Abstract
The detection of Circulating Tumor Cells (CTC), as an innovative liquid biopsy technique, together with ctDNA (Circulating Tumor DNA, ctDNA) and exosomes, is collectively known as the “troika” of liquid biopsy. It shows great potential in the field of precise diagnosis and treatment of gastrointestinal tumors. Through the capture and identification of CTCs, this technique can provide crucial information about tumor dynamics, treatment response, and prognosis, thus helping doctors to formulate personalized treatment plans. This study systematically expounds the basic principles, technological progress, and application value of CTC detection in the diagnosis and treatment of gastrointestinal tumors. In terms of detection methods, the commonly used immunological and physical capture methods currently each have their own advantages. Emerging technologies such as immunomagnetic bead-based separation technology, microfluidic chip technology, and deep learning image recognition technology are continuously improving the sensitivity and specificity of detection. In clinical applications, CTC detection can not only be used for the early diagnosis of gastrointestinal tumors but also effectively monitor the treatment effect and evaluate the prognosis, providing patients with more precise and timely treatment suggestions. The study points out that although CTC detection still faces technical challenges, such as rarity, heterogeneity, and the limitations of existing technologies, these problems are expected to be solved through continuous technological innovation and optimization. In the future, with the further development of technology and the accumulation of clinical data, CTC detection is expected to play a greater role in the precise diagnosis and treatment of gastrointestinal tumors, bringing patients a more personalized diagnosis and treatment experience and a better quality of life.
Chapter One Introduction
The detection of circulating tumor cells, as an emerging liquid biopsy technique, has received extensive attention in recent years. Its importance in the precise diagnosis and treatment of gastrointestinal tumors is increasingly prominent, providing more information about the tumor status for the clinic and helping to guide treatment strategies and prognosis evaluation.
Circulating tumor cells are tumor cells that break off from the primary or metastatic tumor foci and enter the bloodstream. These cells carry rich tumor-related information, such as gene mutations and changes in expression profiles. Through the detection and analysis of these cells, the dynamic changes of the tumor can be monitored in real time, the heterogeneity of the tumor can be understood, and the effects of different treatment regimens can be evaluated[1]. In gastrointestinal tumors, the application of CTC detection is of particular significance. Because the early symptoms of gastrointestinal tumors are not obvious, and traditional diagnostic methods such as endoscopic examination and imaging examination have certain limitations. Imaging can only detect tumors when they grow to a certain size, which is lagging. And serum markers are substances that are produced by tumor cells themselves during the occurrence and proliferation of malignant tumors or are abnormally produced and/or elevated by the body’s reaction to tumor cells, reflecting the existence and growth of tumors. They include proteins, hormones, enzymes, polyamines, and oncogene products, etc. They only carry part of the tumor information and have limited specificity themselves. Therefore, it is especially important to find a non-invasive, sensitive, and specific detection method. CTC detection just meets this need. It can capture the tiny changes of tumor cells through a simple blood test, providing strong support for the precise diagnosis and treatment of gastrointestinal tumors[1].
Some progress has been made in the research on the detection of circulating tumor cells in the diagnosis and treatment of gastrointestinal tumors. Many studies have shown that the number and characteristics of CTCs are closely related to the staging, prognosis, and response to treatment of gastrointestinal tumors. Through in-depth analysis of CTCs, it is expected to provide more personalized treatment regimens for patients with gastrointestinal tumors, improving treatment effects and quality of life [1][2][3][4]. The CTC detection technique still faces some challenges in practical application, such as the sensitivity, specificity, and reproducibility of detection, which require further research and improvement. In the future, with the continuous progress of technology and the in-depth research, the detection of circulating tumor cells is expected to play a greater role in the precise diagnosis and treatment of gastrointestinal tumors.
Chapter Two Basic Principles of Circulating Tumor Cell Detection
2.1 Overview of Detection Methods
The detection of circulating tumor cells has been a research hotspot in the field of oncology in recent years, and it plays an important role in the precise diagnosis and treatment of gastrointestinal tumors. CTCs exist in various forms in the blood, including different molecular subtypes [Epithelial CTC (E-CTC), Mesenchymal CTC (M-CTC), and Mixed CTC] and cell subtypes [Single CTC, Circulating tumor microemboli (CTM), and CTC-neutrophil clusters]. The rarity and high heterogeneity of CTCs are the technical challenges that need to be overcome in the separation and enrichment of CTCs [5]. There are significant differences between CTCs and other cells in the blood in terms of physical characteristics, immunological characteristics, and gene expression. These form the theoretical basis for the separation and enrichment of CTCs [6]. In the “Chinese Expert Consensus on the Application of Circulating Tumor Cell Detection in the Diagnosis and Treatment of Gastrointestinal Tumors (2023 Edition)” jointly released by the Gastric Cancer Group of the Oncology Branch of the Chinese Medical Association, the Colorectal Tumor Professional Committee of the Chinese Medical Association, the Colorectal Cancer Professional Committee of the Chinese Cancer Society, the Gastric Cancer Professional Committee of the Chinese Cancer Society, and the Professional Committee of Digestive Tract Polyps and Precancerous Lesions of the Chinese Cancer Society, five authoritative academic institutions (the Chinese Medical Association, the Chinese Medical Association, and the Chinese Cancer Society), the different cell types of CTCs in gastrointestinal tumors are clearly shown [7].
