulatory regions of genes crucial to Treg cell and MDSC survival and function. Through upregulating these genes, CBP/p300 promotes the growth of tumors by inhibiting lymphocyte activation, proliferation, and immunity mediated by cytotoxic T-cells. 453 Additionally, it has become clear that the sirtuin family of NAD+-dependent deacetylases, which includes mitochondrial SIRT3, SIRT4, and SIRT5, is essential for regulating epigenetic changes like as acetylation, demalonylation, and desuccinylation. 454 It has been demonstrated that SIRT4 loss enhances breast cancer stem cells’ capacity for self-renewal, which is essential for nutritional catabolism. 455 Increased cancer cell proliferation has been associated with desuccinylation and consequently decreased activity of succinate dehydrogenase (SDH), which has been linked to high levels of SIRT5 activity. In contrast, SDH hyper-succinylation and reactivation result from silencing SIRT5, which inhibits the growth of cancer cells. 456 Interferon serves as a potent cytokine with antitumor properties, inhibiting the expansion of CTCs and suppressing their tumor-initiating capabilities. 448 IFN-stimulated genes also play a role in overcoming chemoresistance in CTCs. 448 However, CTCs can develop resistance mechanisms against IFN’s antitumor effects, thereby promoting their survival and inducing the expression of CTC markers while evading immune surveillance through IFN signaling pathways. 447 , 449 The dual role of IFNs in cancer therapy may vary depending on the duration and concentration of IFN exposure. 450 , 451 Suboptimal type-I IFN signaling triggered by immunogenic cell death (ICD) does not consistently result in effective anticancer immunity. Instead, it can paradoxically promote tumor progression by increasing the population CTCs equipped with enhanced immune evasion capabilities. 452 Under specific conditions, elevated levels of IFN-γ have been demonstrated to trigger apoptosis in NSCLC through activation of the JAK1/STAT1/caspase pathway. Conversely, low concentrations of IFN-γ can enhance the properties of CTCs through the ICAM1/PI3K/AKT/NOTCH1 pathway, potentially contributing to tumor progression. 457 Overall, the interplay between various immune cells and CTCs fosters an immunosuppressive TME that facilitates immune evasion, thereby leading to adaptive resistance against cancer immunotherapy.

Clinical research progress targeting CTCs and therapeutic advances

Current methodologies for eradicating metastasis mirror those utilized for primary tumors: focusing on proliferation and tumorigenesis rather than directly addressing the metastatic cascade. 458 , 459 Surgical intervention or systemic treatments for primary tumors may not always eradicate the source of metastasis if dissemination have already happened. 460 , 461 , 462 , 463 The majority of anticancer agents undergo initial evaluation in metastatic contexts before being repurposed for adjuvant therapy to deter metastatic spread, albeit with only moderate success. 464 The scarcity of agents specifically targeting metastasis is being confronted by numerous preclinical investigations and considerations for future clinical trial frameworks. 1 , 459 Theoretically, therapies aimed at CTCs at different points in the metastatic process could halt the progression of metastatic cancers as CTCs are the cause of metastatic cancers and may come from different subpopulations within tumors.

