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Circulating tumor cells: biology and clinical significance

Danfeng Lin, Lesang Shen, Meng Luo and 8 more

Signal Transduction and Targeted Therapy · 2021 · Review · CC BY

Abstract

Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Metastasis is the most lethal feature of cancer. Despite significant developments in cancer diagnosis and treatment over the past centuries, metastasis remains a major obstacle to improving clinical outcomes of cancer patients. Nevertheless, we have witnessed significant progress over the past two hundred years in revealing fundamental concepts underlying the development of metastasis and in creating new technologies to facilitate cancer metastasis research. Fig 1 highlights the key discoveries and milestones in the study of cancer metastasis. The ‘seed and soil’ hypothesis by Steven Paget in the 1830s vividly clarified the progress of cancer metastasis. With the advances of science and technologies, particularly since the 2000s, a plethora of new technologies have been advanced, such as high-throughput sequencing,, transgenic mouse models, CRISPER/Cas9 editing tools, and single-cell sequencing. With these powerful technologies, the biological phenomena underlying metastasis, such as epithelial-mesenchymal transition (EMT) of tumor cells, the role of exosomes in supporting metastasis, circulating tumor cells (CTCs) and CTC clusters in seeding metastatic colonies, and complex interactions between tumor cells and microenvironment, have gradually been unmasked, along with the discovery of numerous metastasis-related driver genes. The ‘black box’ of metastasis is gradually being unveiled, and effective metastasis-targeting agents are believed to be on the horizon in the near future.

2Cancer metastasis is a complex multistep process involving cancer cell invasion in the primary site, intravasation into circulation, survival in the circulation, extravasation from the circulation, and attachment to and colonization of the metastatic site (Fig. 2). CTCs are defined as tumor cells that have been sloughed from the primary tumor and are swept away by the circulatory or lymphatic systems. To date, most CTC research has focused on CTCs in the blood circulation. CTCs were first described in 1869 by Ashworth who observed “some cells” in the blood of a metastatic cancer patient with an appearance similar to tumor cells in the primary tumors. CTCs have been assumed to be the substrate of metastasis. Although CTCs originate from the primary tumor, they are distinct from primary tumor cells, with EMT transition properties that help them break free from the primary tumor and facilitate intravasation into the bloodstream, dissemination in clusters of CTCs to increase metastatic potential, and exhibit stemness features that enhance their ability to initiate metastasis (Fig. 2). However, most CTCs perish in the circulation, and only limited CTCs survive and infiltrate distant organs. Interactions between CTCs and the blood environment (Fig. 2), including how CTCs escape immune surveillance in the blood, have been widely implicated in the metastatic mechanisms of CTCs. It has taken more than a century for researchers to recognize the critical role of CTCs in cancer metastasis, due to the unique technical challenges required to isolate these very rare CTCs from the massive pool of circulating blood cells. However, in the past two decades, emerging technologies for CTC isolation have allowed research on the biology of CTCs and have facilitated the clinical applications of CTCs in cancer screening, treatment response monitoring, and prognosis evaluation.

3In this review, the biology of CTCs, as well as their interaction with the blood microenvironment, is fully reviewed. In addition, the growing number of highly sophisticated CTC enrichment and isolation technologies will be summarized. Finally, we also discuss the tremendous potential of CTCs in clinical applications.

Molecular characterization of CTCs

4Experimental evidence has supported the notion that tumor cells can spread even during the early stages of tumor evolution,. The molecular characterization of CTCs will add knowledge to the underlying mechanism of metastatic processes, contributing to early diagnosis and prevention of metastasis.

Molecular markers of CTCs

5A panel of molecular markers has been used to detect CTCs in various cancers. CTC-associated markers used for different cancers are summarized in Table 1,. As most cancers are of epithelial origin, the most common marker used for CTCs is EpCAM, a “universal” epithelial marker of cancers. EpCAM expression varies among different cancer types, and EpCAM-based CTC detection technologies are widely applied for cancers that strongly express EpCAM, such as breast and prostate cancer. Many studies have shown that CTCs in breast and prostate cancer are EpCAM-positive, and have validated their prognostic value in either early or metastatic stage cases,. Other epithelial-derived cancer types, such as pancreatic, colorectal, and hepatocellular cancers, also have a considerable detection rate of EpCAM-positive CTCs. Similarly, the presence of these EpCAM-positive CTCs predicts early distant metastasis and poorer survival of patients,,. However, using EpCAM as a CTC marker has limitations. It cannot be used in tumors that are EpCAM-negative or with low expression, such as neurogenic cancers. CTCs can undergo EMT, and epithelial markers, including EpCAM, are down-regulated during EMT, which affects the detection rate of EpCAM-positive CTCs. Although there are doubts as to whether EpCAM-based technologies are appropriate to detect all CTCs, numerous studies have illustrated the potential value of EpCAM-positive CTCs in clinical applications. To some extent, EpCAM-positive CTCs are a substantial subgroup of all CTCs, thus EpCAM-positive CTCs still could be a reliable biomarker if the cancer prognosis and therapeutic efficacy is relevant to EpCAM-positive CTCs.

6Due to the EMT activity of some epithelial cancer cells, detecting only EpCAM-positive CTCs probably underestimates the actual total CTC population and misses important biological information of EpCAM-negative CTCs. In some cancer types, such as non-small-cell lung cancer (NSCLC) patients, it was even found that the quantity of EpCAM-negative CTCs was significantly larger than EpCAM-positive CTCs. Nevertheless, the poor isolation of CTCs by EpCAM-based technologies can be rescued by using both epithelial and mesenchymal cancer markers, as well as by marker-independent detection methods. For example, in breast cancer, the use of fluorescent-magnetic nanoparticles consisting of a dual-antibody interface targeting both EpCAM and N-cadherin has contributed to high-efficiency isolation and rapid identification of CTCs,. In biliary tract cancer, a single-cell assay for detecting CTCs allowed identification of both epithelial CTCs and non-conventional CTCs which lacked epithelial and leukocyte markers, and therefore led to an increase of CTC positivity rate. The EMT program of cancer cells exhibits molecular alterations, including decreased expression of epithelial markers (E-cadherin, ZO-1, claudins, and occludins) and increased expression of mesenchymal markers (vimentin, N-cadherin, fibroblast-specific protein1, and fibronectin). EMT is executed by EMT-related transcription factors, mainly belonging to the SNAIL, TWIST, and ZEB families. All these EMT-related molecules can theoretically be used for EMT-CTCs targeting methods. However, many EMT-related molecules are cytoplasmic or nuclear proteins, precluding their usage in the currently available membrane molecular-based technologies of CTC detection. Proteins such as E-cadherin, vimentin, and twist were most often used in the past(Table 1), probably because of their accessibility of detection in traditional CTC detection technologies including flow cytometry sorting, immunostaining, and fluorescence in situ hybridization (FISH) staining. However, the emergence of single-cell CTC sequencing technologies will make it possible to unmask the EMT status of CTCs more comprehensively, and can cover all the EMT-related molecular alternations at the RNA level.

7Other biomarkers, such as human epidermal growth factor receptor-2 (HER2)–, estrogen receptor,–, prostate-specific membrane antigen–, folate receptor–, and survivin, have been described as CTCs markers in different cancers, with different clinical significance. These cancer-specific CTC markers are listed in Table 1. Most of these cancer-specific CTC markers are in accordance with the specific molecular markers of the primary tumor. However, there is discordance in the expression of specific markers between the primary tumor and CTCs. For example, the rates of discordance of HER2 gene amplification between CTCs and primary breast tumor were around 15%, suggesting a clonal selection of CTCs or clonal acquisition, probably due to genetic instability. It should be mentioned that for melanoma, a skin cancer that begins in melanocytes, the detection technologies of CTCs are based on several melanoma cell adhesion molecules, such as HMW-MAA–, MART-1–, CD146,, and MAGE A3,,, which are very specific molecular markers for melanoma.

8The variety of CTCs markers indicates the heterogeneity of CTCs among different cancer types. Even in one patient, CTCs are spatio-temporally heterogenous, which may be the result of a spatially different microenvironment in the blood and temporal changes in therapy response. Thus, it is difficult to define the entire CTC population using the very limited molecular markers currently available. In addition, CTC markers should not be constant among different stages of cancer and treatment periods.

Genome analysis of CTCs

9Genomic instability contributes to tumor evolution and the emergence of resistant tumor subclones. Monitoring tumor genomic instability, especially in terms of tumor resistance and metastases, greatly contributes to the evaluation of treatment response and precision medicine. The evaluation of CTCs assessment using noninvasive liquid biopsy is accessible for serial sampling to detect the genomic instability of the tumor.

10Determining the status of EGFR and KRAS mutations is crucial for guiding treatment in NSCLC patients receiving EGFR tyrosine kinase inhibitors and colorectal cancer patients treated with anti-EGFR therapy respectively. The concordance of mutations between CTCs and matched primary or metastatic tumor tissue has attracted much attention. Using a microfluidic technique to capture CTC, Maheswaran et al. found that only two of 31 patients with mutations were overlooked from their detection assay. They identified the EGFR activating mutation in CTCs in 92% of metastatic patients with NSCLC and detected the drug-resistant mutation T790M in CTCs of 33% of patients who responded to tyrosine kinase inhibitor therapy and in 64% of patients who exhibited clinical progression. For the analysis of the KRAS gene mutation, the mutational concordance rate between CTCs and matched primary tumors ranged from 37% to 90% in colorectal cancer cases–. This difference in the concordance rate may be due to the different CTC selection protocols used in these studies. KRAS mutations are also common in pancreatic ductal adenocarcinoma (PDAC), present in 90% of PDAC cases. However, Kulemann et al. found that the discordance rate of KRAS mutation in CTCs and corresponding PDAC tumors was 42%. Studies of gene mutation analysis in CTCs were also conducted in many cancers such as prostate cancer,, breast cancer,, hepatocellular carcinomas, and a mutational discordance between CTCs and corresponding tumors were often found. The discordance rate was probably attributed to the different detection efficiency of CTC mutations, or the heterogeneity between CTCs and primary tumor cells. Genomic assessment of tumor tissue and CTCs can be complementary. So, a combination of mutational testing of CTCs and tumor specimens would guide treatment more precisely.

11Determining copy number alternations (CNA) of CTCs helps analyze and track cancer profiles as tumors evolve. In lung cancer, Ni et al. found that CTCs exhibit reproducible CNAs patterns, similar to those of metastatic tumors, and different patients shared similar CNAs patterns. In small-cell lung cancer, a CNA-based classifier for CTCs correctly assigned 83.3% of patients as chemorefractory or chemosensitive. In breast cancer, the assessment of CNAs in archived CTCs is feasible. Paoletti et al. found that the CNAs of CTCs and paired metastatic tumor tissue in breast cancer patients were highly concordant, although CTCs and matched tumor tissue harbored several discordant copy number alterations, suggesting that CTCs were the subclone cells of tumor tissues. In triple-negative breast cancer, CTCs with chromosome 10 and 21q CNAs are predictive of clinical progression, and their network analysis presented connected modules including HER/phosphatidylinositol-4,5-bisphosphate 3-kinase/RAS/JAK signaling. In prostate cancer, Lambro et al. revealed that CNAs of CTCs were interpatient and intercell heterogeneous, and could be missed in bulk biopsy analyses. In metastatic castration-resistant prostate cancer, whole genomic copy number analysis of CTCs showed that common genomic gains in CTCs involved genes such as androgen receptor (AR), mesenchymal-to-epithelial transition (MET), ERG, and cyclin-dependent kinase 12, while common genomic losses were observed in genes such as phosphatase and tensin homolog (PTEN), RAF1, and GATA2. Similarly, Malihi et al. also observed that CNAs in genes including PTEN, RB1, TP53, and AR closely associated with genomic instability and survival in aggressive variant prostate cancer.

12Other genome analyses have also been conducted in CTCs. FISH testing was adopted in CTCs to detect biomarkers for treatment sensitivity, such as ALK FISH testing in CTCs of NSCLC patients and HER2 FISH testing in CTCs of breast cancer patients,. Recently, based on the technique of single-cell resolution DNA methylation analysis, the DNA methylome of single CTCs and CTC clusters was revealed for breast cancer patients, and indicated that the CTC cluster hypomethylation profile obtained was associated with a poor prognosis and that treatment with Na+/K+-ATPase inhibitors to dissociate CTC clusters could revert the methylation profile of CTC clusters and suppress metastasis.

Transcriptome analysis of CTCs

13Single-cell sequencing has developed rapidly in recent years and has been applied to investigate the CTC transcriptomes. Single-cell expression profiles can distinguish CTCs from mesothelial cells and blood cells in lung adenocarcinoma, with representative markers including EpCAM for CTCs. Single-cell sequencing-based transcriptome analysis revealed heterogeneity in the CTC subpopulation. By testing the expression of proliferation-associated genes such as the Ki-67 proliferation marker, Magbanua et al. found that 65% of CTC in patients with metastatic breast cancer had low proliferation Ki-67 and that the 35% of patients with a high proliferation Ki-67 expression had a poor prognosis. Cheng et al. performed a single cell transcriptome analysis of 666 CTCs in patients with metastatic breast cancer. They determined that intra-patient CTCs were heterogeneous with regard to EMT-like and MET-like states, and CTCs were enriched for the stem-like phenotype. Single-cell sequencing of CTCs also greatly helped in discovering driver signaling pathways that contributed to metastasis and treatment failure. RNA-Seq of single prostate CTC indicated the activation of noncanonical Wnt signaling in antiandrogen resistant patients. Further, using mouse models, ectopic expression of Wnt5a attenuated the effects of an AR inhibitor and suppression of Wnt5a could partially restore the sensitivity in drug-resistant prostate cancer cells. CTCs have been associated with a poor prognosis in colorectal cancer. A study of the CTC-specific transcriptome profile of six metastatic colorectal cancer patients characterized 410 CTC-specific genes, which were primarily related to cell movement and adhesion, such as VCL ITGB5, bone morphogenetic protein 6, transforming growth factor beta 1, and talin 1, and were related to cell death and proliferation, such as amyloid beta precursor protein, clusterin, and TIMP1.

