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Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset

Chiara Agnoletto, Fabio Corrà, Linda Minotti and 7 more

Cancers · 2019 · Review · CC BY

Abstract

The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial–mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Despite recent medical advances, metastasis, tumor relapse, a lack of effective therapies, and drug resistance remain the major causes of death for tumor patients. Research on circulating tumor cells (CTCs), which have been detected in the majority of epithelial cancers, is a dynamic field of translational and basic research, with more than 270 clinical trials having evaluated CTC enumeration as a biomarker. Further, several studies on CTCs aimed to understand critical pathways that mediate cancer dissemination, and may not be apparent in primary or metastatic tumors.

2Cancer metastasis occurs when tumor cells dissociate from a primary tumor and migrate to distant organs through the peripheral vasculature. Cancer cells within the primary tumor lose cell-cell adhesion and acquire features of invasiveness and motility due to epithelial-to-mesenchymal transition (EMT), leading to their intravasation and survival in blood or lymph vessels, and finally their extravasation at distant sites; here they are subjected to mesenchymal-to-epithelial transition (MET), and proliferate to establish metastatic lesions. Whether the release of CTCs into the circulation is a predetermined biological process still remains a debatable matter. Cancer cells can enter circulation long before a tumor is diagnosed; the majority of cells die and only a minor fraction contains viable metastatic precursors that infiltrate organs and survive as disseminated seeds for eventual relapse. Therefore, metastatic colonization might be a highly inefficient process, but once it is established, current treatments generally fail to provide persistent responses.

3Tumors are thought to arise from mutant normal stem cells in their native niches, or from the progeny of cells that retain their tumor-initiating capacity. Once at distant sites, these cells survive and proliferate through interactions with specialized niches. Data from a number of studies demonstrate that CTCs with stemness properties exist and represent the most aggressive tumor cells in circulation.

4In this review, we will discuss current concepts and will address questions relative to the heterogeneity of CTCs and the presence of cancer stem cells circulating in the bloodstream (See Table 1).

2. Heterogeneity of CTCs

5CTCs are very rare cancer cells released from a primary tumor. A lot of evidence documents that CTCs represent a heterogeneous pool of tumor cells, with highly variable, but generally short, survival times; nevertheless, the pool of these cells in the bloodstream can be continuously replenished by the release of replicating tumor cells in metastatic foci, and thus relates to cancer dormancy. To date, relatively little is known regarding the number of CTCs in cancers, their molecular and biological heterogeneity, and their functionalities. Although heterogeneity in CTCs has not yet been fully defined, a fraction of these cells are thought to be viable metastatic precursors capable of initiating a clonal metastatic lesion. A subset of CTCs is represented by inactive non-cycling cells, termed dormant cancer cells, which act as latent tumor-initiating seeds and eventually reawaken, and might not respond to chemotherapeutics used in clinics. By uncovering phenotypes of CTCs, CTC heterogeneity would be dissected in relation to metastatic competence.

6Recently, clusters of CTCs, consisting of 2–50 cells, have been detected in the vasculature of patients with cancers of different origins, which arise from oligoclonal tumor cell groupings, including breast, prostate, pancreatic, glioblastoma, head and neck cancers. Cells within micro-clusters might be protected either from anoikis, associated with the loss of cell-cell adhesion and attachment to the basement membrane, or shear stresses in the circulation. Both the structural deformability of aggregated cells and the presence of vascular shunts may allow CTC-clusters to circulate, while inducing a rapid clearance within distal tissues. Although rare, CTC-clusters present a dramatically enhanced metastatic potential, as confirmed in mouse models, and by the adverse prognosis in patients with high numbers of CTC-clusters. Additionally, neutrophils directly interact with CTCs, defining CTC–neutrophil clusters, and support cell cycle progression in circulation. This interaction in turn leads to more efficient metastasis generation and represents key vulnerabilities of the metastatic process for drug targeting in breast cancer. Mesenchymal transcripts were found to be expressed in tumor cells from CTC-clusters in a human breast tumor, conferring both migratory and stem-like properties. A recent study has suggested that the coexpression of EpCAM, CD44, CD47, and MET in CTCs identifies a subset of cells with increased metastatic capacity. Novel mediators of metastasis have been identified by comparing clusters of tumor cells, captured by using a negCTC-iChip, with single CTCs from breast cancer patients: single cell-resolution RNA sequencing demonstrated the significantly divergent expression of only a few genes, including plakoglobin. Plakoglobin functions as an intercellular tether that confers added metastatic potential to tumor cells in the circulation. Knockdown of plakoglobin inhibits CTC-cluster generation and lung metastases, while both abundance of CTC-clusters and high plakoglobin levels denote adverse outcome in breast cancer patients, pointing to CTC-clusters as critical mediators of cancer metastasis.

2.1. Partial Mesenchymal Transition in CTCs

7Recent data support the hypothesis that CTC profile changes occur during tumor cell dissemination, in order to enter into the vasculature, survive in circulation, extravasate, and generate secondary tumors. Thus, in response to signaling proteins released by stromal cells, tumor cells undergo reversible phenotypic change, described as epithelial-to-mesenchymal transition (EMT). EMT is also required in tissue repair; consistently, the metastatic process is at least in part similar to tissue regeneration. EMT results in a reduced expression of epithelial markers, and an increased plasticity and capacity for migration and invasion, as well as a resistance to anoikis and apoptosis, and senescence, which are hallmarks required for CTC survival and dissemination.

8Studies of the effects of EMT in CTCs have suggested that mesenchymal transformation may facilitate the initial steps of the metastatic cascade, but may reduce their competence to initiate overt metastases. Disseminated cancer cells may at least partially revert to an epithelial phenotype to promote adhesion and proliferation in distal sites, through mesenchymal–epithelial transition. Cancer-associated EMT may therefore not represent a complete interconversion of phenotypes, or an irreversible commitment to a mesenchymal state. Indeed, the existence of a metastable or partial EMT phenotype, with both epithelial and mesenchymal features, adapts to the concept of a highly plastic stem-like state, reversible and responsive to the microenvironment.

9Several groups investigated this phenotype in breast cancer. At least one of a selected pool of EMT markers (Twist 1, Akt2, or PI3Kalpha) were observed both in CTC-positive and CTC-negative cancer patients. Overexpression of EMT-initiating transcription factors (TF), including Twist, Snail1, Slug, Zeb1, and FoxC2, was detected in CTCs, even if in a minority of patients. The EMT markers fibronectin and/or vimentin were expressed more frequently in cytokeratins (CK)-negative than in CK-positive samples. Of note, patients receiving neoadjuvant therapy were more likely to present a higher expression of EMT markers, predicting worse prognosis more accurately than epithelial markers in patients with CK-negative CTCs; thus, CTCs, subjected to EMT, might be invasive cells resistant to neo-adjuvant therapy.

2.2. Epithelial–Mesenchymal Transition and Stemness

10Several lines of evidence have coherently confirmed the notion that the metastatic potential of a tumor is due to a low number of a minor subpopulation of cancer cells (~1%)—termed cancer stem cells (CSCs)—in primary tumor tissue, that exhibit two defining abilities, to self-renew and to efficiently regenerate the phenotypic heterogeneity of a parental tumor, and which are responsible for initiating overt metastases. Studies of neoplastic tissues have provided evidence of stem-like cells within tumors, of breast (CD44+CD24−/low), pancreatic (CD44+CD24+ESA+), brain (CD133+), head and neck (CD44+), and colon (CD133+ and CD44+ESAhigh) cancer. CSCs have been implicated in both initiating primary tumors and in the seeding and establishment of metastases. Recent studies have pointed to a crucial link between EMT and the acquisition of stem cell properties. In addition to conferring migratory and invasive potential, the induction of EMT in immortalized and transformed human mammary epithelial cells significantly enhanced their self-renewal, tumor-initiating capabilities, and led to the expression of stem-cell markers, associated with breast CSCs, suggesting that passage through EMT is an alternative and/or additional step in tumorigenesis. Indeed, the induction of EMT has been associated with expression of the CD44+CD24−/low antigenic profile, which, in breast tumors, defines a subgroup of enriched cancer cells with stem-like properties, as well as mesenchymal traits and cancer stem cell properties, including self-renewal capabilities and resistance to therapies. These cells can self-renew in vitro to generate both CD44highCD24low cells and CD44lowCD24high cells, providing further evidence of stemness properties. Aberrations in signaling networks and transcription factors implicated in EMT have been documented in breast cancer progression, and numerous conserved genes in the signature of resident stem cells are considered EMT-associated genes. Consistently, the gene expression profile of CD44+CD24−/low breast cancer cells more closely resembles that of CD44+CD24−/low cells from normal breast tissue. This undifferentiated phenotype of CSCs is evident in basal-like breast tumors, which exhibit EMT features accounting for their clinical seriousness. Further, the gene expression signatures of stem cells from normal tissues and of the highly aggressive metaplastic and claudin-low histological breast tumor subtypes share strong similarities with gene expression profiles of cells upon the induction of EMT and cancer stem cells.