At present, there are various methods for CTC detection. The most crucial part is to capture CTCs from the blood, and the identification can be achieved through multiple cytological and molecular biological methods. Currently, immunological and physical methods for capturing circulating tumor cells are two commonly used technical means.
The immunological method is a technique that uses the principles and methods of immunology and cytochemistry to conduct location and qualitative research on specific antigens inside cells. In CTC detection, this method marks the antigens on the surface of tumor cells with specific antibodies, thus realizing the recognition and counting of circulating tumor cells. Since most CTCs express epithelial cell markers such as CK and EpCAM, immunological recognition can be carried out through these specific markers. Based on this core principle, combined with technologies such as nano, microfluid, and magnetic beads, positive or negative separation of CTCs can be achieved. The CellSearch system and CTC-Chip respectively use the magnetic bead method and microfluidic chip for positive separation, and the surface markers are both EpCAM. The CTCs captured by these two methods have a relatively high purity, but some subtypes that have undergone epithelial-mesenchymal transition or lack EpCAM expression will be missed. Negative separation usually directly targets the specific antigens on the surface of white blood cells (such as CD45), preferentially removing white blood cells in the blood to achieve the enrichment of CTCs. This type of method has more operating steps, and the purity of the enriched CTCs is relatively low [8].
Physical capture methods separate CTCs by taking advantage of the differences in physics such as size, shape, and hydrodynamics between CTCs and normal blood cells, and identify CTCs according to the unique karyotype characteristics of tumor cells. Its advantage is that it can ensure the intact morphology of CTCs and be compatible with various downstream cell analysis and identification technologies. Among them, the ISET system and CTC-BIOPSY system are nano-microporous membrane filtration devices. They separate CTCs through 8 μm filtration pores according to the difference in cell size, and then identify them through cytopathological staining [9][10].
The ClearCell®FX system and the Parsortix system use microfluidic technology to separate and enrich CTCs by combining the size of cells and their deformation ability. The OncoQuick system separates CTCs by taking advantage of the density difference between CTCs and white blood cells. After density gradient centrifugation, white blood cells are removed through a porous filter membrane, and CTCs are enriched in the medium layer and can be eluted for collection.
Besides the above two commonly used methods, there are also some emerging technical means that have been applied in CTC detection, such as flow cytometry, microfluidic chip technology, etc. Each of these technologies has its own characteristics and plays an important role in the precise diagnosis and treatment of gastrointestinal tumors. Flow cytometry can achieve rapid analysis and sorting of a large number of cells, with a high throughput and a high degree of automation; while microfluidic chip technology can achieve high-throughput detection and analysis of micro-samples, with advantages such as high sensitivity and simple operation.
There are various methods for detecting circulating tumor cells, and each method has its own unique advantages and limitations. In the precise diagnosis and treatment of gastrointestinal tumors, appropriate detection methods should be selected for comprehensive application according to the specific situation and actual needs of patients, so as to improve the accuracy and effectiveness of diagnosis and treatment. Meanwhile, with the continuous progress and development of science and technology, more emerging CTC detection methods will emerge in the future, bringing greater breakthroughs and hopes for the diagnosis and treatment of gastrointestinal tumors.
2.2 Technological Progress and Application
The continuous progress of circulating tumor cell detection technology has provided a new perspective for the precise diagnosis and treatment of gastrointestinal tumors. These technologies have not only improved the sensitivity and specificity of CTC detection but also promoted their wide application in clinical practice.
In terms of detection technology, many emerging methods have emerged in recent years, such as immunomagnetic bead-based separation technology, microfluidic chip technology, and image recognition technology combined with deep learning [11][12]. These methods have made breakthroughs in enrichment efficiency, detection speed, and accuracy, providing more reliable tools for the early diagnosis, disease monitoring, and prognosis evaluation of gastrointestinal tumors.