Epithelial-to-mesenchymal transition of CTCs

14EMT is the process by which epithelial tumor cells lose their intercellular adhesion and acquire mesenchymal and invasive properties. During dissemination, tumor cells detach themselves from the basement membrane through EMT activation and directly enter the circulation, serving as CTCs traveling to distant sites. When CTCs extravasate, they then undergo a reverse process termed MET and proliferate to form macro-metastases–. Herein, metastatic development depends on the delicate balance of the transition between these two phenotypes. The activity of EMT-MET was also proposed to play an important role in the metastatic process of CTCs. Using mouse models, it was found that epithelial-type CTCs with a restricted mesenchymal transition had the strongest lung metastases formation capacity, whereas mesenchymal-type CTCs showed limited metastatic ability. In breast cancer, CTCs exhibit dynamic changes in EMT composition, and mesenchymal CTCs were found to be closely associated with cancer progression,. A plethora of studies has shown increased EMT of CTCs rather than primary tumor cells in various cancers–. In a study based on the bioinformatics analysis of seven sets of gene chips, Guan et al. showed that compared with primary tumors, the main changes in CTCs involved cell adhesion, EMT, and apoptosis. In a prospective study including 39 patients with invasive breast cancer, Tashireva et al. observed a majority of heterogeneous CTC phenotypes (22 out of 24 detectable samples) exhibiting EMT plasticity. Interestingly, it was found that fluid shear stress can induce the EMT of CTCs via JNK signaling in breast cancer, which further confirmed the relationship between augmented EMT of CTCs and poor patient survival.

15Clinically, combining the total CTC count and the proportion of mesenchymal CTCs can be used to monitor therapeutic resistance and predict prognosis in cancer patients due to the significant survival differences of this criterion. For example, since the baseline presence of total CTCs in advanced NSCLC conferred poor prognosis, and the presence of over five EMT-CTCs indicated progressive disease. Different numbers of total CTCs and EMT CTCs were found to play an important role in determining the prognosis of breast cancer patients. Intriguingly, it was emphasized that a better understanding of EMT-CTC subtypes and their interactions with peripheral blood mononuclear cells could help design better anti-metastatic treatments. As CTC EMT-positive patients with neutrophil-to-lymphocyte ratios ≥3 had an 8.6 times increased risk of disease recurrence compared with CTC EMT-negative patients with lower neutrophil levels, inflammation-based scores increased the prognostic value of CTCs in primary breast cancer. Therefore, targeting the EMT pathway may prevent tumor cell spread in early-stage patients and eradicate metastatic cells in advanced stages.

The stemness of CTCs

16Many previous studies have indicated a subpopulation of aggressive CTCs with “stemness” traits in different cancers, which refer to their properties for self-renewal and tumor growth induction. In bladder cancer, studies have reported the high expression of OCT4, a crucial stemness maintenance protein, in a subgroup of CTCs. In breast cancer, the CD44+/CD24-/low and aldehyde dehydrogenase 1 (ALDH1) + cell phenotypes are reported to be associated with stemness. After detecting the expression of CD44, CD24, and ALDH1 of CTCs in 30 metastatic breast cancer patients, Theodoropoulos et al. found that 35.2% of 1439 CTCs were CD44+/CD24-/low, and 17.7% of 238 CTCs were ALDH1high/CD24-/low, providing evidence of CTCs stemness. A CTC-3 cell line established from the peripheral blood cells of a breast cancer patient showed more aggressive growth than the widely used MCF-7 breast cancer cell line. Gene profiling revealed higher expression of the stemness markers in the CTC-3 cell line compared to MCF-7 cells. In hepatocellular carcinoma (HCC), 71.4% of HCC patients were CTC positive for the cancer stem cell marker, CD44; thus, they had a significant population of CTCs with stem properties, which could contribute to tumor cell survival and dissemination. In glioblastoma, RNA-seq analysis revealed Wnt activation-induced stemness and chemoresistance in CTCs. In prostate cancer, the stem cell marker CD133 was observed in the majority (> 80%) of CTCs of patients with metastatic castration-resistant prostate cancer and a stem-like subpopulation of the C-X-C motif chemokine receptor 4+/CD133+CTCs was more prevalent in EpCAM-negative CTCs than in EpCAM-positive CTCs.

17It is crucial to understand the mechanisms regulating CTCs stemness, and interfering with the CTCs subpopulation stemness properties may more efficiently suppress cancer progression and relapse. CTCs undergo considerable levels of fluid shear flow during their dissemination, and the fluid shear flow itself may have an impact on CTCs. Using a model of breast cancer with brain metastasis, it was suggested that hemodynamic shear flow could upregulate the stemness genes of CTCs in surviving under conditions of shear flow. EMT-like transition of CTCs by downregulating ERK and GSK3β signaling could promote the conversion of CTCs into stem-like CTCs with high sphere-forming and tumor-initiating capacity.

CTCs and the blood microenvironment

18When transported in the bloodstream, a major of CTCs are constrained by detrimental shear stress, or die from anoikis, a programmed cell death mechanism due to loss of cell attachment,. Only a small fraction of CTCs interact tightly with platelets, neutrophils, macrophages, myeloid-derived suppressor cells (MDSCs), or cancer-associated fibroblasts (CAFs) to escape the immune system and promote their survival,. Recently, accumulating studies suggest that the interaction and modulation between CTCs and hostile blood microenvironment is essential for adhesion to endothelial cells, tissue invasion, and tumor metastasis (Fig. 3).

Interaction of CTCs with neutrophils

19Neutrophils are the most abundant circulating leukocytes in humans and have recently been studied to support cancer progression. An increased number of neutrophils in circulation is associated with poor prognosis in several types of cancers–. The formation of CTC-white blood cells (WBCs) clusters was previously reported within the bloodstream. In 2019, Szczerba et al. determined that CTCs were significantly associated with neutrophils in both mouse models and breast cancer patients, exhibiting more metastatic potential with greater expression of genes that involve cell cycle progression compared to CTCs alone. These observations are consistent with previous findings showing the proliferation role of neutrophils on tumor cells. CTC and neutrophil binding is mediated by the cell–cell junction and possibly requires the vascular cell adhesion molecule 1. Furthermore, neutrophils can directly adhere to CTCs through the Mac-1/ICAM-1 interaction and act as a bridge between tumor cells and the liver parenchyma, thus promoting extravasation and liver metastasis. Thus, CTCs clusters with neutrophils anchor to the vascular endothelium for extravasation while resisting shear stress, and the process is mediated by a series of cell adhesion proteins, such as cadherin, integrin, and surface glycoprotein–. Intriguingly, Chen et al. found that IL-8 secreted from neutrophils was essential for neutrophil sequestration with arrested tumor cells and for the extravasation behaviors of adjacent tumor cells through the endothelial barrier.

20Neutrophils can also promote metastasis in an indirect manner. Neutrophil extracellular traps (NETs) are web-like structures formed by DNA–histone complexes and proteins released from activated neutrophils, with the ability to impact on CTC biology. Many studies have found that NETs were able to capture CTCs in the circulation and, in doing so, promoted metastatic dissemination,. In vitro and in vivo experiments have shown that CTC adhesion to NET is mediated by β1-integrin expressed on both NET and cancer cells, while this effect was abrogated following DNAse I administration. In a murine model of surgical stress, the NET formation triggered the release of high-mobility group box 1, which activated TLR9-mediated pathways in CTCs and therefore accelerated the progression of liver metastases. In addition, NETs can also awaken dormant cancer cells and promote metastasis. Recently, Albrengues et al. elegantly demonstrated that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9 (MMP9), concentrate at laminin, provoke its cleavage, by generating an epitope that induced awakening of dormant cancer cells by integrin activation and FAK/ERK/MLCK/YAP signaling. In turn, tumor-expressed protein, such as protease cathepsin, has been shown to support lung metastasis of breast cancer by promoting NET formation in metastatic niches. Coiled-coil domain containing protein 25, another protein expressed on the cancer cell membrane, could serve as a specific sensor for the DNA component NETs, which induces migration and adhesion of tumor cells. In addition, by forming NETs, circulating neutrophils can help CTCs escape immune surveillance by suppressing the activation of peripheral leukocytes, the function of natural killer (NK) cells, the antitumor response of effector T cells, and even cooperation with other immune cells (such as IL17-producing γδT cells). Overall, there is evidence for a pro-metastatic role of neutrophils in their interaction with CTCs, but the specific mechanism remains to be elucidated in more detail.

Interaction of CTCs with macrophages

21Tumor-associated macrophages (TAMs) not only contribute to metastatic progression within the primary tumor, but also promote later stages of metastasis including dissemination and extravasation of CTCs. Hamilton et al. tried to investigate the CTC-macrophage interactions by co-culturing peripheral blood mononuclear cells with CTC cell lines obtained from small-cell lung cancer patients. They found that CTCs were able to induce monocyte differentiation to TAMs, which secrete a host of mediators such as osteopontin, MMP9, chitinase-3-like-1, and platelet factor to promote further leukocyte recruitment, migration, and invasion,. In another study of colorectal cancer, the feedback loop between TAMs and cancer cells is essential for the EMT program of CTCs and intravasation into the blood stream. Mechanistically, IL6 derived from TAMs regulates invasiveness through the STAT3/miR-506-3p/FoxQ1 pathway, which in turn increases CCL2 expression of TAM-educated tumor cells to help recruit macrophages. TAMs seem to promote CTCs acquisition of mechanical adhesiveness and endurance, thereby helping them to form protective cell clusters and confer resistance to shear stress. The fusion of macrophages and tumor cells could be a potential mechanism of immune evasion and invasion. These macrophage-tumor cell hybrids were shown to have M2-like macrophage phenotypes (CD163) as well as epithelial markers (EpCAM),, and have been isolated from the blood of patients with multiple cancers such as PDAC, melanoma, breast, ovarian, and colorectal cancer. Furthermore, when transplanted into mice, they spread widely and formed lesions in distant tissues,. A recent study by Gast et al. revealed that fusion hybrids can increase tumor heterogeneity and metastatic behavior, further correlating with disease stage and overall survival among several cancers. Furthermore, larger hybrid sizes were also associated with worse survival among patients with non-small cell lung cancer. Understanding the mechanism of direct interaction and molecular fusion between CTCs and macrophages is of great significance for identifying therapeutic targets.

Interaction of CTCs with platelets

22The metastasis and progression of cancer are greatly influenced by the recruitment and activation of platelets, which support the survival of CTCs as well as their seeding and outgrowth at secondary sites,. Platelets can bind to and form aggregates with CTCs in the blood stream, and CTCs expand the formation of aggregation by releasing prothrombotic and procoagulant microparticles or by expressing tissue factor,. Platelet-released mediators, such as TGF-β, have been found to accelerate EMT in CTCs and to promote invasion and metastasis,. Xiong et al. recently determined that the expression of the heat shock protein 47 was induced during EMT, which enhanced the cancer cell–platelet interaction through its dependent collagen secretion in breast cancer cells. Interestingly, platelets are believed to protect CTCs against mechanical stress and induce resistance to anoikis, the latter being mediated by the activation of the YAP1 pathway. Furthermore, platelets promote escape of CTCs from NK cell attack through various mechanisms including (1) platelet aggregates that produce surface shielding to defend the cytolysis effect of NK cells; (2) platelet-derived normal MHC-I that are transferred to the surface of the tumor cell, thus preventing the identification of NK cells; (3) downregulation of natural killer group 2, member D (NKG2D) in NK cells by platelet-derived TGF-β, as well as platelet-mediated shedding of NKG2D ligands, which contribute to impaired antitumor cytotoxicity;, and (4) platelet-derived glucocorticoid-induced TNF-related ligand which activates GITR in NK cells and reduces their cytotoxicity. Furthermore, NK cells and platelets can also interfere with neutrophils, T cells, and macrophages and modulate their immune function–. In addition to safeguard CTCs within the bloodstream, platelets are also involved in the adhesion of endothelial cells. The attachment of platelets and CTCs is mediated by platelet adhesion receptors, such as the integrin αIIbβ3 and P-selectin, thereby supporting the firm adherence of CTCs to the endothelial wall–. Furthermore, tumor cell-activated platelets release ATP from dense granules, which then induces the activation of the endothelial P2Y2 receptor and allows transendothelial migration of tumor cells by increasing permeability. One study has also revealed that the interplay between integrin α6β1 on platelets and its receptor, a disintegrin, and metalloprotease 9 on CTCs is necessary for the extravasation process of cancer cells. Platelets could also increase vascular permeability to help tumor cell extravasation. For example, a preclinical lung metastasis model showed that tumor cell-associated CD97, an G protein-coupled receptor, can initiate platelet activation thereby leading to granule secretion, including both ATP and lysophosphatidic acid release. Similarly, the interplay between platelet-specific receptor glycoprotein VI and its ligand galectin-3 expressed on colon and breast cancer cells was revealed to promote platelet activation and ATP secretion. Consequently, these platelet secretions favor a process of tumor metastasis by regulating vascular permeability. Recently, Xu et al. discovered that Ptx@AlbSNO can block tumor-specific platelet functions to suppress tumor EMT as well as prevent platelet adhesion around CTCs. Ptx@AlbSNO can also inhibit TGF-β secretion and enhance intratumoral immune cell infiltration to reverse the immunosuppressive TME, thereby suppressing distant metastasis. Taken together, the close and complex crosstalk between CTCs and platelets might involve distinct molecule variants and signaling pathways and possibly represent a promising antitumor strategy, particularly attractive for the treatment of several cancers.

Interaction of CTCs with MDSCs

23MDSCs are a heterogeneous subset of myeloid cells characterized by immunosuppressive properties that also promote metastatic dissemination. Under a standard protocol for isolating human MDSCs, Cassetta et al. found that polymorphonuclear (PMN)-MDSC were significantly expanded among most cancer types except melanoma compared with infection and inflammation. CTC-MDSC clusters are thought to evade immune surveillance of the T cell response. Indeed, a decrease in circulating MDSCs was associated with an increase in activated OX40+PD-1- T cells in patients with diffuse large B-cell lymphoma. Furthermore, Sprouse et al. found that in vitro co-culture of CTCs derived from melanoma and breast cancer patients and PMN-MDSCs enhanced Notch activation in CTCs through direct interaction between Jagged1 (Notch1 ligands) expressed on MDSCs and the Notch1 receptor expressed on CTCs. The increased production of reactive oxygen species production of MDSCs could upregulate Notch1 receptor expression, therefore, promoting CTC proliferation. The potential mechanisms underlying the interplay between CTCs and MDSCs remains to be determined.

Interaction of CTCs with CAFs

24CAFs are one of the most abundant components in the TME and play a prominent role in tumor initiation, angiogenesis, metastasis, and drug resistance. Mechanistically, CAFs remodel the extracellular matrix structure, which allows tumor cells to invade through the stroma and communicate with cancer cells by secreting growth factors, chemokines, and cytokines. However, little is known about the interplay between CAFs and CTCs. Duda et al. first demonstrated that CTCs could carry CAFs from the primary tumor to the metastatic site in mouse models of lung cancer metastasis. These host-derived CAFs directly enhance tumor cell survival and promote the formation of metastasis, while depleting CAFs from lungs significantly reduces the number of macroscopic metastasis and extends survival rate in mice. Moreover, CAFs can protect CTCs from the fluid shear forces during the dissemination process. In a three-dimensional co-culture model, CAFs were found to induce shear resistance to prostate tumor cells through stable intercellular contact, as well as soluble factors (such as CXCL5, CCL2, and CCL7), which are associated with cell survival, invasion, and EMT. In addition to experimental models, circulating CAFs (identified by FAP and α-SMA co-expression) have been detected in the peripheral blood of patients with metastatic breast, cancer but not in patients in the early stages, and exhibit excellent precision in metastatic diagnosis (AUC–ROC, 0.975) when isolated using a novel acoustic microstreaming platform.