11Both in vitro and in vivo experiments have suggested that long-term maintenance of the EMT/stem cell state depends on continuous EMT-inducing signals. EMT is orchestrated by integrated networks of signal pathways and EMT-related TFs, including TGFβ, NOTCH, and Wnt. Exposure of tumor cells to both cytokines TGFβ and TNFα induced EMT and generated cells with a stable breast cancer stem cell phenotype, enriched in CD24−low/CD44+ cells, with a shift to the claudin low molecular subtype. Targeting proteins required for induction of the claudin-low subtype could be a therapeutic strategy for improving the survival of breast tumor patients, regardless of the primary subtype. TGFβ represents a paradigm of duality in cancer. Of note, the initial tumor suppression effect due to TGFβ is coupled to EMT; however, although the bulk of tumor cells die, EMT-permissive cells can survive from the TGFβ-imposed bottleneck. Moreover, tumorigenicity linked to EMT is a trait that must be selected during carcinoma progression. In accordance, EMT is not always connected with effective metastatic dissemination.

12Several TFs and miRNAs have been implicated in linking EMT to the acquisition of stem cell properties. EMT-inducing TFs have been confirmed to confer malignant traits in neoplastic cells, and the acquisition of stem cell properties of self-renewing and tumor-initiating, thus generating highly aggressive tumors with an EMT phenotype and stem cell features, and providing evidence for the emergence of cells with combined EMT/CSC phenotypes. The discovery of miRNAs has added an additional level of complexity in EMT, metastasis, and stemness. Downmodulation of the miR-200 family has been extensively documented to occur during EMT, and has been described both in invasive pancreatic tumors, inducing the generation of migrating CSCs, and in normal and breast cancer stem cells, reinforcing the links between normal stem cells and CSCs. Additionally, expression levels of let-7, which is poorly expressed in mesenchymal tumors and targets HMGA2, encoding a DNA-binding protein implicated in mesenchymal cell differentiation, are reduced in breast CSCs, but increased during differentiation.

2.3. Putative Stem Cell-Like Phenotype in CTCs

13EMT enables the detachment of tumor cells from a primary site, but it can also be induced after CTCs enter the vasculature. Only recently, different subsets of CTCs have been identified as mesenchymal. However, exclusively mesenchymal CTCs seem to be unable to establish metastases. The current hypothesis is that tumor cells with an intermediate phenotype between epithelial and mesenchymal present the highest plasticity to adapt to secondary sites, and constitute cancer stem cells. Consistently, CTCs expressing EPCAM, CD44, CD47, and MET, once injected in immunodeficient mice, generated metastases with an EPCAMlow/METhigh/CD47high/CD44high phenotype, thus containing functional metastasis-initiating cells. Therefore, the detection of such CTCs is of the utmost importance.

14The use of EpCAM in current CTC detection methods, thus effectively pre-selecting for epithelial CTCs, is a matter of debate, and high expression has been confirmed in CSC from breast, colorectal, and pancreatic tumors. The metastatic potential of EpCAM-positive CTCs has been extensively confirmed in xenograft models, providing the proof of principle that CTCs captured by the CellSearch system are capable of initiating metastasis, at least in murine models. On the contrary, the CellSearch method did not recognize aggressive breast cancer cells, and it suffered from a relatively low sensitivity: only a fraction of patients with metastatic cancer scored positive for any CTCs, with a median yield of approximately 1 CTC per milliliter and typically low purity.

15Although the role of EMT in CTCs is still controversial, EMT signatures have been observed in at least a subset of tumor cells with stemness properties. However, studies in cancer models suggest that EMT could be dispensable for establishing metastasis, despite the fact that it contributes to the aggressiveness by increasing chemoresistance. Some investigators reported that CSCs markers were enriched in CTCs with mesenchymal features and had prognostic relevance, in breast tumors at different stages (stage I–III). These CSC phenotypes need to be further evaluated, also in patients with early stage cancer, and prospectively related to the occurrence of overt metastases. Furthermore, CSCs might develop after the initial diagnosis of a tumor, so serial postoperative blood monitoring might be required to identify CSCs.

16A selection of the more aggressive cells generates clinical evidence of metastasis. Coherently, a significant genetic heterogeneity in early disseminated tumor cells (DTC) in early breast cancer contrasts with homogeneity in tumor cells from metastases. Subsets of CTCs/DTCs demonstrate a stem cell-like phenotype, which confer stemness and pleiotropic roles in cell adhesion, migration, and homing. Only a small subset of CTCs, which migrate into vasculature, termed circulating cancer stem cells (CCSCs), with putative stem cell progenitor phenotypes, present high invasiveness and effectively generate metastasis. Blood-monitoring studies in tumor patients have shown that some CTCs can survive chemotherapy, as postulated for cancer stem cells. CCSCs have been identified in several types of cancer, including metastatic breast cancer, lung carcinoma, hepatocellular carcinoma, colorectal cancer, and gastric cancer. Specific biomarkers associated with stemness detected in CTCs include BMI1 for lung CCSCs, CD90+CXCR4+ for hepatocellular CCSCs, and CD44 variant exon 9 (CD44v9) for colorectal CCSCs.

17Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in CTCs of metastatic breast cancer. Recently, in a breast tumor, a stem cell-like population, defined by the presence of CD44 and absence of CD24, has been identified, which might disseminate into the circulation and escape therapy, and presents an expression profile associated with metastatic relapse. It has been reported that the modulation of HER2 signaling can increase the cancer stem cell pool and might be required for its maintenance; in fact, a strong link between HER2- like-tumors and stem cells has been observed. Preliminary data identified a breast cancer stem cell-like phenotype in CTCs, with increased resistance to chemotherapy and decreased proliferation in circulation. ALDH1, a marker of normal and neoplastic breast stem cells, has been confirmed to be overexpressed in 70% of CTCs, and associated with therapy failure. At least one or more of the EMT markers Twist, Akt2, and PI3Kalpha, and ALDH1 were detectable in a great proportion of CTCs, thus identifying the highly tumorigenic subset of EMT-associated breast CSCs. This subset of CTCs is indicative of therapy-resistance and inferior prognosis in metastatic tumor patients, with clinical relevance. Of note, ALDH1 and EMT markers were measured even before the detection of CTCs in circulation, as assessed through the positivity in RT-PCR to at least one of the transcripts HER2, MUC1, and EpCAM. Consistently, the stem cell-like phenotypes CD44+CD24−/low and ALDH1highCD24−/low have been identified in 35.2% and 17.7% of CTCs, respectively, and the subset of CD44+CD24−/low CTCs among ALDH1-highly positive CTCs present an even higher tumorigenic potential. Finally, although ALDH1-positive cells represented only 5% of cells in tumors expressing ALDH1, ALDH1 staining positivity was associated with a high histological grade and poor clinical outcome.

18According to the cancer stem cell model, tumor progression and drug resistance should depend on putative cancer stem cells, and their presence should correlate with a worse outcome, despite data being discordant. Effective elimination of these cells during medical intervention is difficult, due to their self-renewal potency and resistance to chemotherapeutics. Indeed, patients with ALDH1-positive CTCs more frequently did not respond to chemotherapy. Recently, in 86% of metastatic breast cancer patients, CTCs have been demonstrated to express one or more multidrug resistance-related proteins (MRP), and patients with MRP-positive CTCs had a significantly shorter time to progression. Further studies are required to correlate the presence of CD44+CD24− or ALDH1highCD24−/low CTCs with clinical course and disease progression.

19CSCs of different metastatic sites might have different phenotypes. In HCC, stem-like CTCs were considered as seeds of metastasis and recurrence. A significant positive correlation was measured between CD133+ CTCs and serum levels of Annexin A3 (ANXA3), which is highly accurate in diagnosing early-stage HCC, and in monitoring the therapeutic response. Prognosis was worse for ANXA3-positive patients with detectable CCSCs, suggesting that serum ANXA3 could stimulate and maintain the stem cell-like traits of CD133+ CTCs to promote tumor recurrence and metastasis. In breast tumor patients, both CK+CD44+CD24−/low CTCs, or CTCs expressing CD44, MET, and CD47, might represent CSCs. Moreover, CTCs from patients with metastatic breast cancer, competent in generating brain metastases, were EPCAM− and expressed HER2, EGFR, NOTCH1, and HPSE.

20EpCAM-negative CTCs may efficiently avoid organ arrest due to the presence of stem cell and quiescence properties. The molecular switch to differentiate quiescence in malignant CTCs depends on interactions with the tumor microenvironment. Previous studies have established that the loss of the urokinase plasminogen activator receptor (uPAR) and integrin β1 (intβ1) reduces proliferative signals, with a shift from an invasive or metastatic to a dormant tumor state. In order to identify CTC subsets with properties related to breast cancer dormancy, CTC subgroups were selected for EpCAM and CD45 negativity and positivity for the CD44+CD24− stem cell signature, and the combinatorial expression of uPAR and int β1. A high expression of embryonic stem-cell genes was confirmed in the uPAR+intβ1+ CTC subset, compared to uPAR−intβ1− CTCs. Accordingly, in vitro assays confirmed the metastatic competency of uPARintβ1 CTCs, consistent with previous notions. The characterization of the uPARintβ1 CTC subset can be useful to decipher cellular and molecular mechanisms of organ-homing CTCs and cancer dormancy.