CTCs in clinical trials

As a preventive approach against metastasis in preclinical models, addressing hypoxia-induced cluster release with vascular normalization-inducing drugs (e.g., ephrin B2 Fc chimaera protein, modulating VEGFR signaling) has been proposed. 465 The PLK1 inhibitor BI 2536 also impedes CTC intravasation, 165 suggesting its clinical utility in mitigating metastatic dissemination. 466 Targeting integrins, cadherins, cell-surface glycoproteins, 467 invadopodia (e.g., through N-WASP inhibition), 468 , 469 or employing antibodies against CD36, P-selectin, αIIbβ3, and α6β1 integrins could prevent intravasation and extravasation. HPSE, which facilitates ICAM1-mediated cell adherence in CTC clusters, is the target of one newly developed drugs class. 470 Additionally, urokinase and Na + /K + -ATPase inhibitors like digoxin exhibit promise in dissociating CTC clusters, leading to metastasis suppression in animal models. 5 Digoxin is now under studied in a phase I trial to determine its potential to disrupt CTC clusters in patients with advanced or metastatic breast cancer ( NCT03928210 ). Through cell-cell dissociation, heterotypic clustering may also be disrupted. Blocking key platelet receptors on CTCs, like glycoprotein Ib–IX–V and glycoprotein VI, reduces the potential for metastasis by interfering with platelet–cancer cell interactions. 108 Similarly, targeting VCAM1 on CTC–neutrophil clusters retards proliferation and metastatic efficiency. 111 , 471 , 472 , 473 Alternatively, utilizing CTCs’ VCAM1-mediated affinity for neutrophils for immune-based targeting could imitate the lethal activity of NK cells by energizing neutrophils with nanoscale liposomes that carry TRAIL and E-selectin. 474 Metabolic vulnerabilities could be exploited by either increasing oxidative stress or inhibiting pyruvate metabolism. 475 , 476 , 477 Immune checkpoint inhibitors have the ability to identify CTCs for T cell destruction, 478 and when combined with immune checkpoint inhibitors, dual targeting of HER2 or EpCAM results in improved cancer cell killing as compared to monotherapy. 479 , 480 Additionally, by employing mechanically disrupted CTCs as nanolysates, CTCs can be used as a source to produce cancer vaccines. Harnessing the homing capacity of CTCs to TME could be therapeutically advantageous by identifying homing signals and delivering therapeutic payloads. 126 , 481 Systemically administered CTCs engineered to express the prodrug-converting enzyme cytosine deaminase-uracil phosphoribosyl transferase can convert non-toxic 5′-fluorocytosine into the cytotoxic compound 5′-fluoruridine monophosphate. This conversion causes the CTCs to attach to the neoplastic tissues, where they kill the surrounding cancer cells. Lastly, given the rhythmic nature of CTC release into the bloodstream, 126 , 481 making the most of the current therapeutic opportunities by timing chronotherapy-based designs to coincide with CTC production peaks could optimize efficacy. Although these methods show promise in future research on CTCs, there is a lack of specific tools for dealing with metastatic cells, and the metastatic process is complicated, so testing their effectiveness in clinical settings will necessitate innovative and bold trial designs.

The results of clinical trials have demonstrated that CTCs are found in peripheral blood in all major carcinoma types, and their significance for prognosis in colorectal, breast, prostate, and small- and non-small-cell lung malignancies has been validated. 482 , 483 When a patient is first diagnosed with metastatic breast cancer, higher CTC counts before starting treatment are predictive indicators of shorter disease-free and total survival times. 484 , 485 , 486 For patients with colorectal 487 and prostate 488 , 489 cancer, a negative relationship between pretreatment CTC counts and clinical prognosis has also been reported. Significantly, numerous studies have illustrated that fluctuations in CTC counts following treatment administration offer more robust prognostic insights compared to baseline CTC levels. The persistence of CTCs post-therapy correlates with a poorer prognosis. 490 , 491 , 492 In patients receiving therapy, evaluation of CTC cluster abundance significantly improves the prognostic value in addition to single-CTC counts. 493 However, since most of the studies used antigen-dependent CTC methods, enumeration carries the risk of producing false-negative results in this situation.

CTC counts can be detected 7–9 weeks before the disease’s clinical manifestation. This suggests that CTC analysis in patients may help predict the likelihood of minimal residual disease and relapse in later stages, 163 of the illness 163 , 494 and serve as a tool for early cancer diagnosis. In NSCLC, CTCs taken following surgery showed a strong mutational concordance with metastatic tumors found 10 months later (91%). 156 Although CTCs are useful for risk assessment, there has been limited success in using CTCs for therapeutic patient stratification. This includes monitoring treatment response over time and identifying the onset of therapy resistance in many clinical trials. 491 , 495 , 496 The METABREAST STIC disease trial highlighted scenarios where CTC count could provide useful advice for therapeutic decisions, even though the interventional SWOG-S0500 trial did not show an advantage of CTC count-guided intervention compared to physician’s choice upon disease development. 495 The benefit of therapy selection based on CTC molecular features has been explored in a number of interventional studies. 497 , 498 In two proof-of-principle studies, trastuzumab–emtansine or lapatinib (HER2-targeted treatments) were used to target HER2-positive CTCs in HER2-negative metastatic breast cancer. 498 , 499 Although one trial (DETECT III) still awaits completion, the studies have only found a little benefit thus far. 499 Results from patients receiving endocrine therapy for metastatic prostate cancer are predicted by the expression of AR-V7 in CTCs (PROPHECY trial). 500 , 501 A phase II trial was then started to explore how the microtubule inhibitor cabazitaxel affected patients with AR-V7-positive CTCs and metastatic castration-resistant prostate cancer. However, the European Society for Medical Oncology guidelines do not support AR-V7 testing in this context due to the recent negative outcome of that trial, as it offers no advantage over current decision algorithms. 502 , 503 , 504