Technologies for CTCs enrichment and isolation

25Over the past few years, many methods have been proposed to capture CTCs. Due to the extremely small proportion of CTCs in patients’ blood, it is still a great challenge to accurately isolate CTCs from the numerous blood cells, and especially to invent applicable methods that can efficiently detect viable CTCs for subsequent in-depth analysis. Here, we will discuss the development of CTC-related technologies over the last two decades, as they have experienced tremendous growth. We will emphasize the most innovative methods associated with nanoscale materials or novel microfluidic chips, hoping to provide a useful framework of CTC-related technologies.

26Generally, there are three core strategies of CTCs technologies, which include (1) capture and enrichment, (2) detection and identification, and (3) release. The first strategy of capture and enrichment involves a specific interaction between CTCs and materials through physical interactions or antibody–antigen interactions. The second strategy of detection, which means identifying the CTCs, refers to various methods, such as fluorescence microscopy, fluorescence spectrophotometry, flow cytometry, surface-enhanced Raman scattering, or electrical impedance. In the last strategy, released CTCs are mainly used for downstream analysis, such as genomics, transcriptomics, proteomics, and CTCs culture.

Classic CTC-related technologies based on physical properties

27The physical separation enrichment method of CTCs is based on differences between CTCs and blood cells in size, density, deformability, and electrical properties. The Isolation by size of epithelial tumor cells system can filter blood samples through an 8-μm diameter polycarbonate TRACK-ETCH-type membrane, but it has low efficiency. An improved method, which consists of a pressure regulating system, the flexible micro spring array device, reaches a capture efficiency of 90% with a detection of CTCs in 76% of samples. However, there are various trends of CTC counts observed from different samples, making this method not reliable for widespread use. CTCs can also be sorted using the Oncoquick system, a density-dependent technique that allows red blood cells and WBCs to be filtered, or by Apostream that uses dielectric electrophoresis techniques in the microfluidic chamber to capture CTCs. These systems require large volume of blood and cannot collect the CTCs of a similar size as WBCs, which are their main limitations. Overall, the methods based on physical properties are generally inefficient, poor in purity, and lack of specificity, although the vitality is good and the cost is relatively inexpensive.

Classic CTC-related technologies based on biological properties

28Biological property-based technology is another important method for CTC detection. Based on antibody–antigen interaction, CTCs are usually positively enriched using epithelial (EpCAM) and mesenchymal (vimentin) markers as well as negatively enriched by using CD45 to deplete unwanted leukocytes. EpCAM-dependent techniques are most commonly used by researchers. The CellSearch system, the only FDA-approved device for clinical use, employs EpCAM antibody-coated ferromagnetic beads to enrich CK + /CD45-/DAPI + CTC and remove CK-/CD45 + /DAPI + WBCs. However, CTCs strongly adhere to the surface of the equipment in antibody interaction-based methods, making them difficult to be released. This deficiency can be resolved in another EpCAM-dependent, MagsWeeper system, which uses a magnetic rod to enrich CTCs and eliminate cells not bound to magnetic beads, allowing the release of CTCs for the following biochemical analysis. CanpatrolTM is another representative of the EpCAM-dependent technique, which provides morphological, cytological, and genetic characterization of individual CTCs. In summary, techniques based EpCAM are extensively-used. However, because the CTC surface antigen has high heterogenicity, CTCs that have low expression of EpCAM may not be enriched, causing inaccurate results, while methods based on physical properties do not have this limitation. Therefore, combining the advantages of different technologies or looking for CTCs with high sensitivity and specific tumor markers have gradually won the attention of researchers.

29Recently, with the development of microfluidic chips, nanomaterials, and next-generation sequencing, researchers have many advanced technologies to stimulate progress in CTC-related technologies. Importantly, researchers are trying to reach higher levels of CTC-related technologies in several key parameters: yield, purity, enrichment ratio, throughput, viability, sensitivity, specificity, release rate, accessibility for further analysis, and simplicity of equipment operation).

Recent CTC-related technologies: microfluidic-based and nanotechnology-based techniques

30Besides the classic CTC-related technologies discussed above, some newer technologies, such as microfluidic-based and nanotechnology-based techniques have been developed. Microfluidic-based cell sorting approaches use “intrinsic” (e.g., fluid dynamic forces) versus “extrinsic” external forces (e.g., magnetic, electric field, acoustic, and optical forces) to separate cells, and then select target cells from a sample of heterogeneous cells through different physical and biological properties. The CTC-chip is a silicon microfluidic platform on which the CTCs are captured on the slides of molecular marker coated posts. The CTC-chip can separate viable CTCs from whole blood without pre-labeling or processing of samples, resulting in increased cell activity and separation purity. A modified chip-based platform using gold nanoparticles on a herringbone chip (NP-HB CTC-Chip) easily detaches viable CTCs and safely releases cells for further analysis by utilizing a chemical ligand-exchange reaction with gold nanoparticles on a herringbone chip. Furthermore, the monolithic CTC-iChip has high-efficiency WBC depletion and allows the characterization of CTCs with epithelial and mesenchymal characteristics. Although these microfluidic chips have greatly contributed to the development of the detection of CTCs (i.e., improved capture efficiency, viability, and depletion of WBCs), they are not widely applied for clinical use due to limitations, which include long set-up time, high initial cost, bulky instrumentation, and limited ability to perform single-cell molecular analysis.

31In an attempt to capture CTCs in an automated manner (Table 2), Zhang et al. successfully sorted MCF-7 cells from a 5 mL volume of diluted blood within 23 m with a recovery rate of 85%. Even more remarkable, Jia et al. developed a less costly self-driving micro-cavity array chip to achieve cell loading, lysing, isothermal amplification, and signal read-out on a single chip. This novel chip can perform genetic analysis at the single-cell level, it has great potential in personalized therapy and efficacy monitoring. Furthermore, another automated and integrated microfluidic system proposed by Wang et al. is reported to achieve CTC capture and identification within 90 m. With the advantages of automation, stability, economy, and user-friendly operation, this system provides broad prospects for cancer screening and prognosis, especially in HCC. Additionally, Lee et al. invented a microfluidic-based integrated system to achieve simultaneous on-chip isolation and characterization of circulating tumors utilizing differences in magnetic field gradient and immune fluorescence. Furthermore, this novel system can differentiate on-chip eight different subtypes of heterogenic CTCs, guiding the diagnosis and prognosis of breast cancer. By combining the microfluidic technology and in situ molecular profiling techniques, the On-chip Post-processing Enabling chip platform has the ability to perform molecular analyses of single CTC from metastatic breast cancer and metastatic pancreatic cancer patients without any off-chip processes, suggesting its potential implementation of early molecular detection for cancer metastasis. Taken together, less costly automated and integrated microfluidic systems that allow easy CTCs detection and cell analysis have great clinical value.

32With the progress of nanomaterials, nanotechnology-based methods are becoming promising tools for CTC detection at an early-stage disease and for the monitoring of cancer development, as well as in vivo imaging. Nanomaterials have a large surface-to-volume ratio and allow CTC isolation at high specificity and CTC detection at high sensitivity by adsorbing numbers of targeting ligands to bind specific molecules on cancer cells. At present, studies have reported many types of nanomaterials (Table 2) for CTC detection, including magnetic nanoparticles–, gold nanoparticles–, and quantum dots–. For example, studies have shown that the utilization of tannic acid-functionalized magnetic nanoparticles, CoFe2O4@Ag magnetic nanohybrids, and peptide-based magnetic nanoparticle, enhances the capture efficiency of CTCs in breast cancer patients. Among them, peptide-based magnetic nanoparticles can distinguish epithelial and mesenchymal CTC subgroups and allow analysis at the single-cell level, the detection effects of which are supported by magnetic nanoparticles and microfluidic-based integrated systems. Regarding gold nanoparticles, there have been significant developments. For example, the cytosensor proposed by Yang et al. showed excellent analytical performance, with a wide linear range, satisfactory CTC release (93.7–97.4%), and good cell viability. Liu et al. reported that gold nanoparticle-modified black phosphorus nanosheets improved the stability in detecting CTC. Furthermore, the combination of a microfluidic system and gold nanoparticles presents a wider range of applications. Wang et al. synthesize an interfacial zinc oxide coating with a nanostructure on the microsphere surface, which increases the specific surface area and thus leads to an improved capturing efficiency of CTCs. In addition, the utilization of multicolor magnetic surface-enhanced Raman scattering nanotags and chip-based immunomagnetic separation could detect four different surface protein markers on individual tumor cells in a quantitative and simultaneous manner, thus facilitating the separation of CTC subpopulations.

33Although nanotechnology-based techniques can provide broad prospects for CTC research in various tumors in a cost-effective and simple manner, there are limitations and challenges. First, many factors (e.g., binding of nanoparticle probes, aggregation) can affect nanoparticle-based detections, leading to decreased reliability and reproducibility. Second, most nanoparticle-based assays are prepared for academic studies, and they are still unrealistic for widely clinical translation. Third, there is possible toxicity of nanoparticles.

34In the era of precision medicine, CTCs analysis has great clinical value. Tools must be sharpened first if workers are to do their job well. Therefore, CTC-related technologies are the underlying foundation to the application of CTCs in precision medicine. Herein, we reviewed previous CTCs-related technologies based on physical and biological properties, and the most recent development of techniques associated with microfluidic-based and nanoparticle-based approaches. Although there are strengths and weakness between different methods, we believe that an effective combination of these techniques may benefit CTCs research in many ways, especially the in-depth analysis and possibility in clinical applications.

Clinical applications of CTCs

35Clinically, CTCs are now used as surrogate biomarkers for many solid cancers. Numerous studies have been carried out, mainly in breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, gastric cancer, and melanoma. Although the clinical guidelines have not included the clinical use of CTCs, besides the inclusion of CTCs as part of the cM0 tumor classification (i.e., no clinical of overt metastasis but the detection of tumor cells in blood), many studies have predicted the great potential of CTCs in clinical applications. In this section, we will mainly present the role of CTCs as biomarkers for diagnosis, prognostication, and therapy monitoring in different cancers (Fig. 4).

Early diagnosis of cancer

36As a non-invasive method, CTC detection is attractive in assisting cancer diagnosis. Studies of CTCs used for early diagnosis of cancer in the past three years are listed in Table 3. A tumor lesion already has more than 109 tumor cells by the time they are detectable in patients using current imaging procedures, such as computed tomography, magnetic resonance imaging, and positron emission tomography. Diagnosis of cancers as early as possible, especially for fast-progressing cancers, is the best way to defeat them. Studies have determined that CTCs are correlated with tumor stage, but the clinical utility of CTCs in cancer detection or even in early cancer diagnosis is still a matter of debate. CTCs are considered a surrogate marker of metastatic activity, but whether metastatic dissemination of CTCs in patients occurs early during tumor formation is still controversial. However, in mouse models, early dissemination seeding metastasis has been found in breast, and pancreatic, carcinogenesis, indicating that CTC circulation is likely to be a very early event in cancer progression. In Barrière et al.’s study, CTCs were detected in 41% of T1 stage and 47% of axillary lymph node-negative breast cancer patients, both of which are early-stage breast cancer. In the study by Thery et al. the CTC positivity rate was 21% and 24% in lymph node-negative and positive breast cancer, respectively. Based on this hypothesis, CTCs can be detected earlier before the primary tumor is visible on imaging studies, while the biggest challenge of the application of CTC application in early cancer diagnosis is indeed their scarcity and isolation. The limited sensitivity of CTC detection methods hinders their use as an effective biomarker in early cancer diagnostics.

Evaluation of the cancer prognosis

37The prognostic value of CTCs has been extensively studied. CellSearch is the only FDA-approved system for CTC detection used clinically. Based on CellSearch system,–, CTCs represent an independent prognostic factor. Studies evaluating other CTC detection systems such as CanPatol, CTC-chip obtained the similar results. CTC enumeration is the main target of investigation, with a cut-off value of ≥5 for positivity, which usually indicates a worse prognosis. It is generally considered that increased CTC counts are correlated with higher likelihood of metastasis and cancer aggressiveness. In a meta-analysis pooling 2239 breast cancer patients including 21 studies, the CTC count before neoadjuvant chemotherapy had a detrimental and decremental impact on patient survival, and patients with one, two, three to four, and five or more CTCs displayed a HR of death (95% CI) of 1.09 (0.65–1.69), 2.63 (1.42–4.54), 3.83 (2.08–6.66), and 6.25 (4.34–9.09), respectively. Furthermore, elevated baseline CTCs levels were associated with inferior survival, the presence of CTC clusters often predicted poor prognosis–, and increasing CTC counts or failure to clear CTCs during treatment was also a prognostic factor for worse survival,,. Many studies have found that the molecular phenotypes of CTCs have strong prognostic value. EMT and stemness are the main molecular phenotypes of CTCs studied clinically. CTCs with expression of mesenchymal or stemness-related markers associated with inferior survival. The expression of other molecular markers, such as HER2, CD47, PD-L1 also have prognostic implications. Most studies investigate the prognostic value of CTCs at a single timepoint, while intriguingly, some studies have taken CTC dynamics into account. Magbanua et al. developed a novel latent mixture model to stratify groups with similar CTC trajectory patterns during the treatment course, and they found that analysis of serial CTCs can further stratify the patients of poor prognosis into distinct prognostic subgroups. The dynamic changes of CTCs may act as a surrogate prognosis biomarker over the long course of cancer progression. Given the rapid advancements in the accessibility and strengthening of sequencing technologies at the single-cell level, we may expect that in the future, genomic/transcriptional profiles of CTCs may serve as an outstanding prognostic marker, representing biological information that is more comprehensive and more closely related to prognosis. Studies of CTCs for predicting prognosis in recent three years are summarized in Table 3.