3. Clinical Relevance of Heterogeneity in CTCs

21The liquid biopsy of CTC has received great attention, due to obvious clinical implications for personalized medicine. Clinical applications of CTC detection have been extensively described in recent reviews. Strong evidence for CTCs as prognostic markers of metastatic relapse and progression has been documented. The clinical utility of CTCs enumeration for treatment decisions is currently being evaluated in interventional studies. CTC detection has been proven to predict prognosis also in early-stage tumor patients, without clinical signs of overt metastases. Detection of CTC at the time of diagnosis or after surgery for a primary tumor can identify patients at risk of recurrent or metastatic disease. Moreover, the patterns of drug susceptibility and responses to therapeutic regimens in individual patients, as tumors acquire new mutations over time, could be noninvasively monitored through the characterization of CTCs, as confirmed in a recent proof-of-concept study of drug sensitivity testing in ER–positive breast cancer CTCs. Most agents administered to prevent relapse are designed to target growing cancer cells rather than quiescent DTCs that predominate in metastatic latency. Research on these cells should help in designing novel therapeutic molecules for targeting and monitoring minimal residual disease, and to assess response to therapy.

22Unfortunately, the detection of CTCs is hampered by their still uncertain biology. Profiling of CTCs in serial liquid biopsies holds great potential to significantly improve cancer therapy by: (i) determining patient prognosis, (ii) monitoring tumor recurrence and therapeutic responses, (iii) identifying new therapeutic targets in order to prevent metastasis, (iv) elucidating drug resistance mechanisms, and (v) improving current understanding of tumor progression and metastasis.

23At present, insufficient data on the clinical relevance of stem-like CTCs is still present in the literature, mainly due to technical hurdles in detecting the very rare stem-like tumor cells among CTCs. Nonetheless, as novel non epithelial profiles of CTCs have started to emerge, in this manuscript we underline their relevance to patient management. It is possible that, as for the mesenchymal CTCs, stem-like CTCs will also be proven to bear clinical implications, as suggested from the reported early studies.

24The development of single cell analysis technologies has demonstrated a great heterogeneity in the genetic make-up of CTCs, compared to primary tumor and metastatic cells. Exclusive genetic mutations of CTCs have been identified, while additional mutations in CTCs were also detected in both subclones of primary tumor and metastatic tissues, as assessed in diverse tumors. Discordances have been reported in the expression of cancer-specific antigens between CTCs and primary tumors. CTCs represent an effective alternative to invasive tumor biopsies, thus constituting the actual targets of adjuvant therapies, and point out the emergence of resistant clones and patterns of early disease recurrence and therapy responses. CTCs in women initially diagnosed with advanced ER-positive/HER2-negative breast cancer acquired an HER2-positive subpopulation after multiple courses of therapy for recurrent metastatic tumors. Although they have comparable tumor-initiating potential and cell plasticity and expression profiles of ALDH1, these coexisting discrete chemotherapy-sensitive HER2+NOTCH1− and NOTCH inhibitor-sensitive HER2−NOTCH1+ CTCs interconvert, thus a dual treatment may be required for an effective response. Also, markers relevant to the breast cancer brain-metastasis-selected CTC profile have been reported, and the uPARintβ1 CTC subset may prospectively identify patients at high risk. In breast cancer, the oncogene PIK3CA is closely associated with the reactivation of multipotency, and a complete response is more difficult in HER2-positive tumors mutated in PIK3CA after neoadjuvant anthracycline taxane-based chemotherapy plus anti-HER2 treatment, even with a dual anti-HER2 treatment. A multimarker panel based on single CTC analysis, which defines resistant tumor cells in ovarian cancer by detecting epithelial, EMT, and stemness-associated transcripts, has recently been designed, confirming that the number of CTCs is negatively correlated with patient overall survival. In metastatic castration-resistant prostate cancer (CRPC) patients, a set of EMT-related genes (PTPRN2, ALDH1, ESR2, and WNT5A) were upregulated in CTCs; upon targeted therapy two distinct CTC subgroups were induced, which differ in both AR genotype and genomic CNV profiles. Thus, serial analyses of CTCs represent a reliable test for the molecular evolution of tumors and may be relevant upon effective targeted cancer therapy that induces drug resistance.

25As for EMT in CTCs, the presence of mesenchymal markers can accurately predict clinical outcomes and a poor prognosis. In HCC metastasis, Twist and vimentin expression can be applied as diagnostic and prognostic biomarkers; of note, the expression levels of Twist, vimentin, and E-cadherin were closely associated with the positivity rates of CTCs in peripheral blood, which indicated that EMT promotes the dissemination of primary HCC cells. In breast cancer patients, several differentially expressed genes, involved in EMT, were identified in CTC, including UPA, IGFR1, VEGFR1, and CD44, and their expression was correlated with tumor grade and metastasis. Activation of the urokinase plasminogen system, which has been associated with poor prognosis, and IGFR1 both contribute to recurrence via the inhibition of anoikis. VEGFR1, a positive regulator of angiogenesis, participates in tumor progression through the induction of EMT. Expression of CD44 has been detected in breast primary tumors and significantly increased in CTC-enriched samples, in accordance with a previous report. In pancreatic tumor expression of both epithelial and mesenchymal markers, LGFBP5 and ALDH1 have been detected in CTCs.

26The clinical relevance of mutation analysis of CTCs in assessing prognosis, stratifying patients, defining precise therapies, and monitoring therapeutic efficacy has been confirmed. In breast cancer, the analysis of single CTC with a diagnostic intention identified preexisting cells resistant to ERBB2-targeted therapies. In colorectal cancer, several mutations that induce resistance to anti-EGFR therapy have been reported; CTC monitoring has revealed that the emergence of KRAS mutant clones is a secondary mechanism of drug resistance. The acquired S492R EGFR mutation prevents cetuximab binding, and confers resistance. In non–small-cell lung cancer (NSCLC), the diagnosing of EML4-ALK rearrangement, a potent oncogenic driver, is a critical issue for identifying patients with advanced tumors that eventually respond to crizotinib. A recent study provides the first proof-of-concept that CTCs can be used for highly sensitive and specific diagnostic testing of ALK rearrangement. A unique pattern of ALK rearrangement has been consistently identified in CTCs, despite inter-tumoral heterogeneity. Additionally, results support a role for ALK in generating mesenchymal CTCs, suggesting that CTCs with a unique ALK rearrangement and a mesenchymal phenotype may result from the clonal selection of tumor cells that have acquired the potential to metastasize, such as cancer stem cells.

27As mentioned above, recent advances in the identification of stem-like signatures in primary tumors and CTC may help to improve the accuracy of diagnosis and predict therapeutic responses and overall survival of patients. Molecular profiling of CSCs has revealed their major implications for clinics. Consistently, the phenotypic features of CTCs, including CCSCs, have been analyzed to assess tumor stage, risk of cancer progression and metastases, and disease relapse, and their potential in predicting the overall outcome of patients with locally advanced and metastatic breast, prostate, ovarian, pancreatic, lung, and colorectal cancers has been confirmed. Several biomarkers of stemness have been assayed in CTCs (CD133, CD44, ALDH, and ABC multidrug transporters). In breast cancer, the expression of Nanog, Oct3/4, Sox-2, nestin, and CD34 on CTCs is directly related to disease progression. Recently, a very small cohort of metastatic breast cancer patients was evaluated after palliative chemo-, antibody—or hormonal therapy; most patients received anthracyclines and taxanes in an adjuvant or metastatic setting before the study’s start, and all patients with HER2+ tumors but one received trastuzumab in the metastatic setting. In this cohort, the expression in CTCs of at least one EMT marker and ALDH1 was detected in 62% and 44%, respectively, of patient non responders to therapy, suggesting their potential use as predictive biomarkers. The hypothesis of plasticity and stemness properties in CSCs has been addressed in endometrial carcinomas (EC), in association with a micro-RNA signature of EMT of down-modulation of the miR-200 family. The presence of endometrial CTC, profiled for stem-cell markers ALDH and CD44, was related to recurrent disease. CTCs detected in patients with advanced lung cancer include cells co-expressing cytokeratin and CD133. In a cohort of patients with primary and metastatic melanoma, the melanoma antigen melan-A and the stem cell–like marker ABCB5 were expressed in CTCs in 45% and 49% of patients with recurrence after treatment initiation, respectively.

28A major clinical relevance of CTC early detection is the identification of high-risk subjects that need additional systemic therapies after primary tumor surgery, to prevent metastasis. Currently, the selection of patients is based on the statistical risk of recurrences. Evidence for the presence of CSC in high-risk EC has been reported, and a molecular CTC-phenotype has been identified, associated with plasticity and stemness features. Previously, a six-gene panel has been assessed in CTCs in EC, with a potential in terms of diagnosis/prognosis and follow-up, and identification of new therapeutic strategies to limit metastatic dissemination. Several genes related to plasticity were significantly expressed in CTC (ETV5, NOTCH1, Snai1, TGFB1, Zeb1, Zeb2). Of note, ETV5 up-modulation promoted metastasis in in vivo models and recapitulated the plasticity phenotype of high-risk patients. The sequential assessment of CTC levels during treatment could provide information at early stages about therapeutic efficacy.