In conclusion, CTCs are now included in both the seventh edition of the AJCC Cancer Staging Manual and the fifth version of the WHO Classification of Tumours: Breast Tumours. The designation “cM0 (i+)“ indicates the absence of overt metastasis but the presence of tumor cells in the blood, bone marrow, or lymph nodes. Important cancer societies have yet to incorporate CTCs into their clinical practice recommendations, including the European Society for Medical Oncology and the American Society for Clinical Oncology. Arguably, CTCs’ actual potential lies in their ability to represent highly metastatic tumor subclones and in their abundance as modern biomarkers for molecular and functional studies. CTCs, as living cells, can be cultured outside of the body and analyzed for drugs response, which could offer significant insight to inform treatment choices in a timely manner. 175 , 505 , 506

Despite these advancements, significant enhancements to such workflows are necessary for their transition to clinical application. Innovative, prospective, randomized interventional trials are required to determine whether the use of CTCs as diagnostic aids offers clear benefits over standard-of-care (SOC) methods for specific cancer types. Future validation efforts should give priority to the predicted strengths of CTCs, including their ability to detect little residual illness, express clinically actionable targets for therapy selection, and provide longitudinal follow-up.

Diagnostic and prognostic value of methylation patterns of CTCs

The investigation of DNA methylation patterns in CTCs spans multiple cancer types, offering insights into their potential as biomarkers for diagnosis, prognosis, and therapeutic targeting. 97 , 126 Madhavan et al. highlighted the importance of methylation patterns in circulating cell-free DNA as markers of tumor progression and response to treatment in their investigation of CTC DNA’s potential as a prognostic diagnostic in metastatic breast cancer. 507 Cabel et al. investigated the role of CTCs and circulating tumor DNA in prostate cancer, focusing on DNA methylation markers as potential tools for assessing disease progression and therapeutic response. 508 Widschwendter et al. demonstrated that the methylation status of circulating tumor DNA can be used as a non-invasive diagnostic marker for ovarian cancer, enabling early detection and therapeutic response monitoring. 509 Powrózek et al. examined SHOX2 gene methylation in CTCs of NSCLC patients and discovered that SHOX2 methylation could function as a non-invasive biomarker for NSCLC prognosis and diagnosis. This suggests the possible utility of methylation analysis in CTCs for clinical purposes. 510 The potential of circulating tumor DNA to identify EGFR mutations in lung cancer patients was examined by Hulbert et al. 511 In identifying individuals who may benefit from treatment with tyrosine kinase inhibitors, the study demonstrated the utility of circulating tumor DNA as a feasible alternative to invasive tissue biopsies. Furthermore, the research shed light on the expansion of genetic and epigenetic profiling using circulating tumor material, such as exploring DNA methylation patterns. This highlights the growing importance of utilizing non-invasive biomarkers for precision medicine applications in oncology. 511 Mazor et al. demonstrated how the methylation patterns of circulating tumor DNA in lung cancer patients can serve as indicators of tumor burden and heterogeneity. 512 Their study underlines the potential of DNA methylation profiling of circulating tumor DNA, encompassing CTC-derived DNA, in providing crucial prognostic and diagnostic insights. 512 Aberrant DNA methylation profiles have been detected in CTCs from cancer patients, and these patterns have shown promise as diagnostic or prognostic biomarker. For instance, Wong et al.’s study, which examined the DNA methylation patterns of CTCs from lung cancer patients, found a correlation between patient survival and the methylation levels of specific genes. 513 , 514 Specifically, high methylation of HOXA9 and LMX1A genes was associated with poor overall survival, while high methylation levels of the IGFBP3 gene were associated with better overall survival. 515 , 516 Another study by Wu et al. investigated the DNA methylation patterns of CTCs from patients with lung adenocarcinoma and identified differentially methylated genes that were associated with metastasis. 5 , 111 , 126 They identified that the methylation levels of GABRB2, CLDN3, and SFRP1 were conspicuously different between CTCs from patients with and without metastasis. 517 In addition to their potential as diagnostic or prognostic biomarkers, DNA methylation patterns in CTCs may also have therapeutic implications. For instance, a study by Chen et al. suggested that treatment with a DNA-demethylating agent called decitabine reduced the metastasis of CTCs from lung cancer patients by reversing the aberrant DNA methylation patterns in these cells. 332 , 518 The DNA methylation profile of CTCs has demonstrated a significant potential for lung cancer diagnosis, prognosis, and treatment (Table 4 ). 495 , 519 , 520 , 521 , 522 , 523 , 524 , 525