Monitoring of the therapeutic response

38In many clinical trials, CTCs have been used as useful biomarkers for monitoring cancer treatment responses,–, either combined with imaging examinations, serum biomarkers or alone. Researchers prefer to involve CTCs in the evaluation of therapeutic efficiency, in view of the higher sensitivity of CTCs than imaging examination in some cases. As a non-invasive method, the detection of CTCs may also contribute to avoiding frequent radiation exposure from imaging studies during the evaluation of treatment response. Most studies found a decrease or clearance in CTC counts was associated with a good therapeutic response, while the increase of CTC counts signified the opposite,. The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines are the most often used standard for evaluating therapeutic response in solid tumors. However, in some studies, changes in CTC following therapy were not correlated with RECIST responses in cancer patients. Indeed, CTCs assessment has not been included in the RECIST guidelines. Some CTCs measurement technologies have been recently developed to achieve genotyping for CTCs, which can also detect crucial gene mutations, such as ER,, HER2,, EGFR, KRAS, and TP53, thus helping clinicians in treatment personalization and resistance options at the time of tumor progression. Studies using CTCs to monitor treatment response in recent three years are summarized in Table 3.

39The great potential for CTCs in the clinical application of cancer diagnostics has emerged, although clinically, its use as a surrogate biomarker for cancer screening, treatment monitoring, and prognosis predicting is still limited. Once metastasis occurs, repeat biopsies of metastatic lesions are usually difficult to obtain, and different metastases are heterogenous even in the same patients. CTCs testing using peripheral blood samples is convenient, and may be more representative of the traits of metastatic cells, which are derived from different metastatic lesions in patients. Nevertheless, there is still a lack of guidelines for the clinical use of CTCs, such as a standardized CTCs detecting assay for different cancers, a combination diagnostic scheme with other clinical examinations, and indications for the appropriate timepoints for blood sampling.

Discussion

40Studies investigating CTCs have the great potential to reveal the fundamental processes of metastases, including the mechanisms involved in extravasation of CTCs from the primary tumor, how CTCs interact with blood cells to survive in the circulatory microenvironment, and how CTCs intravasate into the distant metastatic site to initiate new lesions. Significant molecular traits of CTCs can greatly contribute to identify targets for anti-metastatic therapies. Only a small proportion of CTCs can finally generate metastases, thus studies focusing on these strongly metastatic CTCs may provide deeper insights into CTCs-related therapeutic targets.

41Various CTCs detecting technologies have emerged, however, the sensitivity and specificity of these technologies still need to be further improved. Epithelial marker-based CTC detection technology, such as the CellSearch system has opened a new era for CTC analysis and clinical applications, but their drawbacks are rapidly being acknowledged and appreciated by researchers. EMT is a crucial trait of metastatic cancer cells, indicating insufficient capture efficiency of epithelial marker-based CTC detection technology. However, mesenchymal marker-based detection technologies may also be contaminated by non-CTCs, such as tumor-associated fibroblasts and endothelial clusters, which induce the risk of false positivity. Nevertheless, it is intriguing that recent studies have reported that those non-cancerous tumor-derived cells presented in cancer patients are also important surrogate biomarkers for cancer patients. Cancer-type-specific molecular markers for CTCs are likely another option, as CTCs of different cancer types possess different molecular markers. However, the sensitivity and specificity of known cancer-type-specific CTC markers are not satisfactory. Physical-property-based CTC detection technologies also have the problem of contamination by non-CTCs, especially for those with similar physical properties as CTCs. Microfluidic-based and nanotechnology-based CTC detection technologies have become popular in recent years, while the efficiency of these technologies still needs further large-scale clinical validation. High cell detection efficiency and contamination removal capability are the two key strengths of a successful CTC detection technology, while substantial technical optimization of CTC detection is urgently needed to achieve these requirements.

42Comprehensive characterization of CTCs is lacking. The limited amount of genomic DNA, RNA, and protein content of CTCs is a bottleneck for exploring their genome, transcriptome, epigenome, and proteome properties. Nonetheless, the emerging genome and transcriptome studies of CTCs have recently profited from the fast-evolving technology of single-cell sequencing, while the proteome studies of CTCs are still elusive due to the very limited technologies for proteome exploring at a single-cell level. However, the study of the CTC proteome is imminent, not only because it can provide a picture of the biological characterization of CTCs, but also because it can help to discover CTC-specific membrane proteins which may help optimize CTC detection.

43As for the solid tumor microenvironment, the blood microenvironment around CTCs also plays a significant role in tumor survival and invasion capacity. However, knowledge of the underlying mechanisms behind the survival of CTCs is still limited, as it is a complex process that involves not only shear forces and fluid mechanics but also soluble factors and tumor-associated extracellular vesicles, which are not detailed here. Furthermore, it remains to be confirmed whether CTC clusters are more suitable for interacting with other blood components or adapting to shear forces than single migratory CTCs. If combined with specific biomarkers for strategically detecting CTCs and the interaction of CTCs with associated peripheral blood cells, we could improve the clinical practicability and monitoring power of CTCs by obtaining more comprehensive information on tumor burden and immune status of patients.

44Although CTCs have shown initial promise in clinical applications, many challenges must still be overcome before CTC analysis can be widely applied in the clinic. Today, the clinical application of CTCs mainly depends on the analysis of CTC cell enumeration and molecular phenotypes. A more comprehensive characterization of CTCs based on their genome, transcriptome, and proteome with high-throughput sequencing will further benefit clinical application, but also add to the complexity and difficulty of data analysis. CTCs will be a crucial component of “Precision medicine” in the future, as the phenotypic, genotypic, and functional characterization can provide an opportunity to study drug susceptibility that is related to metastasis. The genome and transcriptome analysis of CTCs can unveil potential drug targets. Viable CTCs for drug sensitivity/resistance testing over the therapy course can guide precision medication. However, the culture of CTCs is very challenging: (1) limited methods are available to isolate viable CTCs, which also yield low numbers of CTCs and (2) a favorable circulatory microenvironment for CTC survival is difficult to mimic. Very limited CTC-derived cell lines from cancer patients have been established. Optimization of CTC culture conditions will be needed.

45Furthermore, CTCs, circulating tumor DNA (ctDNA), and exosomes are all present in liquid biopsy samples. An exploration of the advantages and disadvantages of each substrate present in the liquid biopsies, and how to better incorporate them into clinical application is needed to achieve more precise diagnoses. Among liquid biopsy methods, CTCs have tremendous advantages, as isolated CTCs can be viable, which can optimize CTC-derived explants or three-dimensional organoid cultures for functional testing or for drug-screening assays. The study of CTCs is attractive, and CTC detection may likely become an essential component of cancer management in the future. As the picture becomes clearer, we are fully confident about the promising potentials of CTCs.