29Moreover, CSCs, generated through EMT, present intrinsic resistance to conventional chemotherapies. Current chemotherapies target the rapidly proliferating cells of the tumor bulk, with expansion of the CSC pool and/or selection of resistant and highly metastatic competent CSCs. Accordingly, in breast tumors, residual cancer cells exhibited expression profiles of cells with combined tumor-initiating and mesenchymal/claudin-low features. Gene signatures of the EMT/CSC phenotype may disclose novel molecular targets for the therapeutic resistance of breast cancers. In a seminal study, salinomycin, a potassium ionophore, has been identified with selective toxicity against CSCs generated by EMT, reducing the CD44highCD24−/low fraction and the ability of pretreated CSCs to initiate tumors and lung metastases in immunocompromised mice. Further, metformin selectively killed breast CSCs in vitro and in vivo, effectively reducing tumors and preventing relapse in mouse models. Overall, cells with the EMT/CSC phenotype may uncover new therapeutic targets for tumors, irrespective of their subtype.

4. Advancement in Methodologies for the Inclusive Detection of Stem-Like CTCs

30The rarity of CTCs in blood specimens (as few as one cell per 109 haematologic cells) requires highly specialized technologies for detection and capture, but their low sensitivity has limited the clinical utility of CTC-based diagnostics. A lot of reviews have recapitulated and pointed out a conceptual framework of CTC assays, discussing limits of technologies, in light of the recent data (see Table 2 for a list of the most relevant technologies for CTC detection and characterization). Epithelial markers, expressed on epithelial tumors but absent on leukocytes, have been frequently used. While clinical studies using the CellSearch device have confirmed the prognostic potential of CTC enumeration, only a fraction of patients with metastatic cancer score positive for CTCs. Although first defined as nucleated cells expressing EpCAM, and/or cytokeratin, and lacking the leukocyte antigen CD45, new data suggest even greater heterogeneity in CTCs. Considering the phenotypic heterogeneity and plasticity of CTCs, CTCs with no/low levels of EpCAM and a more mesenchymal phenotype, such as CSCs, might be missed by EpCAM-based capturing techniques.

31To effectively capture all diverse CTCs, additional alternative phenotypes need to be detected, and an automated and high-precision device integrating CTC capturing and sequencing is needed. Due to recent advances in the field of microfluidic bioengineering, novel methods have been introduced to improve the accuracy and sensitivity of CTC isolation, with efficient purification of viable CTCs from unprocessed whole blood, in both epithelial and non-epithelial cancers. Once CTCs have been sorted in solution, clinically standardized analyses can be applied, as well as single-cell RNA profiling. To avoid the loss of CTCs, normal haematopoietic cells have been depleted by targeting CD45. However, not all CD45– cells are tumor cells, and a CK+/CD45+ cell phenotype has been reported in metastatic cancer patients. Examples of technologies used to isolate CTCs through both enrichment and depletion include MACS, a size-dictated immunocapture chip, and the CTC-iChip. The CTC-chip enables a high yield of capture and purity, although it is technically difficult and not yet standardized for high throughput applications. The MagSweeper has been used for the genetic profiling of single-cell CTCs, including transcriptional profiling, the detection of mutations, whole exome sequencing, and analyses of stem cells in several cancers.

32High-throughput microscopy and imaging flow cytometry IFC can be combined with cutting-edge CTC isolation technology. One such approach currently under investigation relies on the concept of an inertial microfluidic device, and staining of CTCs with anti-CD45, anti-cytokeratin, anti-E-cadherin, and anti-vimentin. Once clinically validated, this technology, adapted for EMT and stem cell markers, would provide a technological solution for implementation in clinical diagnostics.

33A novel enhanced CTC enrichment strategy was established, which captures heterogeneous EpCAM-depleted CTC subsets by targeting cell surface proteins (CD44, CD47, c-Met, reported to be expressed in CTCs with metastasis-initiating properties, Trop2, CD49f, CK8, ADAM8, TEM8, CD146), as well as extracellular matrix components (laminin, collagen I, HA). In 20 out of 29 EpCAM-depleted fractions from metastatic breast cancer patients, additional EpCAMneg CTCs were identified applying Trop2, CD49f, c-Met, CK8, and/or HA magnetic enrichment. Of note, EpCAMneg cells captured by a CD44 antibody were confirmed to have a malignant nature. Further characterization of identified EpCAMpos/neg and dual-positive subsets will assess CTCs tumor origin. To prove the clinical relevance, a study identifying EpCAMlow/neg CTCs with specific genomic profiles should be designed.

34A selective and sensitive detection method for the isolation of both CTCs and CCSCs is required for advancement in precision medicine. Fluorescence-activated cell sorting has been used for CCSC isolation by comparing a CSC marker (CD133 or CD44) with leucocyte CD45. Overall, only a limited success in CCSC detection has been reported by using immune-affinity-based methods with multiple fluorescent probes. To address this, a novel nanoparticle-mediated Raman imaging method has been described for the detection and analysis of heterogeneous CTC subtypes, with a high isolation efficiency, which profiles CCSCs in accordance with surface marker expression. The selective detection and accurate analysis of tumorigenic properties of CCSCs and CTCs were demonstrated. Five different RANs, as multifunctional probes designed for the detection, isolation, and further analysis of circulating cells through Raman imaging, were designed that identify different CTC subtypes and CCSC’s stemness, by targeting CD133. Transplanted CCSCs could proliferate (CD133+ and CD44+CD24−/low), as well as differentiate, into subtype-specific breast cancer cells in metastatic cancer modeling, including HER2 positive and basal-B. By detecting CCSC, cancer metastasis and relapse would be predicted, and the heterogeneous tumorigenicity of CTCs interrogated, to facilitate the study of chemotherapy effects.

35Stem-cell-like CTCs have also been detected through PCR-based approaches. In CRC patients, the detection of CTCs positive for CEA/CK19/CK20/CD133 expression represented a significant prognostic factor for poorer DFS and OS in Dukes stage C patients, and in stage B patients with unfavorable pathological features. In addition, CEA/CK/CD133+ CTC could be a marker of treatment-resistant stem cells. In a recent study, which aimed to identify stem cell markers for CTSC detection, the differential expression of several stem cell markers was observed between CRC patients’ tumor and matched normal tissue, including OLFM4 and LGR5. Furthermore, plastin 3 (PLS3) is expressed in EMT-induced CTC in CRC, thus identifying tumor cells with a down-modulated expression of epithelial markers; the detection of such cells was an independent prognostic factor for progression-free (PFS) and overall (OS) survival, also in the Dukes B subset. These findings suggest that OLFM4, LGR5, and PLS3 may be useful for the detection of CTSCs.

36The presence of CTCs at different stages of prostate cancer has been assessed, using the ProstateCancerDetect kit and the AdnaTest EMT-2/StemCell designed panel. Positive results were mainly seen in patients with metastatic disease; EMT-like gene expression was exclusively detected in metastatic tumors, while ALDH1 was even increased in localized tumors. Thus, in advanced prostate cancer, CTCs mainly express transcripts associated with progression and metastatic disease. Even so, the test’s prognostic and predictive implications remain to be determined. The expression of several markers has been analyzed by immunocytochemistry in CTCs from patients with CRPC. Most of the CTCs co-expressed CD133 with epithelial and mesenchymal markers. A quantitative PCR method has also been used to detect EMT (Twist1 and vimentin) and stem cell genes (ABCG2, CD133, PSCA) in peripheral blood from patients with metastatic prostate cancer; expression of stem cell-related genes indicates poor prognosis, whereas EMT-related expression does not. Recently, we described a method based on a qRT-PCR assay for the identification of novel CTC markers, irrespective of currently used markers and without pre-selection or enrichment, by using patient-derived xenografts (PDXs) models; the genes identified using this method in PDX are now also being tested for the study of CTC heterogeneity in human patients.

5. Conclusions

37In conclusion, the reports we discussed here suggest a compelling need to address the definition of common criteria describing critical subtypes of CTCs. During the progression of cancer, EMT can confer properties of stem cell state and acquisition of malignant traits by more differentiated neoplastic cells. Of clinical relevance, patients with CTCs presenting a stem cell-like or EMT phenotype respond less to chemotherapies and show shorter progression-free survival. Detection of this type of CTC could be a powerful diagnostic tool for patient stratification and for the early determination of failure of a therapeutic intervention. As proof, gene signatures and stem cell–like markers expressed in CTCs have been identified for non-invasive prognosis. The molecular targeting of CSCs and CTCs represents a potential strategy to counteract cancer progression, and to overcome treatment resistance and relapse. Additionally, the identification of CSC and CTC targets might contribute to addressing the chemo-resistance of circulating CSCs, a major problem in cancer biology and therapeutics.