DNA methylation detection in CTCs

The principal methodology utilized in liquid biopsy is the identification of DNA methylation within the circulatory system. Circulating tumor DNA has better sensitivity and specificity for cancer screening than traditional tumor markers, especially in the early stages of the disease. The sensitivity of Vimentin gene methylation in serum for the diagnosis of CRC was found by Atsushi Shirahata et al. to be significantly higher (57.1% vs. 14.3%) for diagnosing CRC in situ (Stage 0) than for the tumor marker CEA (32.6% vs. 33.1%). 432 Similar to this, the FDA has approved SEPT9, a circulating tumor DNA test, as an effective early non-invasive screening method for colorectal cancer. 526 , 527 SEPT9, also referred to as MSF, was originally discovered by Osaka et al. 530 They observed that MSF acts as a proto-oncogene, promoting leukemia upon fusion with the MLL gene. 528 Further research has shown that SEPT9 generates 18 transcriptional products, each contributing uniquely to the development and progression of cancer. 529 Specifically, the SEPT9 gene, particularly the SEPT9_v2 variant, functions as a tumor suppressor in colorectal cancer. 530 Hypermethylation of the SEPT9_v2 promoter region, leading to decreased SEPT9 gene expression, is a defining characteristic of colorectal cancer (CRC) and is closely associated with the progression from adenoma to atypical hyperplasia to CRC. In their 2021 study, Guoxiang Cai et al. developed a classifier named “ColonAiQ”, which incorporates six circulating tumor DNA markers (SEPT9, SEPT9 region 2, BCAT1, IKZF1, BCAN, VAV3). 531 Their findings showed that “ColonAiQ” was able to achieve a greater detection rate in both early and advanced CRC than fecal immunochemical tests, CEA, and SEPT9. 531 Additionally, the “ColonAiQ” classifier predicted early postoperative recurrence and poor prognosis of CRC, with patients exhibiting higher ColonAiQ risk scores more likely to experience early postoperative recurrence. 531 Using whole-genome bisulfite sequencing technology, Liu et al. conducted a prospective clinical trial to examine tissue and circulating tumor DNA methylation in breast cancer. 423 They found methylation patterns that differed between cancer patients and those with benign tumors, and they developed a diagnostic model. The detection of breast cancer was significantly improved by this combined diagnostic models. One benefit of the study is that it uses whole-genome bisulfite sequencing to identify differential methylation sites in detail. This method measures the average degree of DNA methylation at each CpG site in the target genome. However, this method does not precisely pinpoint methylation sites. A variety of methods have been used in investigations to identify site-specific DNA methylation, including digital PCR, pyrosequencing, bisulfite sequencing, and methylation-specific PCR. 532 , 533 , 534 The study’s examination of methylation differences in tissues and circulating tumor DNA from cancer and benign lesion patients enables the exclusion of non-cancer-related methylation sites in circulating tumor DNA. Differential diagnosis on patients with benign masses improves the detection of tumor-specific sites in contrast to many other studies that employ healthy controls. Additionally, combining imaging examinations (e.g., ultrasound, mammography) with circulating tumor DNA testing improves breast cancer detection sensitivity and specificity, reducing unnecessary invasive procedures. This prospective clinical trial focused on early-stage cancer lesions, offering insights distinct from studies utilizing advanced cancer tissues, which might not be as effective for early cancer screening. Nevertheless, the study had limitations, such as unmatched patient age, smoking, and other influencing factors between case and control groups, potentially introducing heterogeneity and affecting site detection efficacy. 535 , 536 Moreover, the study’s small sample size (10 tissue pairs) diminished locus selection efficiency, likely influenced by the high cost of whole-genome sequencing. Therefore, developing cost-effective sequencing technologies is crucial for early cancer screening. Colonoscopy, ultrasonography, mammography, and low-dose chest CT have become widely used and have greatly improved early screening for lung cancer, breast cancer, and colorectal cancer, as well as early diagnosis rates and patient prognoses. 537 , 538 , 539 However, effective screening tools for pancreatic cancer (PC) remain lacking. Nine studies on blood-based DNA methylation biomarkers for early PC diagnosis, all published in the last decade, have been retrieved. 533 , 540 , 541 , 542 , 543 , 544 Notably, three studies identified ADAMTS1 methylation as a liquid biopsy marker for PC, achieving high diagnostic efficacy (sensitivity >80%, specificity >85%). 540 , 545 , 546 Keiko Shinjo et al. also demonstrated the diagnostic capability of a five-DNA molecule panel, including ADAMTS2, for PC, with sensitivity and specificity of 68 and 86%, respectively, when combined with KRAS mutation. 542 The ADAMTS family, comprising 19 members, plays crucial roles in arthritis, cardiovascular diseases, and cancer, 547 particularly in regulating ECM structure and function. Given the abundant stroma in PC, certain ADAMTS family subtypes may serve as effective biomarkers for PC diagnosis, warranting further investigation. 548 The circulating tumor DNA methylation model is also pivotal in prognosis. Mastoraki et al. discovered that non-small cell lung cancer patients with methylation in the KMT2C promoter region of circulating tumor DNA experienced poorer overall survival (OS) and disease-free survival ( P  = 0.017 and P  < 0.001, respectively). 549 Promising results have been found in numerous studies examining the role of circulating tumor DNA in predicting the prognosis of different cancers, including colorectal, prostate, and ovarian cancer. 549 , 550 , 551 , 552 , 553 , 554 , 555 Establishing a prognostic model based on blood-based DNA methylation facilitates early identification of high-risk groups, enabling timely and effective intervention, while non-high-risk individuals may undergo milder treatment or follow-up, thus minimizing unnecessary invasive treatments and conserving medical resources. Despite the utility of circulating tumor DNA methylation in reflecting patient prognosis across various cancers, challenges remain in developing prognostic methylation markers. The lack of consensus on detection methods and the difficulty in identifying universally accepted prognostic methylation sites contribute to these challenges. In order to determine prognosis and choose adjuvant treatment, DNA gene mutation data derived from tumor tissue or blood is widely used. The clinical application of assessing the methylation status of the MGMT gene promoter in gliomas, which indicates tumor response to temozolomide chemotherapy and patient prognosis, has been successful. 556 , 557 Unfortunately, this application is based on tumor tissue-derived MGMT gene promoter methylation status, with no mature clinical studies on circulating tumor DNA.