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Not in our library10.1016/j.canlet.2013.02.015
69.
Buim ME, et al. Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer. Cancer Biol. Ther. 2015;16:1289-1295.
Not in our library10.1080/15384047.2015.1070991
70.
KRAS genotypic changes of circulating tumor cells during treatment of patients with metastatic colorectal cancer. · 2014
Not checked
71.
KRAS mutation analysis of single circulating tumor cells from patients with metastatic colorectal cancer · 2017
Not checked
72.
Kulemann B, et al. Pancreatic cancer: circulating tumor cells and primary tumors show heterogeneous KRAS mutations. Sci. Rep. 2017;7:4510.
Not in our library10.1038/s41598-017-04601-z
73.
Lohr JG, et al. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat. Biotechnol. 2014;32:479-484.
Not in our library10.1038/nbt.2892
74.
Faugeroux V, et al. An accessible and unique insight into metastasis mutational content through whole-exome sequencing ofcirculating tumor cells in metastatic prostate cancer. Eur. Urol. Oncol. 2020;3:498-508.
Not in our library10.1016/j.euo.2018.12.005
75.
Deng G, et al. Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow. BMC Cancer. 2014;14:456-467.
Not in our library10.1186/1471-2407-14-456
76.
Fernandez V, et al. TP53 mutations detected in circulating tumor cells present in the blood of metastatic triple negative breastcancer patients. Breast Cancer Res. 2014;16:445.
Not in our library10.1186/s13058-014-0445-3
77.
Kelley RK, et al. Circulating tumor cells in hepatocellular carcinoma: a pilot study of detection, enumeration, and nextgenerationsequencing in cases and controls. BMC Cancer. 2015;15:206.
Not in our library10.1186/s12885-015-1195-z
78.
Ni X, et al. Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. Proc. Natl Acad. Sci. USA. 2013;110:21083-21088.
Not in our library10.1073/pnas.1320659110
79.
Carter L, et al. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients withchemosensitive and chemorefractory small-cell lung cancer. Nat. Med. 2017;23:114-119.
Not in our library10.1038/nm.4239
80.
Paoletti C, et al. Comprehensive mutation and copy number profiling in archived circulating breast cancer tumor cellsdocuments heterogeneous resistance mechanisms. Cancer Res. 2018;78:1110-1122.
Not in our library10.1158/0008-5472.can-17-2686
81.
Ortolan E, et al. Blood-based genomics of triple-negative breast cancer progression in patients treated with neoadjuvantchemotherapy. ESMO Open. 2021;6:100086.
Not in our library10.1016/j.esmoop.2021.100086
82.
Lambros MB, et al. Single-cell analyses of prostate cancer liquid biopsies acquired by apheresis. Clin. Cancer Res.:. J. Am. Assoc. Cancer Res. 2018;24:5635-5644.
Not in our library10.1158/1078-0432.ccr-18-0862
83.
Gupta S, et al. Whole genomic copy number alterations in circulating tumor cells from men with abiraterone orenzalutamide-resistant metastatic castration-resistant prostate cancer. Clin. Cancer Res.:. J. Am. Assoc. Cancer Res. 2017;23:1346-1357.
Not in our library10.1158/1078-0432.ccr-16-1211
84.
Malihi PD, et al. Single-cell circulating tumor cell analysis reveals genomic instability as a distinctive feature of aggressiveprostate cancer. Clin. Cancer Res.:. J. Am. Assoc. Cancer Res. 2020;26:4143-4153.
Not in our library10.1158/1078-0432.ccr-19-4100
85.
Pailler E, et al. Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-celllung cancer. J. Clin. Oncol. 2013;31:2273-2281.
Not in our library10.1200/jco.2012.44.5932
86.
Mayer JA, et al. FISH-based determination of HER2 status in circulating tumor cells isolated with the microfluidic CEEplatform. Cancer Genet. 2011;204:589-595.
Not in our library10.1016/j.cancergen.2011.10.011
87.
Frithiof H, Aaltonen K, Ryden L. A FISH-based method for assessment of HER-2 amplification status in breast cancercirculating tumor cells following CellSearch isolation. OncoTargets Ther. 2016;9:7095-7103.
Not in our library10.2147/ott.s118502
88.
Gkountela S, et al. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell. 2019;176:98-112.e114.
Not in our library10.1016/j.cell.2018.11.046
89.
Dong Y, Wang Z, Shi Q. Liquid biopsy based single-cell transcriptome profiling characterizes heterogeneity ofdisseminated tumor cells from lung adenocarcinoma. Proteomics. 2020;20:e1900224.
Not in our library10.1002/pmic.201900224
90.
Magbanua MJM, et al. Expanded genomic profiling of circulating tumor cells in metastatic breast cancer patients to assessbiomarker status and biology over time (CALGB 40502 and CALGB 40503, Alliance). Clin. Cancer Res.:. J. Am. Assoc. Cancer Res. 2018;24:1486-1499.
Not in our library10.1158/1078-0432.ccr-17-2312
91.
Hydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells · 2019
No notice
92.
Miyamoto D, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science. 2015;349:1351-1356.
Not in our library10.1126/science.aab0917
93.
Barbazan J, et al. Molecular characterization of circulating tumor cells in human metastatic colorectal cancer. PloS One. 2012;7:e40476.
Not in our library10.1371/journal.pone.0040476
94.
Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients · 2011
No notice
95.
Balasubramanian P, et al. Multiparameter analysis, including EMT markers, on negatively enriched blood samples frompatients with squamous cell carcinoma of the head and neck. PLoS One. 2012;7:e42048.
Not in our library10.1371/journal.pone.0042048
96.
Theodoropoulos PA, et al. Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients withbreast cancer. Cancer Lett. 2010;288:99-106.
Not in our library10.1016/j.canlet.2009.06.027
97.
Armstrong AJ, et al. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelialand mesenchymal markers. Mol. Cancer Res. 2011;9:997-1007.
Not in our library10.1158/1541-7786.mcr-10-0490
98.
Liu X, et al. Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source ofmetastasis. Sci. Adv. 2019;5:eaav4275.
Not in our library10.1126/sciadv.aav4275
99.
Thiery JP, Lim CT. Tumor dissemination: an EMT affair. Cancer Cell. 2013;23:272-273.
Not in our library10.1016/j.ccr.2013.03.004
100.
Pecot CV, et al. A novel platform for detection of CK+ and CK- CTCs. Cancer Discov. 2011;1:580-586.
Not in our library10.1158/2159-8290.cd-11-0215
101.
Sun YF, et al. Circulating tumor cells from different vascular sites exhibit spatial heterogeneity in epithelial andmesenchymal composition and distinct clinical significance in hepatocellular carcinoma. Clin. Cancer Res.:. J. Am. Assoc. Cancer Res. 2018;24:547-559.
Not in our library10.1158/1078-0432.ccr-17-1063
102.
Xu L, et al. The novel association of circulating tumor cells and circulating megakaryocytes with prostate cancer prognosis. Clin. Cancer Res. 2017;23:5112-5122.
Not in our library10.1158/1078-0432.ccr-16-3081
103.
Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications forcancer. Nat. Rev. Mol. Cell Bio. 2019;20:69-84.
Not in our library10.1038/s41580-018-0080-4
104.
Guan Y, et al. Identification of key genes and functions of circulating tumor cells in multiple cancers through bioinformaticanalysis. BMC Med. Genom. 2020;13:140.
Not in our library10.1186/s12920-020-00795-w
105.
Tashireva LA, et al. Heterogeneous manifestations of epithelial-mesenchymal plasticity of circulating tumor cells in breast cancer patients. Int. J. Mol. Sci. 2021;22:2504-2521.
Not in our library10.3390/ijms22052504
106.
Xin Y, Li K, Yang M, Tan Y. Fluid shear stress induces EMT of circulating tumor cells via jnk signaling in favor of their survival during hematogenous dissemination. Int. J. Mol. Sci. 2020;21:8115-8130.
Not in our library10.3390/ijms21218115
107.
Horimoto Y, et al. Analysis of circulating tumour cell and the epithelial mesenchymal transition (EMT) status duringeribulin-based treatment in 22 patients with metastatic breast cancer: a pilot study. J. Transl. Med. 2018;16:287.
Not in our library10.1186/s12967-018-1663-8
108.
Guan XW, et al. The prognostic and therapeutic implications of circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers in the first-line chemotherapy of HER2-negative metastatic breast cancer. CancerCommun. 2019;39:1-10.
Not in our library10.1186/s40880-018-0346-4
109.
Lindsay CR, et al. A prospective examination of circulating tumor cell profiles in non-small-cell lung cancer molecularsubgroups. Ann. Oncol. 2017;28:1523-1531.
Not in our library10.1093/annonc/mdx156
110.
Satelli A, et al. Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clin. Cancer Res. 2015;21:899-906.
Not in our library10.1158/1078-0432.ccr-14-0894
111.
Brechbuhl HM, et al. Analysis of circulating breast cancer cell heterogeneity and interactions with peripheral bloodmononuclear cells. Mol. Carcinog. 2020;59:1129-1139.
Not in our library10.1002/mc.23242
112.
Miklikova S, et al. Inflammation-based scores increase the prognostic value of circulating tumor cells in primary breast cancer. Cancers. 2020;12:1134-1148.
Not in our library10.3390/cancers12051134
113.
Wu Y, et al. SUMOylation represses Nanog expression via modulating transcription factors Oct4 and Sox2. PloS One. 2012;7:e39606.
Not in our library10.1371/journal.pone.0039606
114.
Zhang R, et al. Co-expression of stem cell and epithelial mesenchymal transition markers in circulating tumor cells ofbladder cancer patients. OncoTargets Ther. 2020;13:10739-10748.
Not in our library10.2147/ott.s259240
115.
Zhao P, et al. Establishment and characterization of a CTC cell line from peripheral blood of breast cancer patient. J. Cancer. 2019;10:6095-6104.
Not in our library10.7150/jca.33157
116.
Wan S, et al. New labyrinth microfluidic device detects circulating tumor cells expressing cancer stem cell marker andcirculating tumor microemboli in hepatocellular carcinoma. Sci. Rep. 2019;9:18575.
Not in our library10.1038/s41598-019-54960-y
117.
Liu T, et al. Circulating glioma cells exhibit stem cell-like properties. Cancer Res. 2018;78:6632-6642.
Not in our library10.1158/0008-5472.can-18-0650
118.
Yin J, et al. Circulating tumor cells enriched by the depletion of leukocytes with bi-antibodies in non-small cell lung cancer:potential clinical application. PloS One. 2015;10:e0137076.
Not in our library10.1371/journal.pone.0137076
119.
Jin J, Tang K, Xin Y, Zhang T, Tan Y. Hemodynamic shear flow regulates biophysical characteristics and functionsof circulating breast tumor cells reminiscent of brain metastasis. Soft Matter. 2018;14:9528-9533.
Not in our library10.1039/c8sm01781f
120.
Hydrodynamic shear stress promotes epithelial-mesenchymal transition by downregulating ERK and GSK3β activities · 2019
Not checked
121.
Follain G, et al. Fluids and their mechanics in tumour transit: shaping metastasis. Nat. Rev. Cancer. 2020;20:107-124.
Not in our library10.1038/s41568-019-0221-x
122.
Strilic B, Offermanns S. Intravascular survival and extravasation of tumor cells. Cancer cell. 2017;32:282-293.
Not in our library10.1016/j.ccell.2017.07.001
123.
Rejniak KA. Circulating tumor cells: when a solid tumor meets a fluid microenvironment. Adv. Exp. Med. Biol. 2016;936:93-106.
Not in our library10.1007/978-3-319-42023-3_5
124.
Garrido-Navas C, et al. Cooperative and escaping mechanisms between circulating tumor cells and blood constituents. Cells. 2019;8:1382-1391.
Not in our library10.3390/cells8111382
125.
Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 2019;16:601-620.
Not in our library10.1038/s41571-019-0222-4
126.
Aliustaoglu M, et al. The effect of peripheral blood values on prognosis of patients with locally advanced gastric cancerbefore treatment. Med. Oncol. 2010;27:1060-1065.
Not in our library10.1007/s12032-009-9335-4
127.
Hu S, et al. The preoperative peripheral blood monocyte count is associated with liver metastasis and overall survival incolorectal cancer patients. PloS One. 2016;11:e0157486.
Not in our library10.1371/journal.pone.0157486
128.
Wang Y, et al. Circulating neutrophils predict poor survival for HCC and promote HCC progression through p53 andSTAT3 signaling pathway. J. Cancer. 2020;11:3736-3744.
Not in our library10.7150/jca.42953
129.
Stott SL, et al. Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc. Natl Acad. Sci. USA. 2010;107:18392-18397.
Not in our library10.1073/pnas.1012539107
130.
Szczerba BM, et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. 2019;566:553-557.
Not in our library10.1038/s41586-019-0915-y
131.
Hattar K, et al. Interactions between neutrophils and non-small cell lung cancer cells: enhancement of tumor proliferationand inflammatory mediator synthesis. Cancer Immunol., Immunother. 2014;63:1297-1306.
Not in our library10.1007/s00262-014-1606-z
132.
Spicer JD, et al. Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells. Cancer Res. 2012;72:3919-3927.
Not in our library10.1158/0008-5472.can-11-2393
133.
Strell C, Lang K, Niggemann B, Zaenker KS, Entschladen F. Surface molecules regulating rolling and adhesion toendothelium of neutrophil granulocytes and MDA-MB-468 breast carcinoma cells and their interaction. Cell. Mol. life Sci. 2007;64:3306-3316.
Not in our library10.1007/s00018-007-7402-6
134.
Huh SJ, Liang S, Sharma A, Dong C, Robertson GP. Transiently entrapped circulating tumor cells interact withneutrophils to facilitate lung metastasis development. Cancer Res. 2010;70:6071-6082.
Not in our library10.1158/0008-5472.can-09-4442
135.
Rowson-Hodel AR, et al. Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficientmetastasis in a mouse model of breast cancer. Oncogene. 2018;37:197-207.
Not in our library10.1038/onc.2017.327
136.
Chen MB, et al. Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumorcell extravasation. Proc. Natl Acad. Sci. USA. 2018;115:7022-7027.
Not in our library10.1073/pnas.1715932115
137.
The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis · 2020
No notice
138.
Cools-Lartigue J, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Investig. 2013;123:3446-3458.
Not in our library10.1172/jci67484
139.
Najmeh S, et al. Neutrophil extracellular traps sequester circulating tumor cells via ?1-integrin mediated interactions. Int. J. Cancer. 2017;140:2321-2330.
Not in our library10.1002/ijc.30635
140.
Tohme S, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgicalstress. Cancer Res. 2016;76:1367-1380.
Not in our library10.1158/0008-5472.can-15-1591
141.
Albrengues J, et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018;361:1353-1367.
Not in our library10.1126/science.aao4227
142.
Xiao Y, et al. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophilextracellular trap formation. Cancer Cell. 2021;39:423-437.e427.
Not in our library10.1016/j.ccell.2020.12.012
143.
Yang L, et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature. 2020;583:133-138.
Not in our library10.1038/s41586-020-2394-6
144.
Zhang J, et al. Circulating tumor-associated neutrophils (cTAN) contribute to circulating tumor cell survival by suppressingperipheral leukocyte activation. Tumour Biol.: J. Int. Soc. Oncodev. Biol. Med. 2016;37:5397-5404.
Not in our library10.1007/s13277-015-4349-3
145.
Spiegel A, et al. Neutrophils suppress intraluminal nk cell-mediated tumor cell clearance and enhance extravasation ofdisseminated carcinoma cells. Cancer Discov. 2016;6:630-649.
Not in our library10.1158/2159-8290.cd-15-1157
146.
Kumagai Y, et al. Surgical stress increases circulating low-density neutrophils which may promote tumor recurrence. J. Surg. Res. 2020;246:52-61.
Not in our library10.1016/j.jss.2019.08.022
147.
Coffelt SB, et al. IL-17-producing ?? T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522:345-348.
Not in our library10.1038/nature14282
148.
Doak GR, Schwertfeger KL, Wood DK. Distant relations: macrophage functions in the metastatic niche. TrendsCancer. 2018;4:445-459.
Not in our library10.1016/j.trecan.2018.03.011
149.
Hamilton G, Rath B, Klameth L, Hochmair MJ. Small cell lung cancer: recruitment of macrophages by circulatingtumor cells. Oncoimmunology. 2016;5:e1093277.
Not in our library10.1080/2162402x.2015.1093277
150.
Hamilton G, Rath B. Circulating tumor cell interactions with macrophages: implications for biology and treatment. Transl. Lung Cancer Res. 2017;6:418-430.
Not in our library10.21037/tlcr.2017.07.04
151.
Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis · 2019
No notice
152.
Osmulski PA, et al. Contacts with macrophages promote an aggressive nanomechanical phenotype of circulating tumorcells in prostate cancer. Cancer Res. 2021;81:4110-4123.