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Not in our library10.1080/2162402x.2015.1102827
90.
Hou J.-M., Krebs M., Ward T., Sloane R., Priest L., Hughes A., Clack G., Ranson M., Blackhall F., Dive C. Circulating tumor cells as a window on metastasis biology in lung cancer. Am. J. Pathol. 2011;178:989-996.
Not in our library10.1016/j.ajpath.2010.12.003
91.
Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition · 2012
No notice
92.
Fischer K.R., Durrans A., Lee S., Sheng J., Li F., Wong S.T.C., Choi H., El Rayes T., Ryu S., Troeger J., et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527:472-476.
Not in our library10.1038/nature15748
93.
Papadaki M.A., Kallergi G., Zafeiriou Z., Manouras L., Theodoropoulos P.A., Mavroudis D., Georgoulias V., Agelaki S. Co-expression of putative stemness and epithelial-to-mesenchymal transition markers on single circulating tumour cells from patients with early and metastatic breast cancer. BMC Cancer. 2014;14:651.
Not in our library10.1186/1471-2407-14-651
94.
Markiewicz A., Nagel A., Szade J., Majewska H., Skokowski J., Seroczynska B., Stokowy T., Welnicka-Jaskiewicz M., Zaczek A.J. Aggressive Phenotype of Cells Disseminated via Hematogenous and Lymphatic Route in Breast Cancer Patients. Transl. Oncol. 2018;11:722-731.
Not in our library10.1016/j.tranon.2018.03.006
95.
Klein C.A., Blankenstein T.J.F., Schmidt-Kittler O., Petronio M., Polzer B., Stoecklein N.H., Riethmüller G. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet. 2002;360:683-689.
Not in our library10.1016/s0140-6736(02)09838-0
96.
Mizrak D., Brittan M., Alison M.R. CD133: Molecule of the moment. J. Pathol. 2008;214:3-9.
Not in our library10.1002/path.2283
97.
Zöller M. CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule? Nat. Rev. Cancer. 2011;11:254-267.
Not in our library10.1038/nrc3023
98.
Riethdorf S., Wikman H., Pantel K. Review: Biological relevance of disseminated tumor cells in cancer patients. Int. J. Cancer. 2008;123:1991-2006.
Not in our library10.1002/ijc.23825
99.
Malanchi I., Santamaria-Martínez A., Susanto E., Peng H., Lehr H.-A., Delaloye J.-F., Huelsken J. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature. 2011;481:85-89.
Not in our library10.1038/nature10694
100.
Kennecke H., Yerushalmi R., Woods R., Cheang M.C.U., Voduc D., Speers C.H., Nielsen T.O., Gelmon K. Metastatic behavior of breast cancer subtypes. J. Clin. Oncol. 2010;28:3271-3277.
Not in our library10.1200/jco.2009.25.9820
101.
Koren A., Rijavec M., Kern I., Sodja E., Korosec P., Cufer T. BMI1, ALDH1A1, and CD133 Transcripts Connect Epithelial-Mesenchymal Transition to Cancer Stem Cells in Lung Carcinoma. Stem Cells Int. 2016;2016:9714315.
Not in our library10.1155/2016/9714315
102.
Nel I., David P., Gerken G.G.H., Schlaak J.F., Hoffmann A.-C. Role of circulating tumor cells and cancer stem cells in hepatocellular carcinoma. Hepatol. Int. 2014;8:321-329.
Not in our library10.1007/s12072-014-9539-3
103.
Katoh S., Goi T., Naruse T., Ueda Y., Kurebayashi H., Nakazawa T., Kimura Y., Hirono Y., Yamaguchi A. Cancer stem cell marker in circulating tumor cells: Expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer. Anticancer Res. 2015;35:239-244.
Not in our library
104.
Li M., Zhang B., Zhang Z., Liu X., Qi X., Zhao J., Jiang Y., Zhai H., Ji Y., Luo D. Stem cell-like circulating tumor cells indicate poor prognosis in gastric cancer. Biomed. Res. Int. 2014;2014:981261.
Not in our library10.1155/2014/981261
105.
Zhu L., Zhang W., Wang J., Liu R. Evidence of CD90+CXCR4+ cells as circulating tumor stem cells in hepatocellular carcinoma. Tumor Biol. 2015;36:5353-5360.
Not in our library10.1007/s13277-015-3196-6
106.
Pantel K., Brakenhoff R.H., Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat. Rev. Cancer. 2008;8:329-340.
Not in our library10.1038/nrc2375
107.
Korkaya H., Paulson A., Iovino F., Wicha M.S. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27:6120-6130.
Not in our library10.1038/onc.2008.207
108.
Trumpp A., Wiestler O.D. Mechanisms of Disease: Cancer stem cells—Targeting the evil twin. Nat. Clin. Pract. Oncol. 2008;5:337-347.
Not in our library10.1038/ncponc1110
109.
Mylona E., Giannopoulou I., Fasomytakis E., Nomikos A., Magkou C., Bakarakos P., Nakopoulou L. The clinicopathologic and prognostic significance of CD44+/CD24(−/low) and CD44−/CD24+ tumor cells in invasive breast carcinomas. Hum. Pathol. 2008;39:1096-1102.
Not in our library10.1016/j.humpath.2007.12.003
110.
Gradilone A., Naso G., Raimondi C., Cortesi E., Gandini O., Vincenzi B., Saltarelli R., Chiapparino E., Spremberg F., Cristofanilli M., et al. Circulating tumor cells (CTCs) in metastatic breast cancer (MBC): Prognosis, drug resistance and phenotypic characterization. Ann. Oncol. 2011;22:86-92.
Not in our library10.1093/annonc/mdq323
111.
Ma X.-L., Jiang M., Zhao Y., Wang B.-L., Shen M.-N., Zhou Y., Zhang C.-Y., Sun Y.-F., Chen J.-W., Hu B., et al. Application of Serum Annexin A3 in Diagnosis, Outcome Prediction and Therapeutic Response Evaluation for Patients with Hepatocellular Carcinoma. Ann. Surg. Oncol. 2018;25:1686-1694.
Not in our library10.1245/s10434-018-6402-0
112.
Zhang L., Ridgway L.D., Wetzel M.D., Ngo J., Yin W., Kumar D., Goodman J.C., Groves M.D., Marchetti D. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci. Transl. Med. 2013;5:180ra48.
Not in our library10.1126/scitranslmed.3005109
113.
Sosa M.S., Bragado P., Aguirre-Ghiso J.A. Mechanisms of disseminated cancer cell dormancy: An awakening field. Nat. Rev. Cancer. 2014;14:611-622.
Not in our library10.1038/nrc3793
114.
Obermayr E., Sanchez-Cabo F., Tea M.-K.M., Singer C.F., Krainer M., Fischer M.B., Sehouli J., Reinthaller A., Horvat R., Heinze G., et al. Assessment of a six gene panel for the molecular detection of circulating tumor cells in the blood of female cancer patients. BMC Cancer. 2010;10:666.
Not in our library10.1186/1471-2407-10-666
115.
Raimondi C., Gradilone A., Naso G., Vincenzi B., Petracca A., Nicolazzo C., Palazzo A., Saltarelli R., Spremberg F., Cortesi E., et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res. Treat. 2011;130:449-455.
Not in our library10.1007/s10549-011-1373-x
116.
Armstrong A.J., Marengo M.S., Oltean S., Kemeny G., Bitting R.L., Turnbull J.D., Herold C.I., Marcom P.K., George D.J., Garcia-Blanco M.A. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol. Cancer Res. 2011;9:997-1007.
Not in our library10.1158/1541-7786.mcr-10-0490
117.
Wang N., Shi L., Li H., Hu Y., Du W., Liu W., Zheng J., Huang S., Qu X. Detection of circulating tumor cells and tumor stem cells in patients with breast cancer by using flow cytometry: A valuable tool for diagnosis and prognosis evaluation. Tumor Biol. 2012;33:561-569.
Not in our library10.1007/s13277-011-0303-1
118.
Apostolou P., Toloudi M., Chatziioannou M., Ioannou E., Papasotiriou I. Cancer stem cells stemness transcription factors expression correlates with breast cancer disease stage. Curr. Stem Cell Res. Ther. 2012;7:415-419.
Not in our library10.2174/157488812804484639
119.
Papadaki M.A., Stoupis G., Theodoropoulos P.A., Mavroudis D., Georgoulias V., Agelaki S. Circulating tumor cells with stemness and epithelial-to-mesenchymal transition features are chemoresistant 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
120.
Molecular Biomarker Analyses Using Circulating Tumor Cells · 2010
No notice
121.
Obermayr E., Castillo-Tong D.C., Pils D., Speiser P., Braicu I., Van Gorp T., Mahner S., Sehouli J., Vergote I., Zeillinger R. Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance—A study of the OVCAD consortium. Gynecol. Oncol. 2013;128:15-21.
Not in our library10.1016/j.ygyno.2012.09.021
122.
Alonso-Alconada L., Muinelo-Romay L., Madissoo K., Diaz-Lopez A., Krakstad C., Trovik J., Wik E., Hapangama D., Coenegrachts L., Cano A., et al. Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer. Mol. Cancer. 2014;13:223.
Not in our library10.1186/1476-4598-13-223
123.
Blassl C., Kuhlmann J.D., Webers A., Wimberger P., Fehm T., Neubauer H. Gene expression profiling of single circulating tumor cells in ovarian cancer—Establishment of a multi-marker gene panel. Mol. Oncol. 2016;10:1030-1042.
Not in our library10.1016/j.molonc.2016.04.002
124.