Therapeutic targeting of methylation in CTCs

To evaluate the effectiveness of treatment and track any tumor recurrence, tumor markers and cross-sectional exams are widely used in the postoperative follow-up of cancer patients. After surgery, a decrease in serum tumor markers indicates effective treatment, whereas an increase indicates a possibility of metastasis or recurrence. 558 , 559 Tumor marker detection has been shown to predict tumor recurrence up to six months ahead of cross-sectional imaging 560 ; however, higher tumor markers are correlated with tumor burden and may not be visible in the early stages of relapse. 561 Other factors can also elevate tumor marker levels; for example, CA19-9, a reliable marker for monitoring postoperative PAAD recurrence, can be elevated due to pancreatic inflammation, obstructive jaundice, and persistent diabetes. 558 Approximately 8–10% of the population are Lewis-negative, and over 70% of Lewis-negative PAAD patients exhibit low CA19-9 expression, rendering this marker ineffective for prognosis in these patients who typically have worse outcomes. 562 Because it is noninvasive, highly reproducible, and sensitive, the detection of circulating tumor DNA methylation has become a crucial method for dynamically monitoring tumor response after treatment. 563 In order to highlight the importance of circulating tumor DNA in cancer surveillance, Michail Ignatiadis et al. introduced the term “circulating tumor DNA relapse”. 564 Nakayama et al. found that P16INK4a methylation is a sensitive marker of colorectal cancer recurrence, highlighting the crucial role circulating tumor DNA plays in the postoperative follow-up of CRC patients. 565 In their study of 21 CRC patients, 13 exhibited elevated P16INK4a methylation pre-surgery, with all patients showing decreased methylation levels within 2 weeks post-surgery, except for two with residual metastases or subsequent relapse. In these two patients, there was noticeably higher P16INK4a methylation at relapse; this was not the case in the individuals without tumor recurrence. 565 Jin et al. found that cfDNA follow-up could detect colon cancer recurrence early, with circulating tumor DNA reappearing in 70% of patients (14 cases) before recurrence, approximately eight months earlier than imaging suggested. 566 Therefore, early tumor relapse detection is made possible by dynamic monitoring of circulating tumor DNA methylation, which aids in clinical decision-making. The tumor information provided by circulating tumor DNA aids in guiding subsequent targeted therapy selection. Tumor heterogeneity partially explains the poor response to antitumor therapy, with new clonal subtypes forming during tumor progression, a significant factor in therapeutic inefficacy. 567 Circulating tumor DNA detection provides great reproducibility when compared to standard tissue biopsy, which decreases the effects of tumor tissue heterogeneity and allows for timely treatment plan adjustments and dynamic monitoring of therapy response. However, compared to traditional tissue exams, circulating tumor DNA extraction and sequencing involves greater technical demands and expenses.