Not in our library10.1158/0008-5472.can-20-3595
153.
Shabo I, et al. Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained bycellular interaction. BMC Cancer. 2015;15:922.
Not in our library10.1186/s12885-015-1935-0
154.
Macrophage-tumor cell fusions from peripheral blood of melanoma patients. · 2015
Not checked
155.
Clawson GA, et al. “Stealth dissemination” of macrophage-tumor cell fusions cultured from blood of patients withpancreatic ductal adenocarcinoma. PloS One. 2017;12:e0184451.
Not in our library10.1371/journal.pone.0184451
156.
Manjunath Y, et al. Tumor-cell-macrophage fusion cells as liquid biomarkers and tumor enhancers in cancer. Int. J. Mol. Sci. 2020;21:1872.
Not in our library10.3390/ijms21051872
157.
Gast CE, et al. Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage andsurvival. Sci. Adv. 2018;4:eaat7828.
Not in our library10.1126/sciadv.aat7828
158.
Manjunath Y, et al. Circulating giant tumor-macrophage fusion cells are independent prognosticators in patients withNSCLC. J. Thorac. Oncol.:. Publ. Int. Assoc. Study Lung Cancer. 2020;15:1460-1471.
Not in our library10.1016/j.jtho.2020.04.034
159.
Role of platelets and platelet receptors in cancer metastasis · 2018
No notice
160.
Gaertner F, Massberg S. Patrolling the vascular borders: platelets in immunity to infection and cancer. Nat. Rev. Immunol. 2019;19:747-760.
Not in our library10.1038/s41577-019-0202-z
161.
Thomas GM, et al. Tissue factor expressed by circulating cancer cell-derived microparticles drastically increases theincidence of deep vein thrombosis in mice. J. thrombosis Haemost. 2015;13:1310-1319.
Not in our library10.1111/jth.13002
162.
Stark K, et al. Distinct pathogenesis of pancreatic cancer microvesicle-associated venous thrombosis identifies newantithrombotic targets in vivo. Arteriosclerosis, thrombosis, Vasc. Biol. 2018;38:772-786.
Not in our library10.1161/atvbaha.117.310262
163.
Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelialmesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20:576-590.
Not in our library10.1016/j.ccr.2011.09.009
164.
Guo Y, Cui W, Pei Y, Xu D. Platelets promote invasion and induce epithelial to mesenchymal transition in ovariancancer cells by TGF-? signaling pathway. Gynecol. Oncol. 2019;153:639-650.
Not in our library10.1016/j.ygyno.2019.02.026
165.
Xiong G, et al. Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction. Proc. Natl Acad. Sci. USA. 2020;117:3748-3758.
Not in our library10.1073/pnas.1911951117
166.
Egan K, Cooke N, Kenny D. Living in shear: platelets protect cancer cells from shear induced damage. Clin. Exp. Metastasis. 2014;31:697-704.
Not in our library10.1007/s10585-014-9660-7
167.
Platelets reduce anoikis and promote metastasis by activating YAP1 signaling · 2017
No notice
168.
Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impededby platelets. Cancer Res. 1999;59:1295-1300.
Not in our library
169.
Placke T, et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumorreactivity of natural killer immune cells. Cancer Res. 2012;72:440-448.
Not in our library10.1158/0008-5472.can-11-1872
170.
Kopp HG, Placke T, Salih HR. Platelet-derived transforming growth factor-beta down-regulates NKG2D therebyinhibiting natural killer cell antitumor reactivity. Cancer Res. 2009;69:7775-7783.
Not in our library10.1158/0008-5472.can-09-2123
171.
Maurer S, et al. Platelet-mediated shedding of NKG2D ligands impairs NK cell immune-surveillance of tumor cells. Oncoimmunology. 2018;7:e1364827.
Not in our library10.1080/2162402x.2017.1364827
172.
Placke T, Salih HR, Kopp HG. GITR ligand provided by thrombopoietic cells inhibits NK cell antitumor activity. J. Immunol. 2012;189:154-160.
Not in our library10.4049/jimmunol.1103194
173.
Ren J, et al. Platelet TLR4-ERK5 axis facilitates net-mediated capturing of circulating tumor cells and distant metastasisafter surgical stress. Cancer Res. 2021;81:2373-2385.
Not in our library10.1158/0008-5472.can-20-3222
174.
Rachidi S, et al. Platelets subvert T cell immunity against cancer via GARP-TGFβ axis. Sci. Immunol. 2017;2:7911-7937.
Not in our library10.1126/sciimmunol.aai7911
175.
Xiang B, et al. Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via thecyclooxygenase 1 signalling pathway. Nat. Commun. 2013;4:2657.
Not in our library10.1038/ncomms3657
176.
Cancer Cell Adhesion and Metastasis: Selectins, Integrins, and the Inhibitory Potential of Heparins · 2012
No notice
177.
Lonsdorf AS, et al. Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis. J. Biol. Chem. 2012;287:2168-2178.
Not in our library10.1074/jbc.m111.269811
178.
Coupland LA, Chong BH, Parish CR. Platelets and P-selectin control tumor cell metastasis in an organ-specificmanner and independently of NK cells. Cancer Res. 2012;72:4662-4671.
Not in our library10.1158/0008-5472.can-11-4010
179.
Schumacher D, Strilic B, Sivaraj KK, Wettschureck N, Offermanns S. Platelet-derived nucleotides promote tumorcelltransendothelial migration and metastasis via P2Y2 receptor. Cancer Cell. 2013;24:130-137.
Not in our library10.1016/j.ccr.2013.05.008
180.
Mammadova-Bach E, et al. Platelet integrin ?6?1 controls lung metastasis through direct binding to cancer cell-derivedADAM9. JCI Insight. 2016;1:e88245.
Not in our library10.1172/jci.insight.88245
181.
Ward Y, et al. Platelets promote metastasis via binding tumor CD97 leading to bidirectional signaling that coordinatestransendothelial migration. Cell Rep. 2018;23:808-822.
Not in our library10.1016/j.celrep.2018.03.092
182.
Mammadova-Bach E, et al. Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derivedgalectin-3. Blood. 2020;135:1146-1160.
Not in our library10.1182/blood.2019002649
183.
Xu Y, et al. Blockade of platelets using tumor-specific NO-releasing nanoparticles prevents tumor metastasis and reversestumor immunosuppression. ACS Nano. 2020;14:9780-9795.
Not in our library10.1021/acsnano.0c01687
184.
Cassetta L, et al. Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation. J. Immunother. Cancer. 2020;8:1223-1235.
Not in our library10.1136/jitc-2020-001223
185.
Liu Q, Liao Q, Zhao Y. Myeloid-derived suppressor cells (MDSC) facilitate distant metastasis of malignancies byshielding circulating tumor cells (CTC) from immune surveillance. Med. Hypotheses. 2016;87:34-39.
Not in our library10.1016/j.mehy.2015.12.007
186.
Jiménez-Cortegana C, et al. Circulating myeloid-derived suppressor cells and regulatory T cells as immunological biomarkers in refractory/relapsed diffuse large B-cell lymphoma: translational results from the R2-GDP-GOTEL trial. J. Immunother. Cancer. 2021;9:2323-2334.
Not in our library10.1136/jitc-2020-002323
187.
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling · 2019
No notice
188.
Chen X, Song E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat. Rev. Drug Discov. 2019;18:99-115.
Not in our library10.1038/s41573-018-0004-1
189.
Gaggioli C, et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading andfollowing cells. Nat. Cell Biol. 2007;9:1392-1400.
Not in our library10.1038/ncb1658
190.
Duda DG, et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl Acad. Sci. USA. 2010;107:21677-21682.
Not in our library10.1073/pnas.1016234107
191.
Ortiz-Otero N, et al. Cancer associated fibroblasts confer shear resistance to circulating tumor cells during prostate cancermetastatic progression. Oncotarget. 2020;11:1037-1050.
Not in our library10.18632/oncotarget.27510
192.
Ao Z, et al. Identification of cancer-associated fibroblasts in circulating blood from patients with metastatic breast cancer. Cancer Res. 2015;75:4681-4687.
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193.
Jiang, R. et al. Rapid isolation of circulating cancer associated fibroblasts by acoustic microstreaming for assessing metastatic propensity of breast cancer patients. Lab. Chip 969-981 (2020).
Not in our library10.1039/d0lc00969e
194.
Shen Z, Wu A, Chen X. Current detection technologies for circulating tumor cells. Chem. Soc. Rev. 2017;46:2038-2056.
Not in our library10.1039/c6cs00803h
195.
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196.
Harouaka RA, et al. Flexible micro spring array device for high-throughput enrichment of viable circulating tumor cells. Clin. Chem. 2014;60:323-333.
Not in our library10.1373/clinchem.2013.206805
197.
Rosenberg R, et al. Comparison of two density gradient centrifugation systems for the enrichment of disseminated tumorcells in blood. Cytometry. 2002;49:150-158.
Not in our library10.1002/cyto.10161
198.
Gupta V, et al. ApoStream(), a new dielectrophoretic device for antibody independent isolation and recovery of viablecancer cells from blood. Biomicrofluidics. 2012;6:24133.
Not in our library10.1063/1.4731647
199.
Sajay BN, et al. Microfluidic platform for negative enrichment of circulating tumor cells. Biomed. Microdevices. 2014;16:537-548.
Not in our library10.1007/s10544-014-9856-2
200.
Allard WJ, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects orpatients with nonmalignant diseases. Clin. Cancer Res. 2004;10:6897-6904.
Not in our library10.1158/1078-0432.ccr-04-0378
201.
Talasaz AH, et al. Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood usinga magnetic sweeper device. Proc. Natl Acad. Sci. USA. 2009;106:3970-3975.
Not in our library10.1073/pnas.0813188106
202.
Wu S, et al. Enrichment and enumeration of circulating tumor cells by efficient depletion of leukocyte fractions. Clin. Chem. Lab. Med. 2015;53:337.
Not in our library10.1515/cclm-2015-5000
203.
Nasiri R, et al. Microfluidic-based approaches in targeted cell/particle separation based on physical properties: fundamentalsand applications. Small. 2020;16:e2000171.
Not in our library10.1002/smll.202000171
204.
Nagrath S, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235-1239.
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205.
Park MH, et al. Enhanced isolation and release of circulating tumor cells using nanoparticle binding and ligand exchangein a microfluidic chip. J. Am. Chem. Soc. 2017;139:2741-2749.
Not in our library10.1021/jacs.6b12236
206.
Monolithic Chip for High-throughput Blood Cell Depletion to Sort Rare Circulating Tumor Cells · 2017
No notice
207.
Zhang X, Zhu Z, Xiang N, Long F, Ni Z. Automated microfluidic instrument for label-free and high-throughput cellseparation. Anal. Chem. 2018;90:4212-4220.
Not in our library10.1021/acs.analchem.8b00539
208.
Jia Z, et al. Single-cell genetic analysis of lung tumor cells based on self-driving micro-cavity array chip. Talanta. 2021;226:122172.
Not in our library10.1016/j.talanta.2021.122172
209.
Wang J, et al. A fully automated and integrated microfluidic system for efficient ctc detection and its application inhepatocellular carcinoma screening and prognosis. ACS Appl. Mater. Interfaces. 2021;13:30174-30186.
Not in our library10.1021/acsami.1c06337
210.
Lee J, Kwak B. Simultaneous on-chip isolation and characterization of circulating tumor cell sub-populations. Biosens. Bioelectron. 2020;168:112564.
Not in our library10.1016/j.bios.2020.112564
211.
Lee AC, et al. OPENchip: an on-chip in situ molecular profiling platform for gene expression analysis and oncogenicmutation detection in single circulating tumour cells. Lab Chip. 2020;20:912-922.
Not in our library10.1039/c9lc01248f
212.
Nanotechnology in cancer diagnosis: progress, challenges and opportunities · 2019
No notice
213.
Jia F, et al. Novel peptide-based magnetic nanoparticle for mesenchymal circulating tumor cells detection. Anal. Chem. 2021;93:5670-5675.
Not in our library10.1021/acs.analchem.1c00577
214.
Ding P, et al. Tannic acid (TA)-functionalized magnetic nanoparticles for EpCAM-independent circulating tumor cell(CTC) isolation from patients with different cancers. ACS Appl. Mater. Interfaces. 2021;13:3694-3700.
Not in our library10.1021/acsami.0c20916
215.
Li F, et al. Nondestructive capture, release, and detection of circulating tumor cells with cystamine-mediated folic aciddecorated magnetic nanospheres. J. Mater. Chem. B. 2020;8:9971-9979.
Not in our library10.1039/d0tb01091j
216.
Vajhadin F, et al. MXene-based cytosensor for the detection of HER2-positive cancer cells using CoFe2O4@Ag magneticnanohybrids conjugated to the HB5 aptamer. Biosens. Bioelectron. 2021;195:113626.
Not in our library10.1016/j.bios.2021.113626
217.
Wilson RE, et al. Immunomagnetic capture and multiplexed surface marker detection of circulating tumor cells withmagnetic multicolor surface-enhanced Raman scattering nanotags. ACS Appl. Mater. Interfaces. 2020;12:47220-47232.
Not in our library10.1021/acsami.0c12395
218.
Liu S, Luo J, Jiang X, Li X, Yang M. Gold nanoparticle-modified black phosphorus nanosheets with improvedstability for detection of circulating tumor cells. Mikrochim. Acta. 2020;187:397.
Not in our library10.1007/s00604-020-04367-8
219.
Dou B, Xu L, Jiang B, Yuan R, Xiang Y. Aptamer-functionalized and gold nanoparticle array-decorated magneticgraphene nanosheets enable multiplexed and sensitive electrochemical detection of rare circulating tumor cells in whole blood. Anal. Chem. 2019;91:10792-10799.
Not in our library10.1021/acs.analchem.9b02403
220.
Sheng W, Chen T, Tan W, Fan ZH. Multivalent DNA nanospheres for enhanced capture of cancer cells inmicrofluidic devices. ACS Nano. 2013;7:7067-7076.
Not in our library10.1021/nn4023747
221.
Gold nanorods-mediated efficient synergistic immunotherapy for detection and inhibition of postoperative tumor recurrence · 2021
Not checked
222.
Zhang J, et al. Sensitive signal amplifying a diagnostic biochip based on a biomimetic periodic nanostructure for detectingcancer exosomes. ACS Appl. Mater. Interfaces. 2020;12:33473-33482.
Not in our library10.1021/acsami.0c06785
223.
Cui H, et al. Rapid and efficient isolation and detection of circulating tumor cells based on ZnS:Mn(2+) quantum dots andmagnetic nanocomposites. Talanta. 2019;202:230-236.
Not in our library10.1016/j.talanta.2019.05.001
224.
Yang W, et al. Reversible capturing and voltammetric determination of circulating tumor cells using two-dimensionalnanozyme based on PdMo decorated with gold nanoparticles and aptamer. Mikrochim. Acta. 2021;188:319.
Not in our library10.1007/s00604-021-04927-6
225.
Su Y, et al. Antibody-functional microsphere-integrated filter chip with inertial microflow for size-immune-capturing anddigital detection of circulating tumor cells. ACS Appl Mater. Interfaces. 2019;11:29569-29578.
Not in our library10.1021/acsami.9b09655
226.
Husemann Y, et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008;13:58-68.
Not in our library10.1016/j.ccr.2007.12.003
227.
Hosseini H, et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016;540:552-558.
Not in our library10.1038/nature20785
228.
Rhim AD, et al. Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology. 2014;146:647-651.
Not in our library10.1053/j.gastro.2013.12.007
229.
Yamaguchi J, et al. Premalignant pancreatic cells seed stealth metastasis in distant organs in mice. Oncogene. 2021;40:2273-2284.
Not in our library10.1038/s41388-021-01706-8
230.
Barrière G, Riouallon A, Renaudie J, Tartary M, Rigaud M. Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis. BMC Cancer. 2012;12:114-120.
Not in our library10.1186/1471-2407-12-114
231.
Thery L, et al. Circulating tumor cells in early breast. Cancer JNCI Cancer Spectr. 2019;3:pkz026.
Not in our library10.1093/jncics/pkz026
232.
Paoletti C, et al. Circulating tumor cell clusters in patients with metastatic breast cancer: a SWOG S0500 translationalmedicine study. Clin. Cancer Res. 2019;25:6089-6097.
Not in our library10.1158/1078-0432.ccr-19-0208
233.
Magbanua MJM, et al. Synchronous detection of circulating tumor cells in blood and disseminated tumor cells in bonemarrow predicts adverse outcome in early breast cancer. Clin. Cancer Res. 2019;25:5388-5397.
Not in our library10.1158/1078-0432.ccr-18-3888
234.
Magbanua MJM, et al. Clinical significance of circulating tumor cells in hormone receptor-positive metastatic breastcancer patients who received letrozole with or without Bevacizumab. Clin. Cancer Res. 2020;26:4911-4920.
Not in our library10.1158/1078-0432.ccr-20-1329
235.
Bortolini Silveira A, et al. Multimodal liquid biopsy for early monitoring and outcome prediction of chemotherapy inmetastatic breast cancer. NPJ Breast Cancer. 2021;7:115.
Not in our library10.1038/s41523-021-00319-4
236.