Hofman V., Ilie M.I., Long E., Selva E., Bonnetaud C., Molina T., Vénissac N., Mouroux J., Vielh P., Hofman P. Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non-small-cell lung carcinoma: Comparison of the efficacy of the CellSearch AssayTM and the isolation by size of epithelial tumor cell method. Int. J. Cancer. 2011;129:1651-1660.
Not in our library10.1002/ijc.25819
125.
Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer · 2011
No notice
126.
Pailler E., Adam J., Barthélémy A., Oulhen M., Auger N., Valent A., Borget I., Planchard D., Taylor M., André F., et al. Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer. J. Clin. Oncol. 2013;31:2273-2281.
Not in our library10.1200/jco.2012.44.5932
127.
Hou H.W., Warkiani M.E., Khoo B.L., Li Z.R., Soo R.A., Tan D.S.-W., Lim W.-T., Han J., Bhagat A.A.S., Lim C.T. Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci. Rep. 2013;3:1259.
Not in our library10.1038/srep01259
128.
Yang Z.F., Ho D.W., Ng M.N., Lau C.K., Yu W.C., Ngai P., Chu P.W.K., Lam C.T., Poon R.T.P., Fan S.T. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008;13:153-166.
Not in our library10.1016/j.ccr.2008.01.013
129.
Liu S., Li N., Yu X., Xiao X., Cheng K., Hu J., Wang J., Zhang D., Cheng S., Liu S. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology. 2013;144:1031.e10-1041.e10.
Not in our library10.1053/j.gastro.2013.01.046
130.
Nel I., Baba H.A., Ertle J., Weber F., Sitek B., Eisenacher M., Meyer H.E., Schlaak J.F., Hoffmann A.-C. Individual profiling of circulating tumor cell composition and therapeutic outcome in patients with hepatocellular carcinoma. Transl. Oncol. 2013;6:420-428.
Not in our library10.1593/tlo.13271
131.
Li Y.-M., Xu S.-C., Li J., Han K.-Q., Pi H.-F., Zheng L., Zuo G.-H., Huang X.-B., Li H.-Y., Zhao H.-Z., et al. Epithelial-mesenchymal transition markers expressed in circulating tumor cells in hepatocellular carcinoma patients with different stages of disease. Cell Death Dis. 2013;4:e831.
Not in our library10.1038/cddis.2013.347
132.
Gazzaniga P., Gradilone A., Petracca A., Nicolazzo C., Raimondi C., Iacovelli R., Naso G., Cortesi E. Molecular markers in circulating tumour cells from metastatic colorectal cancer patients. J. Cell. Mol. Med. 2010;14:2073-2077.
Not in our library10.1111/j.1582-4934.2010.01117.x
133.
Fang C., Fan C., Wang C., Huang Q., Meng W., Yu Y., Yang L., Hu J., Li Y., Mo X., et al. Prognostic value of CD133+ CD54+ CD44+ circulating tumor cells in colorectal cancer with liver metastasis. Cancer Med. 2017;6:2850-2857.
Not in our library10.1002/cam4.1241
134.
A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker · 2011
No notice
135.
Single-Cell RNA Sequencing Identifies Extracellular Matrix Gene Expression by Pancreatic Circulating Tumor Cells · 2014
No notice
136.
van den Hoogen C., van der Horst G., Cheung H., Buijs J.T., Lippitt J.M., Guzmán-Ramírez N., Hamdy F.C., Eaton C.L., Thalmann G.N., Cecchini M.G., et al. High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 2010;70:5163-5173.
Not in our library10.1158/0008-5472.can-09-3806
137.
Chen C.-L., Mahalingam D., Osmulski P., Jadhav R.R., Wang C.-M., Leach R.J., Chang T.-C., Weitman S.D., Kumar A.P., Sun L., et al. Single-cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT-related genes in metastatic prostate cancer. Prostate. 2013;73:813-826.
Not in our library10.1002/pros.22625
138.
Reid A.L., Millward M., Pearce R., Lee M., Frank M.H., Ireland A., Monshizadeh L., Rai T., Heenan P., Medic S., et al. Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression. Br. J. Dermatol. 2013;168:85-92.
Not in our library10.1111/bjd.12057
139.
Cristofanilli M., Reuben J., Uhr J. Circulating tumor cells in breast cancer: Fiction or reality? J. Clin. Oncol. 2008;26:3656-3658.
Not in our library10.1200/jco.2008.18.0356
140.
Braun S., Vogl F.D., Naume B., Janni W., Osborne M.P., Coombes R.C., Schlimok G., Diel I.J., Gerber B., Gebauer G., et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N. Engl. J. Med. 2005;353:793-802.
Not in our library10.1056/nejmoa050434
141.
Zhang L., Riethdorf S., Wu G., Wang T., Yang K., Peng G., Liu J., Pantel K. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin. Cancer Res. 2012;18:5701-5710.
Not in our library10.1158/1078-0432.ccr-12-1587
142.
Scher H.I., Jia X., de Bono J.S., Fleisher M., Pienta K.J., Raghavan D., Heller G. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: A reanalysis of IMMC38 trial data. Lancet Oncol. 2009;10:233-239.
Not in our library10.1016/s1470-2045(08)70340-1
143.
Hou J.-M., Krebs M.G., Lancashire L., Sloane R., Backen A., Swain R.K., Priest L.J.C., Greystoke A., Zhou C., Morris K., et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J. Clin. Oncol. 2012;30:525-532.
Not in our library10.1200/jco.2010.33.3716
144.
Krebs M.G., Sloane R., Priest L., Lancashire L., Hou J.-M., Greystoke A., Ward T.H., Ferraldeschi R., Hughes A., Clack G., et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J. Clin. Oncol. 2011;29:1556-1563.
Not in our library10.1200/jco.2010.28.7045
145.
Aggarwal C., Meropol N.J., Punt C.J., Iannotti N., Saidman B.H., Sabbath K.D., Gabrail N.Y., Picus J., Morse M.A., Mitchell E., et al. Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Ann. Oncol. 2013;24:420-428.
Not in our library10.1093/annonc/mds336
146.
Denève E., Riethdorf S., Ramos J., Nocca D., Coffy A., Daurès J.-P., Maudelonde T., Fabre J.-M., Pantel K., Alix-Panabières C. Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin. Chem. 2013;59:1384-1392.
Not in our library10.1373/clinchem.2013.202846
147.
Bidard F.-C., Fehm T., Ignatiadis M., Smerage J.B., Alix-Panabières C., Janni W., Messina C., Paoletti C., Müller V., Hayes D.F., et al. Clinical application of circulating tumor cells in breast cancer: Overview of the current interventional trials. Cancer Metastasis Rev. 2013;32:179-188.
Not in our library10.1007/s10555-012-9398-0
148.
Cristofanilli M., Braun S. Circulating tumor cells revisited. JAMA. 2010;303:1092-1093.
Not in our library10.1001/jama.2010.292
149.
Hardingham J.E., Kotasek D., Sage R.E., Eaton M.C., Pascoe V.H., Dobrovic A. Detection of circulating tumor cells in colorectal cancer by immunobead-PCR is a sensitive prognostic marker for relapse of disease. Mol. Med. 1995;1:789-794.
Not in our library10.1007/bf03401893
150.
Hardingham J.E., Hewett P.J., Sage R.E., Finch J.L., Nuttall J.D., Kotasek D., Dobrovic A. Molecular detection of blood-borne epithelial cells in colorectal cancer patients and in patients with benign bowel disease. Int. J. Cancer. 2000;89:8-13.
Not in our library10.1002/(sici)1097-0215(20000120)89:1<8::aid-ijc2>3.0.co;2-k
151.
Miyamoto D.T., Zheng Y., Wittner B.S., Lee R.J., Zhu H., Broderick K.T., Desai R., Fox D.B., Brannigan B.W., Trautwein J., 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
152.
Fernandez S.V., Bingham C., Fittipaldi P., Austin L., Palazzo J., Palmer G., Alpaugh K., Cristofanilli M. TP53 mutations detected in circulating tumor cells present in the blood of metastatic triple negative breast cancer patients. Breast Cancer Res. 2014;16:445.
Not in our library10.1186/s13058-014-0445-3
153.
Jordan N.V., Bardia A., Wittner B.S., Benes C., Ligorio M., Zheng Y., Yu M., Sundaresan T.K., Licausi J.A., Desai R., et al. HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature. 2016;537:102-106.
Not in our library10.1038/nature19328
154.
Houssami N., Macaskill P., Balleine R.L., Bilous M., Pegram M.D. HER2 discordance between primary breast cancer and its paired metastasis: Tumor biology or test artefact? Insights through meta-analysis. Breast Cancer Res. Treat. 2011;129:659-674.
Not in our library10.1007/s10549-011-1632-x
155.
Heitzer E., Auer M., Gasch C., Pichler M., Ulz P., Hoffmann E.M., Lax S., Waldispuehl-Geigl J., Mauermann O., Lackner C., et al. Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res. 2013;73:2965-2975.
Not in our library10.1158/0008-5472.can-12-4140
156.
Lohr J.G., Adalsteinsson V.A., Cibulskis K., Choudhury A.D., Rosenberg M., Cruz-Gordillo P., Francis J.M., Zhang C.-Z., Shalek A.K., Satija R., 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
157.
Ferreira M.M., Ramani V.C., Jeffrey S.S. Circulating tumor cell technologies. Mol. Oncol. 2016;10:374-394.
Not in our library10.1016/j.molonc.2016.01.007
158.
Arteaga C.L., Engelman J.A. ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25:282-303.
Not in our library10.1016/j.ccr.2014.02.025
159.