In specific applications, CTC detection has shown important value in the clinical diagnosis and treatment of gastrointestinal tumors. For patients with colorectal cancer, CTC detection helps to detect signs of early recurrence and metastasis, thus guiding the timely adjustment of treatment plans [13]. Studies have shown that the number of CTCs is closely related to the prognosis of patients with colorectal cancer. A high level of CTCs often indicates a higher risk of recurrence and a poorer survival outcome [14]. Therefore, by regularly monitoring the number of CTCs in the blood of patients, doctors can more accurately assess the progress of the disease and formulate personalized treatment plans. CTC detection also plays an important role in the diagnosis and treatment of gastric cancer. The recurrence and metastasis after gastric cancer surgery are one of the main reasons for the decline in the survival rate of patients, and CTCs play a key role in this process [15]. By detecting CTCs in the blood of patients, doctors can detect signs of tumor recurrence earlier and take timely intervention measures to extend the survival period of patients. At the same time, CTC detection also helps to evaluate the response of patients with gastric cancer to treatment and guide the formulation of individualized treatment strategies [11][15].
With the continuous progress of technology and the expansion of application fields, CTC detection has shown broad application prospects in the precise diagnosis and treatment of gastrointestinal tumors. In the future, with more in-depth research and the accumulation of clinical data, there is reason to believe that CTC detection will become an indispensable part of the diagnosis and treatment process of gastrointestinal tumors.
Although significant progress has been made in the application of CTC detection in the diagnosis and treatment of gastrointestinal tumors, there are still some challenges and problems that need to be solved. For example, how to further improve the sensitivity and specificity of CTC detection, how to standardize the detection process and interpret the results, and how to combine CTC detection with other biomarkers and imaging examinations to provide more comprehensive diagnosis and treatment information. The solution of these problems will help to promote the wider application and deeper development of CTC detection in the precise diagnosis and treatment of gastrointestinal tumors.
Chapter Three Application Value of Circulating Tumor Cell Detection in the Diagnosis and Treatment of Gastrointestinal Tumors
3.1 Auxiliary Means for Early Diagnosis
As a non-invasive liquid biopsy technique, the detection of circulating tumor cells has shown broad application prospects in the early diagnosis of gastrointestinal tumors in recent years. This technique can provide important information about tumor status, treatment response, and disease progress for clinicians by capturing and analyzing tumor cells in peripheral blood. In the early stage of gastrointestinal tumors, due to the tiny metastasis and concealment of tumor cells, traditional diagnostic methods are often difficult to detect them, while CTC detection has become a powerful auxiliary means for early diagnosis with its high sensitivity and specificity.
In terms of sensitivity, CTC detection can identify and count extremely rare tumor cells in peripheral blood. This is due to the continuous progress of detection technologies, including the combined application of immunomagnetic bead separation, flow cytometry, and high-resolution microscopy, which makes it possible to capture and identify single tumor cells. Through these technologies, CTCs can be effectively detected even when the tumor burden is low, thus improving the accuracy rate of early diagnosis of gastrointestinal tumors.
In terms of specificity, CTC detection relies on specific markers on the surface of tumor cells for identification. These markers may be tumor-related antigens, gene mutations, or chromosomal abnormalities, etc. Their expression patterns in tumor cells are significantly different from those in normal cells. Through specific antibodies or probes targeting these markers, CTC detection can accurately distinguish tumor cells from the complex blood background. This high specificity not only helps to reduce the occurrence of false positive results but also can provide precise target information for subsequent individualized treatment.
Besides sensitivity and specificity, CTC detection also has other advantages in the early diagnosis of gastrointestinal tumors. For example, this detection method does not require invasive tissue biopsy, reducing the pain and risk of complications for patients. Meanwhile, due to the easy accessibility of blood samples, CTC detection can achieve dynamic monitoring and continuous evaluation, which helps to timely detect the recurrence and metastasis of the disease. In addition, with the continuous development of technology, CTC detection is expected to achieve automation and high-throughput processing, further improving the diagnostic efficiency and accuracy.
Although CTC detection has shown great potential in the early diagnosis of gastrointestinal tumors, there are still some challenges and limitations at present. For example, the rarity and heterogeneity of CTCs make the detection process require extremely high standards for sample handling and analysis technologies, and any mistake in any link may lead to deviation of the results. In addition, the CTC characteristics may vary between different patients and between different disease stages of the same patient, which brings difficulties to standardization and normalization of detection. Therefore, in future research, it is necessary to continuously explore and optimize CTC detection technology to improve its reliability and practicability in the early diagnosis of gastrointestinal tumors.