Paoletti C, et al. Circulating tumor cell number and endocrine therapy index in ER positive metastatic breast cancerpatients. NPJ Breast Cancer. 2021;7:77.
Not in our library10.1038/s41523-021-00281-1
237.
Magbanua MJM, et al. Serial analysis of circulating tumor cells in metastatic breast cancer receiving first-linechemotherapy. J. Natl Cancer Inst. 2021;113:443-452.
Not in our library10.1093/jnci/djaa113
238.
de Kruijff IE, et al. Circulating tumor cell enumeration and characterization in metastatic castration-resistant prostate cancer patients treated with cabazitaxel. Cancers. 2019;11:1212-1225.
Not in our library10.3390/cancers11081212
239.
Cieslikowski WA, et al. Circulating tumor cells as a marker of disseminated disease in patients with newly diagnosed high-risk prostate cancer. Cancers. 2020;12:160-175.
Not in our library10.3390/cancers12010160
240.
Basso U, et al. Prognostic role of circulating tumor cells in metastatic renal cell carcinoma: a large, multicenter, prospectivetrial. Oncologist. 2021;26:740-750.
Not in our library10.1002/onco.13842
241.
Chemi F, et al. Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse. Nat. Med. 2019;25:1534-1539.
Not in our library10.1038/s41591-019-0593-1
242.
Messaritakis I, et al. Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lungcancer (SCLC) and evaluation of their clinical relevance during front-line treatment. Lung Cancer. 2019;135:33-39.
Not in our library10.1016/j.lungcan.2019.06.025
243.
Sun YF, et al. Postoperative circulating tumor cells: an early predictor of extrahepatic metastases in patients withhepatocellular carcinoma undergoing curative surgical resection. Cancer Cytopathol. 2020;128:733-745.
Not in our library10.1002/cncy.22304
244.
Matsushita D, et al. Clinical significance of circulating tumor cells in the response to trastuzumab for HER2-negativemetastatic gastric cancer. Cancer Chemother. Pharm. 2021;87:789-797.
Not in our library10.1007/s00280-021-04251-z
245.
Sastre J, et al. Association between baseline circulating tumor cells, molecular tumor profiling, and clinical characteristics ina large cohort of chemo-naive metastatic colorectal cancer patients prospectively collected. Clin. Colorectal Cancer. 2020;19:e110-e116.
Not in our library10.1016/j.clcc.2020.02.014
246.
Bidard FC, et al. Circulating tumor cells in breast cancer patients treated by neoadjuvant chemotherapy: a meta-analysis. J. Natl Cancer Inst. 2018;110:560-567.
Not in our library10.1093/jnci/djy018
247.
Murlidhar V, et al. Poor prognosis indicated by venous circulating tumor cell clusters in early-stage lung cancers. CancerRes. 2017;77:5194-5206.
Not in our library10.1158/0008-5472.can-16-2072
248.
Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort · 2016
No notice
249.
Wang C, et al. Longitudinally collected CTCs and CTC-clusters and clinical outcomes of metastatic breast cancer. BreastCancer Res. Treat. 2017;161:83-94.
Not in our library10.1007/s10549-016-4026-2
250.
Wang C, et al. Improved prognostic stratification using circulating tumor cell clusters in patients with metastatic castration-resistant prostate cancer. Cancers. 2021;13:268-280.
Not in our library10.3390/cancers13020268
251.
Lozano R, et al. Value of early circulating tumor cells dynamics to estimate docetaxel benefit in metastatic castration-resistant prostate cancer (mCRPC) patients. Cancers. 2021;13:2334-2344.
Not in our library10.3390/cancers13102334
252.
Su P, et al. Mesenchymal and phosphatase of regenerating liver-3 status in circulating tumor cells may serve as a crucialprognostic marker for assessing relapse or metastasis in postoperative patients with colorectal cancer. Clin. Transl. Gastroenterol. 2020;11:e00265.
Not in our library10.14309/ctg.0000000000000265
253.
Strati A, Nikolaou M, Georgoulias V, Lianidou ES. Prognostic significance of TWIST1, CD24, CD44, and ALDH1 transcript quantification in EpCAM-positive circulating tumor cells from early stage breast cancer patients. Cells. 2019;8:652-667.
Not in our library10.3390/cells8070652
254.
Papadaki MA, et al. Clinical relevance of immune checkpoints on circulating tumor cells in breast cancer. Cancers. 2020;12:376-396.
Not in our library10.3390/cancers12020376
255.
Wang XQ, Liu B, Li BY, Wang T, Chen DQ. Effect of CTCs and INHBA level on the effect and prognosis ofdifferent treatment methods for patients with early breast cancer. Eur. Rev. Med. Pharm. Sci. 2020;24:12735-12740.
Not in our library10.26355/eurrev_202012_24172
256.
Graf RP, et al. Clinical utility of the nuclear-localized AR-V7 biomarker in circulating tumor cells in improving physiciantreatment choice in castration-resistant prostate cancer. Eur. Urol. 2020;77:170-177.
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257.
Wei T, et al. Vimentin-positive circulating tumor cells as a biomarker for diagnosis and treatment monitoring in patientswith pancreatic cancer. Cancer Lett. 2019;452:237-243.
Not in our library10.1016/j.canlet.2019.03.009
258.
Economos C, Morrissey C, Vessella RL. Circulating tumor cells as a marker of response: implications for determiningtreatment efficacy and evaluating new agents. Curr. Opin. Urol. 2012;22:190-196.
Not in our library10.1097/mou.0b013e3283519b58
259.
Li Y, Wu S, Bai F. Molecular characterization of circulating tumor cells-from bench to bedside. Semin. Cell Dev. Biol. 2018;75:88-97.
Not in our library10.1016/j.semcdb.2017.09.013
260.
Massard C, et al. RECIST response and variation of circulating tumour cells in phase 1 trials: a prospective multicentricstudy. Eur. J. Cancer. 2017;83:185-193.
Not in our library10.1016/j.ejca.2017.05.016
261.
Ntzifa A, Kotsakis A, Georgoulias V, Lianidou E. Detection of EGFR mutations in plasma cfDNA and paired CTCs of NSCLC patients before and after osimertinib therapy using crystal digital PCR. Cancers. 2021;13:2376-2394.
Not in our library10.3390/cancers13112736
262.
Pan X, Zhang X. Utility of circulating tumor cells and DNA in the management of advanced colorectal cancer. FutureOncol. 2020;16:1289-1299.
Not in our library10.2217/fon-2020-0073
263.
Garrido-Navas MC, et al. The polemic diagnostic role of tp53 mutations in liquid biopsies from breast, colon and lung cancers. Cancers. 2020;12:3343-3359.
Not in our library10.3390/cancers12113343
264.
Mong J, Tan MH. Size-based enrichment technologies for non-cancerous tumor-derived cells in blood. TrendsBiotechnol. 2018;36:511-522.
Not in our library10.1016/j.tibtech.2018.02.010
265.
Cristofanilli M, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 2004;351:781-791.
Not in our library10.1056/nejmoa040766
266.
Liu MC, et al. Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J. Clin. Oncol. 2009;27:5153-5159.
Not in our library10.1200/jco.2008.20.6664
267.
Pestrin M, et al. Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib inpatients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. BreastCancer Res. Treat. 2012;134:283-289.
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268.
Pierga, J. Y. et al. High independent prognostic and predictive value of circulating tumor cells compared with serum tumormarkers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients. Ann. Oncol. 23, 618-624
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269.
Giordano A, et al. Circulating tumor cells in immunohistochemical subtypes of metastatic breast cancer: lack of predictionin HER2-positive disease treated with targeted therapy. Ann. Oncol. 2012;23:1144-1150.
Not in our library10.1093/annonc/mdr434
270.
Jiang ZF, et al. Circulating tumor cells predict progression-free and overall survival in Chinese patients with metastaticbreast cancer, HER2-positive or triple-negative (CBCSG004): a multicenter, double-blind, prospective trial. Ann. Oncol. 2013;24:2766-2772.
Not in our library10.1093/annonc/mdt246
271.
Pierga JY, et al. Circulating tumor cells and brain metastasis outcome in patients with HER2-positive breast cancer: theLANDSCAPE trial. Ann. Oncol. 2013;24:2999-3004.
Not in our library10.1093/annonc/mdt348
272.
Smerage JB, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J. Clin. Oncol. 2014;32:3483-3489.
Not in our library10.1200/jco.2014.56.2561
273.
Hall C, et al. Circulating tumor cells after neoadjuvant chemotherapy in stage I-III triple-negative breast cancer. Ann. Surg. Oncol. 2015;22:S552-S558.
Not in our library10.1245/s10434-015-4600-6
274.
Hall CS, et al. Prognostic value of circulating tumor cells identified before surgical resection in nonmetastatic breastcancer patients. J. Am. Coll. Surg. 2016;223:20-29.
Not in our library10.1016/j.jamcollsurg.2016.02.021
275.
Riethdorf S, et al. Prognostic impact of circulating tumor cells for breast cancer patients treated in the neoadjuvant“geparquattro” trial. Clin. Cancer Res. 2017;23:5384-5393.
Not in our library10.1158/1078-0432.ccr-17-0255
276.
Sparano J, et al. Association of circulating tumor cells with late recurrence of estrogen receptor-positive breast cancer: asecondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4:1700-1706.
Not in our library10.1001/jamaoncol.2018.2574
277.
Rossi G, et al. Cell-free DNA and circulating tumor cells: comprehensive liquid biopsy analysis in advanced breast cancer. Clin. Cancer Res. 2018;24:560-568.
Not in our library10.1158/1078-0432.ccr-17-2092
278.
Trapp E, et al. Presence of circulating tumor cells in high-risk early breast cancer during follow-up and prognosis. J. NatlCancer Inst. 2019;111:380-387.
Not in our library10.1093/jnci/djy152
279.
Radovich M, et al. Association of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy withdisease recurrence in patients with triple-negative breast cancer: preplanned secondary analysis of the BRE12-158 randomizedclinical trial. JAMA Oncol. 2020;6:1410-1415.
Not in our library10.1001/jamaoncol.2020.2295
280.
Zhou J, et al. Epithelial-mesenchymal transition status of circulating tumor cells in breast cancer and its clinical relevance. Cancer Biol. Med. 2020;17:169-180.
Not in our library10.20892/j.issn.2095-3941.2019.0118
281.
Le Du,F, et al. EpCAM-independent isolation of circulating tumor cells with epithelial-to-mesenchymal transition andcancer stem cell phenotypes using ApoStream(R) in patients with breast cancer treated with primary systemic therapy. PLoS One. 2020;15:e0229903.
Not in our library10.1371/journal.pone.0229903
282.
Zhang SR, et al. Mesenchymal phenotype of circulating tumor cells is associated with distant metastasis in breast cancerpatients. Cancer Manag. Res. 2017;9:691-700.
Not in our library10.2147/cmar.s149801
283.
In patients with metastatic breast cancer the identification of circulating tumor cells in epithelial-to-mesenchymal transition is associated with a poor prognosis · 2016
No notice
284.
Papadaki MA, et al. Circulating tumor cells with stemness and epithelial-to-mesenchymal transition features arechemoresistant and predictive of poor outcome in metastatic breast Cancer. Mol. Cancer Ther. 2019;18:437-447.
Not in our library10.1158/1535-7163.mct-18-0584
285.
de Kruijff IE, et al. Androgen receptor expression in circulating tumor cells of patients with metastatic breast cancer. Int. J. Cancer. 2019;145:1083-1089.
Not in our library10.1002/ijc.32209
286.
Bock C, et al. Distinct expression of cytokeratin, N-cadherin and CD133 in circulating tumor cells of metastatic breastcancer patients. Future Oncol. 2014;10:1751-1765.
Not in our library10.2217/fon.14.58
287.
Goodman OB, et al. Circulating tumor cells in patients with castration-resistant prostate cancer baseline values andcorrelation with prognostic factors. Cancer Epidemiol. Biomark. Prev. 2009;18:1904-1913.
Not in our library10.1158/1055-9965.epi-08-1173
288.
Goldkorn A, et al. Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase iii trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. J. Clin. Oncol. 2014;32:1136-113.
Not in our library10.1200/jco.2013.51.7417
289.
Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients · 2016
No notice
290.
Chen J, et al. Metabolic reprogramming-based characterization of circulating tumor cells in prostate cancer. J. Exp. Clin. Cancer Res. 2018;37:127.
Not in our library10.1186/s13046-018-0789-0
291.
Liu H, Ding J, Wu Y, Wu D, Qi J. Prospective study of the clinical impact of epithelial and mesenchymal circulatingtumor cells in localized prostate cancer. Cancer Manag. Res. 2020;12:4549-4560.
Not in our library10.2147/cmar.s253997
292.
Antonarakis ES, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 2014;371:1028-1038.
Not in our library10.1056/nejmoa1315815
293.
Okegawa T, et al. AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate andenzalutamide treatment in castration-resistant prostate cancer patients. Prostate. 2018;78:576-582.
Not in our library10.1002/pros.23501
294.
Tagawa ST, et al. Expression of AR-V7 and ARv(567es) in circulating tumor cells correlates with outcomes to taxanetherapy in men with metastatic prostate cancer treated in TAXYNERGY. Clin. Cancer Res. 2019;25:1880-1888.
Not in our library10.1158/1078-0432.ccr-18-0320
295.
Markou A, et al. PIM-1 Is Overexpressed at a high frequency in circulating tumor cells from metastatic castration-resistant prostate cancer patients. Cancers. 2020;12:1188-1201.
Not in our library10.3390/cancers12051188
296.
Liu S, et al. Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high-efficiency capture of circulatingtumor cells in clear cell renal cell carcinoma patients. Oncotarget. 2016;7:59877-59891.
Not in our library10.18632/oncotarget.10979
297.
Naoe M, et al. Detection of circulating urothelial cancer cells in the blood using the CellSearch System. Cancer. 2007;109:1439-1445.
Not in our library10.1002/cncr.22543
298.
Gallagher DJ, et al. Detection of circulating tumor cells in patients with urothelial cancer. Ann. Oncol. 2009;20:305-308.
Not in our library10.1093/annonc/mdn627
299.
Rink M, et al. Detection of circulating tumour cells in peripheral blood of patients with advanced non-metastatic bladdercancer. BJU Int. 2011;107:1668-1675.
Not in our library10.1111/j.1464-410x.2010.09562.x
300.
Gazzaniga P, et al. Prognostic value of circulating tumor cells in nonmuscle invasive bladder cancer: a CellSearch analysis. Ann. Oncol. 2012;23:2352-2356.
Not in our library10.1093/annonc/mdr619
301.
Cohen SJ, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival inpatients with metastatic colorectal cancer. J. Clin. Oncol. 2008;26:3213-3221.
Not in our library10.1200/jco.2007.15.8923
302.
Cohen SJ, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann. Oncol. 2009;20:1223-1229.
Not in our library10.1093/annonc/mdn786
303.
Wang W, et al. Mesenchymal marker and LGR5 expression levels in circulating tumor cells correlate with colorectal cancerprognosis. Cell Oncol. 2018;41:495-504.
Not in our library10.1007/s13402-018-0386-4
304.
Wu F, et al. Associations between the epithelial-mesenchymal transition phenotypes of circulating tumor cells and theclinicopathological features of patients with colorectal cancer. Dis. Markers. 2017;2017:9474532.
Not in our library10.1155/2017/9474532
305.
Zhao R, et al. Expression and clinical relevance of epithelial and mesenchymal markers in circulating tumor cells fromcolorectal cancer. Oncotarget. 2017;8:9293-9302.
Not in our library10.18632/oncotarget.14065
306.
Ning Y, et al. Clinical relevance of EMT and stem-like gene expression in circulating tumor cells of metastatic colorectalcancer patients. Pharmacogenom. J. 2018;18:29-34.
Not in our library10.1038/tpj.2016.62
307.
Bao H, et al. High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells isassociated with poor clinical response to the immune checkpoint inhibitor nivolumab. Oncol. Lett. 2018;15:3061-3067.
Not in our library10.3892/ol.2017.7671
308.
Shen C, Hu L, Xia L, Li Y. Quantitative real-time RT-PCR detection for survivin, CK20 and CEA in peripheral bloodof colorectal cancer patients. Jpn. J. Clin. Oncol. 2008;38:770-776.
Not in our library10.1093/jjco/hyn105
309.
Shimada R, Iinuma H, Akahane T, Horiuchi A, Watanabe T. Prognostic significance of CTCs and CSCs of tumordrainage vein blood in Dukes' stage B and C colorectal cancer patients. Oncol. Rep. 2012;27:947-953.
Not in our library10.3892/or.2012.1649
310.
Barbazan J, et al. A multimarker panel for circulating tumor cells detection predicts patient AQ5 outcome and therapyresponse in metastatic colorectal cancer. Int. J. Cancer. 2014;135:2633-2643.
Not in our library10.1002/ijc.28910
311.