Van Keymeulen A., Lee M.Y., Ousset M., Brohée S., Rorive S., Giraddi R.R., Wuidart A., Bouvencourt G., Dubois C., Salmon I., et al. Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature. 2015;525:119-123.
Not in our library10.1038/nature14665
160.
Loibl S., von Minckwitz G., Schneeweiss A., Paepke S., Lehmann A., Rezai M., Zahm D.M., Sinn P., Khandan F., Eidtmann H., et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J. Clin. Oncol. 2014;32:3212-3220.
Not in our library10.1200/jco.2014.55.7876
161.
Rapid Phenotypic and Genomic Change in Response to Therapeutic Pressure in Prostate Cancer Inferred by High Content Analysis of Single Circulating Tumor Cells · 2014
No notice
162.
Bednarz-Knoll N., Alix-Panabières C., Pantel K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev. 2012;31:673-687.
Not in our library10.1007/s10555-012-9370-z
163.
Zhou Y.-M., Cao L., Li B., Zhang R.-X., Sui C.-J., Yin Z.-F., Yang J.-M. Clinicopathological significance of ZEB1 protein in patients with hepatocellular carcinoma. Ann. Surg. Oncol. 2012;19:1700-1706.
Not in our library10.1245/s10434-011-1772-6
164.
de Witte J.H., Foekens J.A., Brünner N., Heuvel J.J., van Tienoven T., Look M.P., Klijn J.G., Geurts-Moespot A., Grebenchtchikov N., Benraad T., et al. Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours. Br. J. Cancer. 2001;85:85-92.
Not in our library10.1054/bjoc.2001.1867
165.
Alfano D., Iaccarino I., Stoppelli M.P. Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. J. Biol. Chem. 2006;281:17758-17767.
Not in our library10.1074/jbc.m601812200
166.
Ravid D., Maor S., Werner H., Liscovitch M. Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling. Oncogene. 2005;24:1338-1347.
Not in our library10.1038/sj.onc.1208337
167.
Yang A.D., Camp E.R., Fan F., Shen L., Gray M.J., Liu W., Somcio R., Bauer T.W., Wu Y., Hicklin D.J., et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006;66:46-51.
Not in our library10.1158/0008-5472.can-05-3086
168.
CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers · 2011
No notice
169.
Navin N., Hicks J. Future medical applications of single-cell sequencing in cancer. Genome Med. 2011;3:31.
Not in our library10.1186/gm247
170.
Riethdorf S., Pantel K. Advancing personalized cancer therapy by detection and characterization of circulating carcinoma cells. Ann. N. Y. Acad. Sci. 2010;1210:66-77.
Not in our library10.1111/j.1749-6632.2010.05779.x
171.
Molecular profiling of single circulating tumor cells with diagnostic intention · 2014
No notice
172.
Diaz L.A., Williams R.T., Wu J., Kinde I., Hecht J.R., Berlin J., Allen B., Bozic I., Reiter J.G., Nowak M.A., et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537-540.
Not in our library10.1038/nature11219
173.
Misale S., Yaeger R., Hobor S., Scala E., Janakiraman M., Liska D., Valtorta E., Schiavo R., Buscarino M., Siravegna G., et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532-536.
Not in our library10.1038/nature11156
174.
Montagut C., Dalmases A., Bellosillo B., Crespo M., Pairet S., Iglesias M., Salido M., Gallen M., Marsters S., Tsai S.P., et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat. Med. 2012;18:221-223.
Not in our library10.1038/nm.2609
175.
Pao W., Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180.
Not in our library10.1016/s1470-2045(10)70087-5
176.
Soda M., Choi Y.L., Enomoto M., Takada S., Yamashita Y., Ishikawa S., Fujiwara S., Watanabe H., Kurashina K., Hatanaka H., et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566.
Not in our library10.1038/nature05945
177.
Kwak E.L., Bang Y.-J., Camidge D.R., Shaw A.T., Solomon B., Maki R.G., Ou S.-H.I., Dezube B.J., Jänne P.A., Costa D.B., et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 2010;363:1693-1703.
Not in our library10.1056/nejmoa1006448
178.
Glinsky G.V., Berezovska O., Glinskii A.B. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J. Clin. Investig. 2005;115:1503-1521.
Not in our library10.1172/jci23412
179.
Glinsky G.V. “Stemness” genomics law governs clinical behavior of human cancer: Implications for decision making in disease management. J. Clin. Oncol. 2008;26:2846-2853.
Not in our library10.1200/jco.2008.17.0266
180.
Toloudi M., Apostolou P., Chatziioannou M., Papasotiriou I. Correlation between Cancer Stem Cells and Circulating Tumor Cells and Their Value. Case Rep. Oncol. 2011;4:44-54.
Not in our library10.1159/000324403
181.
Qin J., Liu X., Laffin B., Chen X., Choy G., Jeter C.R., Calhoun-Davis T., Li H., Palapattu G.S., Pang S., et al. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell. 2012;10:556-569.
Not in our library10.1016/j.stem.2012.03.009
182.
de Bono J.S., Scher H.I., Montgomery R.B., Parker C., Miller M.C., Tissing H., Doyle G.V., Terstappen L.W.W.M., Pienta K.J., Raghavan D. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin. Cancer Res. 2008;14:6302-6309.
Not in our library10.1158/1078-0432.ccr-08-0872
183.
Punnoose E.A., Atwal S., Liu W., Raja R., Fine B.M., Hughes B.G.M., Hicks R.J., Hampton G.M., Amler L.C., Pirzkall A., 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
184.
Mirantes C., Espinosa I., Ferrer I., Dolcet X., Prat J., Matias-Guiu X. Epithelial-to-mesenchymal transition and stem cells in endometrial cancer. Hum. Pathol. 2013;44:1973-1981.
Not in our library10.1016/j.humpath.2013.04.009
185.
Wang G., Guo X., Hong W., Liu Q., Wei T., Lu C., Gao L., Ye D., Zhou Y., Chen J., et al. Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation. Proc. Natl. Acad. Sci. USA. 2013;110:2858-2863.
Not in our library10.1073/pnas.1212769110
186.
Wik E., Ræder M.B., Krakstad C., Trovik J., Birkeland E., Hoivik E.A., Mjos S., Werner H.M.J., Mannelqvist M., Stefansson I.M., et al. Lack of estrogen receptor-α is associated with epithelial-mesenchymal transition and PI3K alterations in endometrial carcinoma. Clin. Cancer Res. 2013;19:1094-1105.
Not in our library10.1158/1078-0432.ccr-12-3039
187.
Colas E., Muinelo-Romay L., Alonso-Alconada L., Llaurado M., Monge M., Barbazan J., Gonzalez M., Schoumacher M., Pedrola N., Ertekin T., et al. ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas. Oncogene. 2012;31:4778-4788.
Not in our library10.1038/onc.2011.632
188.
Phillips T.M., McBride W.H., Pajonk F. The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J. Natl. Cancer Inst. 2006;98:1777-1785.
Not in our library10.1093/jnci/djj495
189.
Li X., Lewis M.T., Huang J., Gutierrez C., Osborne C.K., Wu M.-F., Hilsenbeck S.G., Pavlick A., Zhang X., Chamness G.C., et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl. Cancer Inst. 2008;100:672-679.
Not in our library10.1093/jnci/djn123
190.
Creighton C.J., Li X., Landis M., Dixon J.M., Neumeister V.M., Sjolund A., Rimm D.L., Wong H., Rodriguez A., Herschkowitz J.I., et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci. USA. 2009;106:13820-13825.
Not in our library10.1073/pnas.0905718106
191.
Zhang M., Atkinson R.L., Rosen J.M. Selective targeting of radiation-resistant tumor-initiating cells. Proc. Natl. Acad. Sci. USA. 2010;107:3522-3527.
Not in our library10.1073/pnas.0910179107
192.
Gupta P.B., Onder T.T., Jiang G., Tao K., Kuperwasser C., Weinberg R.A., Lander E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645-659.
Not in our library10.1016/j.cell.2009.06.034
193.
Hirsch H.A., Iliopoulos D., Tsichlis P.N., Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69:7507-7511.
Not in our library10.1158/0008-5472.can-09-2994
194.
Hardingham J.E., Grover P., Winter M., Hewett P.J., Price T.J., Thierry B. Detection and Clinical Significance of Circulating Tumor Cells in Colorectal Cancer--20 Years of Progress. Mol. Med. 2015;21(Suppl. 1):S25-S31.
Not in our library10.2119/molmed.2015.00149
195.
Nagrath S., Sequist L.V., Maheswaran S., Bell D.W., Irimia D., Ulkus L., Smith M.R., Kwak E.L., Digumarthy S., Muzikansky A., et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235-1239.
Not in our library10.1038/nature06385
196.
Maheswaran S., Sequist L.V., Nagrath S., Ulkus L., Brannigan B., Collura C.V., Inserra E., Diederichs S., Iafrate A.J., Bell D.W., et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 2008;359:366-377.
Not in our library10.1056/nejmoa0800668
197.
Stott S.L., Hsu C.-H., Tsukrov D.I., Yu M., Miyamoto D.T., Waltman B.A., Rothenberg S.M., Shah A.M., Smas M.E., Korir G.K., 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
198.
Pantel K., Alix-Panabières C., Riethdorf S. Cancer micrometastases. Nat. Rev. Clin. Oncol. 2009;6:339-351.