The detection of circulating tumor cells is playing an increasingly important role in the early diagnosis of gastrointestinal tumors with its high sensitivity and specificity. With the continuous progress of technology and the in-depth expansion of clinical applications, there is reason to believe that CTC detection will become an indispensable part of the precise diagnosis and treatment field of gastrointestinal tumors in the future.
3.2 Treatment Monitoring and Efficacy Evaluation
As a non-invasive liquid biopsy technique, the detection of circulating tumor cells is playing an increasingly important role in the treatment monitoring and efficacy evaluation of gastrointestinal tumors. By continuously monitoring the changes in the number of CTCs in the blood of patients, clinicians can obtain real-time information about tumor dynamics, treatment efficacy, and prognosis, thus guiding the adjustment of individualized treatment regimens.
In terms of treatment monitoring, CTC detection provides a convenient way to track the tumor’s response to treatment. Traditional imaging methods, such as CT or MRI, although they can show the size and position of the tumor, often fail to promptly reflect the killing effect of treatment on tumor cells. In contrast, CTC detection can capture the free tumor cells in the blood, which are the potential sources of tumor metastasis and recurrence. Therefore, by regularly detecting the changes in the number of CTCs, the response to treatment can be detected earlier, including the decrease or increase of tumor cells.
In terms of efficacy evaluation, CTC detection provides clinicians with an objective indicator to evaluate the effectiveness of treatment. Traditional efficacy evaluation mainly relies on imaging examinations and the patient’s clinical symptoms, which have certain subjectivity and lag. Meanwhile, CTC detection can directly reflect the survival state of tumor cells in the body, thus more accurately evaluating the effectiveness of treatment. For example, during chemotherapy, if the number of CTCs continues to decrease, it indicates that the chemotherapy drugs have an effective killing effect on tumor cells; conversely, if the number of CTCs increases or new mutations occur, it may suggest that the tumor has developed resistance to chemotherapy and the treatment regimen needs to be adjusted in a timely manner.
CTC detection also helps to predict the prognosis of patients. Many studies have shown that patients with a higher number of CTCs before or during treatment tend to have a poorer prognosis, and the risk of recurrence and metastasis is also relatively high. Therefore, by monitoring the changes in the number of CTCs, signs of poor prognosis in patients can be detected in a timely manner, and corresponding intervention measures can be taken to reduce the risk of recurrence and metastasis.
Overall, the detection of circulating tumor cells has important application value in the treatment monitoring and efficacy evaluation of gastrointestinal tumors. By continuously monitoring the changes in the number of CTCs in the blood of patients, clinicians can more accurately understand the dynamics of the tumor and the effectiveness of treatment, thus guiding the formulation and adjustment of individualized treatment regimens. With the continuous progress of technology and the in-depth expansion of application, the detection of circulating tumor cells is expected to play a greater role in the precise diagnosis and treatment of gastrointestinal tumors in the future.
Chapter Four Challenges and Prospects of Circulating Tumor Cell Detection
4.1 Technical Challenges and Solutions
As an emerging means of precise diagnosis and treatment of gastrointestinal tumors, the detection of circulating tumor cells has shown great potential both in theory and practice. However, it still faces a series of technical challenges in the actual application process. These challenges mainly stem from the rarity, heterogeneity of circulating tumor cells, and the limitations of existing detection technologies. To fully utilize the value of circulating tumor cell detection in the diagnosis and treatment of gastrointestinal tumors, it is necessary to thoroughly discuss these technical problems and put forward practical solutions.
The rarity of circulating tumor cells is one of the most prominent problems in the detection process. In the peripheral blood of patients, the number of circulating tumor cells is usually extremely low, and it may even reach the level of only a few cells per milliliter of blood. This requires that the detection technology must have extremely high sensitivity and specificity to accurately identify the rare circulating tumor cells from a vast number of normal cells. To meet this challenge, researchers are devoting themselves to developing new high-sensitivity detection technologies, such as nanotechnology-based detection methods, single-cell sequencing technologies, etc., hoping to achieve efficient capture and accurate identification of circulating tumor cells.
In addition to rarity, the heterogeneity of circulating tumor cells is also a major problem in the detection process. Due to gene mutations and epigenetic changes in tumor cells, circulating tumor cells in different patients or even within the same patient may have significant differences. This heterogeneity not only increases the difficulty of detection but also may lead to misjudgment of the detection results. To solve this problem, researchers are exploring integrated analysis methods based on multi-omics data. By comprehensively analyzing the information at multiple levels such as the genome, transcriptome, and proteome of circulating tumor cells, they aim to reveal their inherent biological characteristics and change patterns, thereby improving the accuracy and reliability of detection.