Current research primarily focuses on mutation information within circulating tumor DNA. Detailed gene mutation analysis can elucidate the cancer molecular landscape, potentially leading to more suitable treatment options. However, studies on using circulating tumor DNA methylation for therapeutic target selection are scarce. This disparity might result from the theory that tumor responses rather than tumor causes are the reason for variations in the circulating tumor DNA methylation state in cancer patients. More research is needed in this area. DNA methylation in tissues is critical for tumor suppressor gene inactivation and tumorigenesis. Cancers including pancreatic, breast, and bladder cancer have demonstrated benefit from targeted therapy of DNA methylation, notably when DNA methyltransferase inhibitors are used. 568 , 569 , 570

Therapeutic targeting of histone modification enzyme in CTCs

Beyond broad-spectrum modifiers, drugs designed to target particular mutations within enzymes that modify the epigenome are becoming part of the landscape of epigenetic therapies. One such drug is tazemetostat, a selective inhibitor that specifically targets the EZH2 mutation. EZH2, the PRC2 complex’s catalytic component, regulates transcriptional repression via H3K27 trimethylation. Overexpression of EZH2 is associated with poor prognosis and increased malignancy in various cancers, 571 prompting its exploration as a therapeutic target. Based on phase 2 trial results that demonstrated a 69% objective response rate (ORR) in patients with EZH2 mutations, compared to 35% in those with wild-type EZH2, Tazemetostat was approved by the FDA. 572 Dual inhibitors that target both EZH1 and EZH2 have been found to be more effective than selective EZH2 inhibition in reducing cellular H3K27me3 levels and increasing anticancer effects in mouse models of hematologic malignancies. 573 In a phase 2 trial, the dual inhibitor valemetostat demonstrated promise in treating adult T-cell leukemia/lymphoma, with a 48% ORR. 574 Currently, a phase 1 trial for metastatic urothelial cancer is exploring the possible synergistic effects of valemetostat with ipilimumab. In a similar vein, DOT1L, the sole H3K79 methyltransferase, has been studied as a possible therapeutic target in tumors containing MLL gene rearrangements, particularly in cases of acute leukemia. 575 Even though the outcomes of early clinical trials of DOT1L inhibitors were inconsistent, pinometostat may make juvenile AML cells more sensitive to the multikinase inhibitor sorafenib, opening the door to novel therapeutic options. 576 These developments are poised to reshape the therapeutic landscape for pediatric AML and highlight the evolving precision in targeting specific epigenetic mutations for cancer therapy.

The advancement of cancer has been linked to abnormal LSD1 amplification and activity. 577 LSD1’s role in transcriptional repression involves removing methylation from H3K4me1/2, a marker of gene activation. 578 Preclinical evidence of differentiation and growth attenuation has prompted the evaluation of LSD1 inhibitors, including pulrodemstat (CC-90011), iadademstat, seclidemstat, and GSK2879552, in a number of clinical trials. Results from early phase studies, notably those employing pulrodemstat for solid tumors and non-Hodgkin lymphoma, show significant anti-neoplastic effects, particularly in neuroendocrine tumors. 579 Several non-histone proteins, including as DNMT1, are impacted by LSD1 in addition to histones. 580 LSD1-mediated demethylation of DNMT1 is critical for its stabilization and the maintenance of global DNA methylation patterns. 581 LSD1 inhibitors have the potential to be used in combination therapy for hematological malignancies. A clinical trial, with the ClinicalTrials.gov code NCT04734990, is presently exploring the use of seclidemstat in combination with azacytidine for the treatment of chronic myelomonocytic leukemia. Preclinical studies have also demonstrated that by raising tumor immunogenicity and T-cell infiltration, LSD1 inhibition can improve the effectiveness of immune checkpoint blockade. Clinical trials exploring combination therapies have been started to optimize the effects of immunotherapy, particularly in tumor forms with previously limited responses, including lung cancer. 582 , 583 These developments underscore the expanding potential of LSD1 inhibitors in both standalone and combination treatments across a spectrum of cancers.