Yokobori T, et al. Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transitionand is associated with colorectal cancer prognosis. Cancer Res. 2013;73:2059-2069.
Not in our library10.1158/0008-5472.can-12-0326
312.
Bian J, Yan K, Liu N, Xu X. Correlations between circulating tumor cell phenotyping and 18F-fluorodeoxyglucosepositron emission tomography uptake in non-small cell lung cancer. J. Cancer Res. Clin. Oncol. 2020;146:2621-2630.
Not in our library10.1007/s00432-020-03244-4
313.
Dong J, et al. Detection of circulating tumor cell molecular subtype in pulmonary vein predicting prognosis of stage I-IIInon-small cell lung cancer patients. Front Oncol. 2019;9:1139.
Not in our library10.3389/fonc.2019.01139
314.
Manjunath Y, et al. PD-L1 Expression with epithelial mesenchymal transition of circulating tumor cells is associated with poor survival in curatively resected non-small cell lung cancer. Cancers. 2019;11:806-816.
Not in our library10.3390/cancers11060806
315.
Krebs MG, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lungcancer. J. Clin. Oncol. 2011;29:1556-1563.
Not in our library10.1200/jco.2010.28.7045
316.
Punnoose EA, et al. Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer:association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib. Clin. Cancer Res. 2012;18:2391-2401.
Not in our library10.1158/1078-0432.ccr-11-3148
317.
Liang N, et al. Efficient isolation and quantification of circulating tumor cells in non-small cell lung cancer patients usingpeptide-functionalized magnetic nanoparticles. J. Thorac. Dis. 2020;12:4262-4273.
Not in our library10.21037/jtd-20-1026a
318.
Tamminga M, et al. Circulating tumor cells in advanced non-small cell lung cancer patients are associated with worse tumorresponse to checkpoint inhibitors. J. Immunother. Cancer. 2019;7:173.
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319.
Tamminga M, et al. Analysis of released circulating tumor cells during surgery for non-small cell lung cancer. Clin. CancerRes. 2020;26,:1656-1666.
Not in our library10.1158/1078-0432.ccr-19-2541
320.
Frick MA, et al. Circulating tumor cells are associated with recurrent disease in patients with early-stage non-small celllung cancer treated with stereotactic body radiotherapy. Clin. Cancer Res. 2020;26:2372-2380.
Not in our library10.1158/1078-0432.ccr-19-2158
321.
Hiltermann TJN, et al. Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor. Ann. Oncol. 2012;23:2937-2942.
Not in our library10.1093/annonc/mds138
322.
Hou JM, et al. Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patientsundergoing chemotherapy. Am. J. Pathol. 2009;175:808-816.
Not in our library10.2353/ajpath.2009.090078
323.
Hou JM, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumormicroemboli in patients with small-cell lung cancer. J. Clin. Oncol. 2012;30:525-532.
Not in our library10.1200/jco.2010.33.3716
324.
Huang CH, et al. A multicenter pilot study examining the role of circulating tumor cells as a blood-based tumor marker inpatients with extensive small-cell lung cancer. Front Oncol. 2014;4:271.
Not in our library10.3389/fonc.2014.00271
325.
Naito T, et al. Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J. Thorac. Oncol. 2012;7:512-519.
Not in our library10.1097/jto.0b013e31823f125d
326.
Normanno N, et al. Prognostic value of circulating tumor cells' reduction in patients with extensive small-cell lung cancer. Lung Cancer. 2014;85:314-319.
Not in our library10.1016/j.lungcan.2014.05.002
327.
Messaritakis I, et al. Phenotypic characterization of circulating tumor cells in the peripheral blood of patients with small celllung cancer. PLoS One. 2017;12:e0181211.
Not in our library10.1371/journal.pone.0181211
328.
Bidard FC, et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study tothe LAP 07 trial. Ann. Oncol. 2013;24:2057-2061.
Not in our library10.1093/annonc/mdt176
329.
Court CM, et al. Circulating tumor cells predict occult metastatic disease and prognosis in pancreatic cancer. Ann. Surg. Oncol. 2018;25:1000-1008.
Not in our library10.1245/s10434-017-6290-8
330.
Gall TM, et al. Reduced dissemination of circulating tumor cells with no-touch isolation surgical technique in patients withpancreatic cancer. JAMA Surg. 2014;149:482-485.
Not in our library10.1001/jamasurg.2013.3643
331.
Hugenschmidt H, et al. Circulating tumor cells are an independent predictor of shorter survival in patients undergoingresection for pancreatic and periampullary adenocarcinoma. Ann. Surg. 2020;271:549-558.
Not in our library10.1097/sla.0000000000003035
332.
Okubo K, et al. Clinical impact of circulating tumor cells and therapy response in pancreatic cancer. Eur. J. Surg. Oncol. 2017;43:1050-1055.
Not in our library10.1016/j.ejso.2017.01.241
333.
Dong X, et al. Spatial heterogeneity in epithelial to mesenchymal transition properties of circulating tumor cells associatedwith distant recurrence in pancreatic cancer patients. Ann. Transl. Med. 2020;8:676.
Not in our library10.21037/atm-20-782
334.
Zhao XH, et al. Molecular detection of epithelial-mesenchymal transition markers in circulating tumor cells frompancreatic cancer patients: Potential role in clinical practice. World J. Gastroenterol. 2019;25:138-150.
Not in our library10.3748/wjg.v25.i1.138
335.
Zhu P, et al. Circulating tumor cells expressing Kruppel-like factor 8 and vimentin as predictors of poor prognosis inpancreatic cancer patients. Cancer Control. 2021;28:10732748211027163.
Not in our library10.1177/10732748211027163
336.
Ou H, et al. Circulating tumor cell phenotype indicates poor survival and recurrence after surgery for hepatocellularcarcinoma. Dig. Dis. Sci. 2018;63:2373-2380.
Not in our library10.1007/s10620-018-5124-2
337.
Circulating tumor cells are an indicator for the administration of adjuvant transarterial chemoembolization in hepatocellular carcinoma: A single‐center, retrospective, propensity‐matched study · 2020
Not checked
338.
Effect of surgical liver resection on circulating tumor cells in patients with hepatocellular carcinoma · 2018
Not checked
339.
Zhou J, et al. Preoperative circulating tumor cells to predict microvascular invasion and dynamical detection indicate theprognosis of hepatocellular carcinoma. BMC Cancer. 2020;20:1047.
Not in our library10.1186/s12885-020-07488-8
340.
Zhou KQ, et al. Effect of surgical margin on recurrence based on preoperative circulating tumor cell status inhepatocellular carcinoma. EBioMedicine. 2020;62:103107.
Not in our library10.1016/j.ebiom.2020.103107
341.
Liu YK, et al. An improved strategy to detect the epithelial-mesenchymal transition process in circulating tumor cells inhepatocellular carcinoma patients. Hepatol. Int. 2016;10:640-646.
Not in our library10.1007/s12072-016-9732-7
342.
Qi LN, et al. Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients withhepatocellular carcinoma. Cancer Res. 2018;78:4731-4744.
Not in our library10.1158/0008-5472.can-17-2459
343.
Wang Z, et al. Correlation between postoperative early recurrence of hepatocellular carcinoma and mesenchymal circulatingtumor cells in peripheral blood. J. Gastrointest. Surg. 2018;22:633-639.
Not in our library10.1007/s11605-017-3619-3
344.
Court CM, et al. A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellularcarcinoma. Liver Transpl. 2018;24:946-960.
Not in our library10.1002/lt.25062
345.
Yi B, et al. The clinical significance of CTC enrichment by GPC3-IML and its genetic analysis in hepatocellular carcinoma. J. Nanobiotechnol. 2021;19:74.
Not in our library10.1186/s12951-021-00818-3
346.
Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma · 2021
No notice
347.
Yin LC, et al. Twist expression in circulating hepatocellular carcinoma cells predicts metastasis and prognoses. Biomed. Res. Int. 2018;2018:3789613.
Not in our library10.1155/2018/3789613
348.
Sun YF, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis ofhepatocellular carcinoma after curative resection. Hepatology. 2013;57:1458-1468.
Not in our library10.1002/hep.26151
349.
Lee SJ, et al. Circulating tumor cells are predictive of poor response to chemotherapy in metastatic gastric cancer. Int. J. Biol. Markers. 2015;30:e382-e386.
Not in our library10.5301/jbm.5000151
350.
Uenosono Y, et al. Clinical significance of circulating tumor cells in peripheral blood from patients with gastric cancer. Cancer. 2013;119:3984-3991.
Not in our library10.1002/cncr.28309
351.
Zhang Q, et al. A prospective study on the changes and clinical significance of pre-operative and post-operative circulatingtumor cells in resectable gastric cancer. J. Transl. Med. 2018;16:171.
Not in our library10.1186/s12967-018-1544-1
352.
Liu M, et al. Prognostic significance of PD-L1 expression on cell-surface vimentin-positive circulating tumor cells in gastriccancer patients. Mol. Oncol. 2020;14:865-881.
Not in our library10.1002/1878-0261.12643
353.
Hatakeyama K, et al. A novel splice variant of XIAP-associated factor 1 (XAF1) is expressed in peripheral bloodcontaining gastric cancer-derived circulating tumor cells. Gastr. Cancer. 2015;18:751-761.
Not in our library10.1007/s10120-014-0426-3
354.
Vaiopoulos AG, et al. Detection of circulating tumor cells in colorectal and gastric cancer using a multiplex PCR assay. Anticancer Res. 2014;34:3083-3092.
Not in our library
355.
Ishiguro Y, et al. Prognostic significance of circulating tumor cells with mesenchymal phenotypes in patients with gastriccancer: a prospective study. Ann. Surg. Oncol. 2021;28:1178-1186.
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356.
Mimori K, et al. A large-scale study of MT1-MMP as a marker for isolated tumor cells in peripheral blood and bonemarrow in gastric cancer cases. Ann. Surg. Oncol. 2008;15:2934-2942.
Not in our library10.1245/s10434-008-9916-z
357.
Prognostic value of circulating tumor cells detected with the CellSearch system in esophageal cancer patients: a systematic review and meta-analysis · 2020
Not checked
358.
Tewari KS, et al. Circulating tumor cells in advanced cervical cancer: NRG Oncology-Gynecologic Oncology Group study240 (NCT 00803062). Mol. Cancer Ther. 2020;19:2363-2370.
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359.
Anand K, et al. Pilot study of circulating tumor cells in early-stage and metastatic uveal melanoma. Cancers. 2019;11:856-863.
Not in our library10.3390/cancers11060856
360.
Kim DD, Yang CS, Chae HD, Kwak SG, Jeon CH. Melanoma antigen-encoding gene family member A1-6and hTERT in the detection of circulating tumor cells following CD45(-) depletion and RNA extraction. Oncol. Lett. 2017;14:837-843.
Not in our library10.3892/ol.2017.6226
361.
Mego M, et al. Circulating tumor cells with epithelial-to-mesenchymal transition phenotypes associated with inferioroutcomes in primary breast cancer. Anticancer Res. 2019;39:1829-1837.
Not in our library10.21873/anticanres.13290
362.
Zhang Y, et al. Utility of circulating tumor cells for detection of early-stage luminal a breast cancer. Am. J. Med Sci. 2020;360:543-551.
Not in our library10.1016/j.amjms.2020.01.020
363.
Stefanovic S, et al. The lack of evidence for an association between cancer biomarker conversion patterns and CTC-status in patients with metastatic breast cancer. Int. J. Mol. Sci. 2020;21:2161-2171.
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364.
Jin L, et al. Evaluation of the diagnostic value of circulating tumor cells with CytoSorter((R)) CTC capture system inpatients with breast cancer. Cancer Med. 2020;9:1638-1647.
Not in our library10.1002/cam4.2825
365.
Shliakhtunou YA. CTCs-oriented adjuvant personalized cytostatic therapy non-metastatic breast cancer patients:continuous non-randomized prospective study and prospective randomized controlled study. Breast Cancer Res. Treat. 2021;186:439-451.
Not in our library10.1007/s10549-020-06036-z
366.
AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel · 2019
Not checked
367.
Schonhoft JD, et al. Morphology-predicted large-scale transition number in circulating tumor cells identifies achromosomal instability biomarker associated with poor outcome in castration-resistant prostate cancer. Cancer Res. 2020;80:4892-4903.
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368.
Armstrong AJ, et al. Prospective multicenter study of circulating tumor cell AR-V7 and taxane versus hormonal treatment outcomes in metastatic castration-resistant prostate cancer. JCO Precis. Oncol. 2020;4:1285-1301.
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369.
Xu L, et al. Noninvasive detection of clinically significant prostate cancer using circulating tumor cells. J. Urol. 2020;203:73-82.
Not in our library10.1097/ju.0000000000000475
370.
Sperger JM, et al. Prospective evaluation of clinical outcomes using a multiplex liquid biopsy targeting diverse resistancemechanisms in metastatic prostate cancer. J. Clin. Oncol. 2021;39:2926-2937.
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371.
Zhang P, et al. The significance of detection of circulating tumor cells and BECLIN1 in peripheral blood of patients withrenal cell carcinoma. Crit. Rev. Eukaryot. Gene Expr. 2020;30:483-492.
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372.
Li Z, et al. Circulating tumor cells can predict the prognosis of patients with non-small cell lung cancer after resection: aretrospective study. Transl. Lung Cancer Res. 2021;10:995-1006.
Not in our library10.21037/tlcr-21-149
373.
Wang PP, et al. Circulating tumor cells as a new predictive and prognostic factor in patients with small cell lung cancer. J. Cancer. 2020;11:2113-2122.
Not in our library10.7150/jca.35308
374.
Ha Y, et al. Circulating tumor cells are associated with poor outcomes in early-stage hepatocellular carcinoma: aprospective study. Hepatol. Int. 2019;13:726-735.
Not in our library10.1007/s12072-019-09994-9
375.
Chen Y, et al. Circulating tumor cells undergoing EMT are poorly correlated with clinical stages or predictive of recurrencein hepatocellular carcinoma. Sci. Rep. 2019;9:7084.
Not in our library10.1038/s41598-019-43572-1
376.
Cheng Y, et al. Diagnostic value of different phenotype circulating tumor cells in hepatocellular carcinoma. J. Gastrointest. Surg. 2019;23:2354-2361.
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377.
Lei Y, et al. Association of preoperative NANOG-positive circulating tumor cell levels with recurrence of hepatocellularcarcinoma. Front. Oncol. 2021;11:601668.
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378.
Szczepanik A, et al. CD44(+) cytokeratin-positive tumor cells in blood and bone marrow are associated with poor prognosisof patients with gastric cancer. Gastr. Cancer. 2019;22:264-272.
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379.
Miki Y, et al. Circulating CEA-positive and EpCAM-negative tumor cells might be a predictive biomarker for recurrence inpatients with gastric cancer. Cancer Med. 2021;10:521-528.
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380.
Kuroda K, et al. Circulating tumor cells with FGFR2 expression might be useful to identify patients with existing FGFR2-overexpressing tumor. Cancer Sci. 2020;111:4500-4509.
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381.
Wang D, et al. Prognostic models based on postoperative circulating tumor cells can predict poor tumor recurrence-freesurvival in patients with stage II-III colorectal cancer. J. Cancer. 2019;10:4552-4563.
Not in our library10.7150/jca.30512
382.
Bidard FC, et al. Circulating tumor cells and circulating tumor DNA detection in potentially resectable metastatic colorectal cancer: a prospective ancillary study to the unicancer Prodige-14 Trial. Cells. 2019;8:516-528.
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383.
Wang L, et al. Circulating tumor cells as an independent prognostic factor in advanced colorectal cancer: a retrospectivestudy in 121 patients. Int. J. Colorectal Dis. 2019;34:589-597.
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384.
Messaritakis I, et al. Evaluation of the role of circulating tumor cells and microsatellite instability status in predicting outcome of advanced CRC patients. J. Pers. Med. 2020;10:235-347.
Not in our library10.3390/jpm10040235
385.
Pan RJ, et al. Detection and clinical value of circulating tumor cells as an assisted prognostic marker in colorectal cancerpatients. Cancer Manag. Res. 2021;13:4567-4578.
Not in our library10.2147/cmar.s300554

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