The limitations of existing circulating tumor cell detection technologies are also a problem that cannot be ignored. Currently, although many detection methods have been applied to the detection of circulating tumor cells, each method has certain advantages and disadvantages and still cannot meet all the needs of clinical diagnosis and treatment. For example, although immunohistochemistry has relatively high specificity, its sensitivity is relatively low; while PCR has an advantage in sensitivity, its specificity may be affected. Therefore, developing a new type of circulating tumor cell detection technology with both high sensitivity and high specificity has become a hot and difficult topic in current research. In response to this need, researchers will actively explore various detection methods based on artificial intelligence and machine learning technologies. By constructing efficient algorithm models with multi-dimensional parameters, they aim to achieve precise identification and quantitative analysis of circulating tumor cells.
The detection of circulating tumor cells has important application value in the precise diagnosis and treatment of gastrointestinal tumors, but it still faces a series of technical challenges. To fully exert its potential, it is necessary to thoroughly discuss the scientific problems behind these challenges and actively seek practical solutions. With the continuous emergence and improvement of new detection technologies, it is believed that in the not-too-distant future, the detection of circulating tumor cells will become an indispensable important means in the field of gastrointestinal tumor diagnosis and treatment.
4.2 Development Prospects
As an emerging technology in the field of precise diagnosis and treatment of gastrointestinal tumors, the detection of circulating tumor cells has broad development prospects and is full of potential. With the continuous progress of science and technology and the in-depth research, this technology is expected to achieve major breakthroughs in the next few years, bringing revolutionary changes to the diagnosis and treatment of gastrointestinal tumors.
From the technical level, the detection of circulating tumor cells is developing towards higher precision, higher sensitivity, and higher specificity. The continuous emergence of new detection methods, such as nanotechnology-based detection platforms, single-cell sequencing technologies, etc., provides more refined and comprehensive means for the capture and analysis of circulating tumor cells. The progress of these technologies will greatly improve the accuracy and reliability of the detection of circulating tumor cells, further highlighting its value in clinical applications.
In terms of clinical applications, the detection of circulating tumor cells is expected to become an important tool for the early diagnosis, treatment monitoring, and prognosis evaluation of gastrointestinal tumors. By regularly monitoring the number and changes of circulating tumor cells in the blood of patients, doctors can understand the dynamics of the tumor more timely and formulate more personalized treatment plans for patients.
In addition, the detection of circulating tumor cells is also helpful for detecting minimal residual disease and early recurrence of tumors, thus providing more precise treatment and a better quality of life for patients. In addition, the detection of circulating tumor cells also has important significance in basic medical research. Through in-depth research on circulating tumor cells, scientists can understand the mechanisms of tumor occurrence, development, and metastasis more deeply, providing new ideas and methods for the research on the biological characteristics of tumors and treatment targets. For example, through single-cell sequencing downstream of CTCs, changes in gene mutations related to gastrointestinal tumors and the expression of genes in relevant signaling pathways can be discovered.
However, to achieve the wide application and popularization of this technology, many technical and clinical challenges still need to be overcome. In the future, with the continuous in-depth research and cooperation of all parties, it is believed that the detection of circulating tumor cells will bring more precise and effective solutions to the diagnosis and treatment of gastrointestinal tumors.
Chapter Five Conclusions
As an emerging technical means, the detection of circulating tumor cells has shown remarkable importance and application value in the precise diagnosis and treatment of gastrointestinal tumors. Through the capture and analysis of circulating tumor cells, this technology provides clinicians with more comprehensive and in-depth tumor information, thus helping to formulate more precise treatment regimens. In the research process of this paper, the basic principles, technological progress, and specific applications of circulating tumor cell detection in the diagnosis and treatment of gastrointestinal tumors have been thoroughly explored. The results show that this technology performs excellently in aspects such as early diagnosis, treatment monitoring, and efficacy evaluation, demonstrating high sensitivity and specificity.
The detection of circulating tumor cells still faces many challenges, such as technical problems and the need for further improvement in accuracy and reliability. In response to these issues, a series of possible solutions have been proposed above. It is expected that through continuous research and practice in the future, these difficulties will be gradually overcome. Looking ahead, with the continuous progress of science and technology and the increasing clinical demand, the application of circulating tumor cell detection in the field of gastrointestinal tumor diagnosis and treatment will become more widespread, and its potential clinical significance will be further highlighted. It is believed that the CTC detection technology will bring more precise and personalized diagnosis and treatment experiences to patients with gastrointestinal tumors, thus promoting the progress and development of the entire field of tumor diagnosis and treatment.
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