HDACs have zinc-enriched active sites, which HDAC inhibitors (HDACi) bind to in order to impede their function and maintain a hyperacetylated state of chromatin that promotes a transcriptionally active configuration. 584 In order to treat cutaneous T-cell lymphoma, the FDA approved vorinostat, one of the first-generation HDACi, in 2006. This approval was based on clinical trials demonstrating ORRs of ~30%. 585 Similar to DNMT inhibitors, HDACi have shown synergistic effects in preclinical studies when combined with other anticancer agents, leading to the strategic design of combination clinical trials. HDAC inhibitors not only enhance the expression of PD-L1, potentially priming tumors for immunotherapy, but also reduce populations of Tregs, which can bolster immune responses against tumors. 586 Vorinostat’s capacity to make hormone-resistant ER-positive breast tumors more susceptible to apoptosis has been validated in preclinical studies, indicating that it may be used in combination with antiestrogen drugs to improve therapeutic results in hormone therapy. 587 In 2014, Belinostat, a second-generation HDAC inhibitor, obtained expedited FDA approval for the treatment of peripheral T-cell lymphoma based on the results of a single-arm trial with 120 patients. 588 To address toxicity concerns related to earlier generations of HDACi, selectivity against specific members of the HDAC family has been improved through advancements in HDAC inhibition. A benzamide derivative called entinostat has shown promise as a strong and specific inhibitor of class I and IV HDACs. Low-dose azacitidine plus entinostat has been explored in clinical studies for patients with advanced breast cancer and recurrent metastatic NSCLC, particularly in those who have had extensive prior treatment. 589 , 590 These studies reflect ongoing efforts to optimize the efficacy and safety profiles of HDAC inhibitors in cancer therapy.

Proteins called bromodomain and extraterminal (BET) domains are important chromatin dynamics regulators and have become promising targets in cancer research. The BRD2, BRD3, BRD4, and BRDT proteins belong to the BET protein family and use their bromodomains to identify acetylated lysine residues on histones. This recognition initiates chromatin remodeling and gene expression by recruiting additional transcriptional effectors. 591 A key factor in identifying the oncogenic functions of BET proteins has been the emergence of small-molecule BET inhibitors like JQ1. These inhibitors disrupt the binding of BET proteins to acetylated histones, thereby modulating the expression of key oncogenes implicated in cancer progression. 592 , 593 Despite their initial promise in preclinical models, the clinical translation of BET inhibitors has been limited by pharmacokinetic challenges, including short half-lives and poor oral bioavailability. Tyrosine kinase inhibitors like lapatinib can be resistant to BET inhibitors like JQ1 and I-BET151 in TNBC. In order to prolong the therapeutic response, they achieve this by suppressing the production of certain kinases which drive resistance mechanisms. 594 , 595 Furthermore, homologous recombination, a crucial DNA damage repair pathway, is disrupted by BET inhibitors by the transcription of proteins involved. This disruption has significant implications for cancer therapy, particularly in combination approaches. When PARP inhibitors and BET inhibitors are used together, tumors that are proficient in homologous recombination may become more sensitive to the PARP inhibitors and may eventually acquire resistance to them. 596 , 597 Clinical investigations have been prompted by the synergistic benefits between PARP and BET inhibition observed in preclinical studies, particularly in breast and ovarian cancers. In order to provide novel avenues for targeted cancer therapy, these studies aim to validate these results in patient populations. 598 , 599 This strategic combination approach highlights the potential of BET inhibitors to enhance the efficacy of existing therapies and to address resistance mechanisms in cancer treatment.

Conclusion and perspective

Cancers remain the highest number of cancer-related deaths globally. CTCs are tumor cells that have separated from the primary tumor and entered the lymphatic or circulatory system. This allows the tumor cells to spread throughout the body and result in the formation of new tumors. According to studies, patients with lung cancer can have CTCs in their blood, and the number of CTCs in a patient’s blood is correlated with the disease’s progression and chances of metastasis. CTCs have been found in the blood of lung cancer patients even before a tumor has been identified by conventional methods, providing evidence that they may be a valuable tool for the early identification and monitoring of lung cancer.

DNA methylation is the addition of methyl groups to the cytosine residues of DNA, and it is necessary for regulation the expression of certain genes. Numerous cancer types, including lung cancer, have been related to abnormal DNA methylation patterns at the onset and progression of the disease. It has been discovered that DNA methylation has a role in both immune surveillance and metastasis in the setting of CTCs. 600 The immune system’s method of identifying and getting rid of cancer cells is called immune surveillance. However, by DNA methylation, CTCs can suppress the expression of immune-related genes, enabling them to elude the immune system and persist in the bloodstream. For example, some CTCs have been found to have DNA hypermethylation of genes that are involved in antigen processing and presentation, which may help them escape recognition and elimination by the immune system. Furthermore, DNA methylation has also been involved in the metastasis of CTCs. The EMT process, for example, is essential for cancer cell invasion and metastasis, and it has been linked to DNA hypermethylation of E-cadherin, a gene involved in cell adhesion and migration. Additionally, it has been found that the metastatic potential of CTCs 273 , 601 is influenced by hypomethylation of genes related to DNA repair and cell cycle regulation. 273 , 601

There are several limitations that must be addressed before CTC analysis can be widely employed in the clinic, despite the fact that it has showed promise in the diagnosis and treatment of lung cancer. One of the major limitations is the low sensitivity of CTC detection methods. The number of CTCs in the bloodstream is usually very low, and current methods for CTC detection and isolation may miss a significant proportion of these cells. This may limit the clinical value of CTC analysis and lead to false negative results. The diversity of CTCs presents another difficulty. In contrast to the primary tumor or other CTCs, CTCs are a diverse population of cells that may exhibit various phenotypic and genetic characteristics. This heterogeneity can make it difficult to identify and isolate CTCs that are representative of the entire tumor and to develop targeted therapies. 602 , 603 Furthermore, CTCs are often found in a dormant state, meaning they are not actively dividing or producing detectable levels of tumor markers. This can make it challenging to monitor the response of the tumor to therapy using CTC analysis alone. Finally, there are technical challenges correlated with CTC analysis, such as the need for specialized equipment and expertise, which may limit the availability and accessibility of this technology to all patients. Addressing these limitations may require the development of new technologies and methods for the detection and analysis of CTCs as well as an improved comprehension of CTC biology and role in lung cancer. 604 , 605

This review has encapsulated the obstacles surrounding the genesis of CTCs in the context of cancers, as well as the effect of epigenetics modifications on CTCs pertaining to EMT, immune surveillance, cluster formation, and colonization. The epigenetic modifications resulting from DNA methylation in CTCs may serve as a key to unlock the underlying mechanisms of metastasis in lung cancer, and holds significant promise in the areas of lung cancer diagnosis, prognosis, and treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82372155), Project of Key Supported Disciplines by Shanghai Municipal Health Commission (grant number: 2023ZDFC0204), Program of Shanghai Academic Research Leader (No. 21XD1402800), and Development Fund for the Department of Anesthesiology, Shanghai Pulmonary Hospital.

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These authors contributed equally: Xuyu Gu, Shiyou Wei

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Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

Shiyou Wei & Xin Lv

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Xin Lv, Xuyu Gu, and Shiyou Wei proposed the study conception. Xuyu Gu and Shiyou Wei searched the references. Xuyu Gu assisted with the chart making. Xuyu Gu and Shiyou Wei drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xin Lv .

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Gu, X., Wei, S. & Lv, X. Circulating tumor cells: from new biological insights to clinical practice. Sig Transduct Target Ther 9 , 226 (2024). https://doi.org/10.1038/s41392-024-01938-6

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Received : 02 November 2023

Revised : 31 May 2024

Accepted : 29 July 2024

Published : 02 September 2024

DOI : https://doi.org/10.1038/s41392-024-01938-6

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