Not in our library10.1038/nrclinonc.2009.44
199.
Pantel K., Alix-Panabières C. Circulating tumour cells in cancer patients: Challenges and perspectives. Trends Mol. Med. 2010;16:398-406.
Not in our library10.1016/j.molmed.2010.07.001
200.
Pantel K., Alix-Panabières C. Real-time liquid biopsy in cancer patients: Fact or fiction? Cancer Res. 2013;73:6384-6388.
Not in our library10.1158/0008-5472.can-13-2030
201.
Riethdorf S., Fritsche H., Müller V., Rau T., Schindlbeck C., Rack B., Janni W., Coith C., Beck K., Jänicke F., et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: A validation study of the CellSearch system. Clin. Cancer Res. 2007;13:920-928.
Not in our library10.1158/1078-0432.ccr-06-1695
202.
Coumans F.A.W., Ligthart S.T., Uhr J.W., Terstappen L.W.M.M. Challenges in the enumeration and phenotyping of CTC. Clin. Cancer Res. 2012;18:5711-5718.
Not in our library10.1158/1078-0432.ccr-12-1585
203.
Detection of EpCAM-Negative and Cytokeratin-Negative Circulating Tumor Cells in Peripheral Blood · 2011
No notice
204.
Pecot C.V., Bischoff F.Z., Mayer J.A., Wong K.L., Pham T., Bottsford-Miller J., Stone R.L., Lin Y.G., Jaladurgam P., Roh J.W., 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
205.
Serrano M.J., Ortega F.G., Alvarez-Cubero M.J., Nadal R., Sanchez-Rovira P., Salido M., Rodríguez M., García-Puche J.L., Delgado-Rodriguez M., Solé F., et al. EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer. Oncotarget. 2014;5:7486-7497.
Not in our library10.18632/oncotarget.2217
206.
Schneck H., Gierke B., Uppenkamp F., Behrens B., Niederacher D., Stoecklein N.H., Templin M.F., Pawlak M., Fehm T., Neubauer H., et al. EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer. PLoS ONE. 2015;10:e0144535.
Not in our library10.1371/journal.pone.0144535
207.
Joosse S.A., Hannemann J., Spötter J., Bauche A., Andreas A., Müller V., Pantel K. Changes in keratin expression during metastatic progression of breast cancer: Impact on the detection of circulating tumor cells. Clin. Cancer Res. 2012;18:993-1003.
Not in our library10.1158/1078-0432.ccr-11-2100
208.
Lawson D.A., Bhakta N.R., Kessenbrock K., Prummel K.D., Yu Y., Takai K., Zhou A., Eyob H., Balakrishnan S., Wang C.-Y., et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature. 2015;526:131-135.
Not in our library10.1038/nature15260
209.
Lu J., Fan T., Zhao Q., Zeng W., Zaslavsky E., Chen J.J., Frohman M.A., Golightly M.G., Madajewicz S., Chen W.-T. Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int. J. Cancer. 2010;126:669-683.
Not in our library10.1002/ijc.24814
210.
Harb W., Fan A., Tran T., Danila D.C., Keys D., Schwartz M., Ionescu-Zanetti C. Mutational Analysis of Circulating Tumor Cells Using a Novel Microfluidic Collection Device and qPCR Assay. Transl. Oncol. 2013;6:528-538.
Not in our library10.1593/tlo.13367
211.
Riahi R., Gogoi P., Sepehri S., Zhou Y., Handique K., Godsey J., Wang Y. A novel microchannel-based device to capture and analyze circulating tumor cells (CTCs) of breast cancer. Int. J. Oncol. 2014;44:1870-1878.
Not in our library10.3892/ijo.2014.2353
212.
Kim Y.J., Koo G.-B., Lee J.-Y., Moon H.-S., Kim D.-G., Lee D.-G., Lee J.-Y., Oh J.H., Park J.-M., Kim M.S., et al. A microchip filter device incorporating slit arrays and 3-D flow for detection of circulating tumor cells using CAV1-EpCAM conjugated microbeads. Biomaterials. 2014;35:7501-7510.
Not in our library10.1016/j.biomaterials.2014.05.039
213.
Gabriel M.T., Calleja L.R., Chalopin A., Ory B., Heymann D. Circulating Tumor Cells: A Review of Non-EpCAM-Based Approaches for Cell Enrichment and Isolation. Clin. Chem. 2016;62:571-581.
Not in our library10.1373/clinchem.2015.249706
214.
Cho H.-Y., Hossain M.K., Lee J.-H., Han J., Lee H.J., Kim K.-J., Kim J.-H., Lee K.-B., Choi J.-W. Selective isolation and noninvasive analysis of circulating cancer stem cells through Raman imaging. Biosens. Bioelectron. 2018;102:372-382.
Not in our library10.1016/j.bios.2017.11.049
215.
Yoon H.J., Kim T.H., Zhang Z., Azizi E., Pham T.M., Paoletti C., Lin J., Ramnath N., Wicha M.S., Hayes D.F., et al. Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets. Nat. Nanotechnol. 2013;8:735-741.
Not in our library10.1038/nnano.2013.194
216.
Sheng W., Ogunwobi O.O., Chen T., Zhang J., George T.J., Liu C., Fan Z.H. Capture, release and culture of circulating tumor cells from pancreatic cancer patients using an enhanced mixing chip. Lab Chip. 2014;14:89-98.
Not in our library10.1039/c3lc51017d
217.
Miyamoto D.T., Lee R.J., Stott S.L., Ting D.T., Wittner B.S., Ulman M., Smas M.E., Lord J.B., Brannigan B.W., Trautwein J., et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov. 2012;2:995-1003.
Not in our library10.1158/2159-8290.cd-12-0222
218.
Yang L., Lang J.C., Balasubramanian P., Jatana K.R., Schuller D., Agrawal A., Zborowski M., Chalmers J.J. Optimization of an enrichment process for circulating tumor cells from the blood of head and neck cancer patients through depletion of normal cells. Biotechnol. Bioeng. 2009;102:521-534.
Not in our library10.1002/bit.22066
219.
Karabacak N.M., Spuhler P.S., Fachin F., Lim E.J., Pai V., Ozkumur E., Martel J.M., Kojic N., Smith K., Chen P., et al. Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nat. Protoc. 2014;9:694-710.
Not in our library10.1038/nprot.2014.044
220.
Warkiani M.E., Guan G., Luan K.B., Lee W.C., Bhagat A.A.S., Chaudhuri P.K., Tan D.S.-W., Lim W.T., Lee S.C., Chen P.C.Y., et al. Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells. Lab Chip. 2014;14:128-137.
Not in our library10.1039/c3lc50617g
221.
Mostert B., Kraan J., Bolt-de Vries J., van der Spoel P., Sieuwerts A.M., Schutte M., Timmermans A.M., Foekens R., Martens J.W.M., Gratama J.-W., et al. Detection of circulating tumor cells in breast cancer may improve through enrichment with anti-CD146. Breast Cancer Res. Treat. 2011;127:33-41.
Not in our library10.1007/s10549-010-0879-y
222.
Mostert B., Kraan J., Sieuwerts A.M., van der Spoel P., Bolt-de Vries J., Prager-van der Smissen W.J.C., Smid M., Timmermans A.M., Martens J.W.M., Gratama J.W., et al. CD49f-based selection of circulating tumor cells (CTCs) improves detection across breast cancer subtypes. Cancer Lett. 2012;319:49-55.
Not in our library10.1016/j.canlet.2011.12.031
223.
Obermajer N., Doljak B., Kos J. Cytokeratin 8 ectoplasmic domain binds urokinase-type plasminogen activator to breast tumor cells and modulates their adhesion, growth and invasiveness. Mol. Cancer. 2009;8:88.
Not in our library10.1186/1476-4598-8-88
224.
Romagnoli M., Mineva N.D., Polmear M., Conrad C., Srinivasan S., Loussouarn D., Barillé-Nion S., Georgakoudi I., Dagg Á., McDermott E.W., et al. ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis. EMBO Mol. Med. 2014;6:278-294.
Not in our library10.1002/emmm.201303373
225.
Chen D., Bhat-Nakshatri P., Goswami C., Badve S., Nakshatri H. ANTXR1, a stem cell-enriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer. Cancer Res. 2013;73:5821-5833.
Not in our library10.1158/0008-5472.can-13-1080
226.
Kantara C., O’Connell M.R., Luthra G., Gajjar A., Sarkar S., Ullrich R.L., Singh P. Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis. Lab. Investig. 2015;95:100-112.
Not in our library10.1038/labinvest.2014.133
227.
Pattabiraman D.R., Weinberg R.A. Tackling the cancer stem cells—What challenges do they pose? Nat. Rev. Drug Discov. 2014;13:497-512.
Not in our library10.1038/nrd4253
228.
Lee H.J., Cho H.-Y., Oh J.H., Namkoong K., Lee J.G., Park J.-M., Lee S.S., Huh N., Choi J.-W. Simultaneous capture and in situ analysis of circulating tumor cells using multiple hybrid nanoparticles. Biosens. Bioelectron. 2013;47:508-514.
Not in our library10.1016/j.bios.2013.03.040
229.
Iinuma H., Watanabe T., Mimori K., Adachi M., Hayashi N., Tamura J., Matsuda K., Fukushima R., Okinaga K., Sasako M., et al. Clinical significance of circulating tumor cells, including cancer stem-like cells, in peripheral blood for recurrence and prognosis in patients with Dukes’ stage B and C colorectal cancer. J. Clin. Oncol. 2011;29:1547-1555.
Not in our library10.1200/jco.2010.30.5151
230.
Grover P.K., Hardingham J.E., Cummins A.G. Stem cell marker olfactomedin 4: Critical appraisal of its characteristics and role in tumorigenesis. Cancer Metastasis Rev. 2010;29:761-775.
Not in our library10.1007/s10555-010-9262-z
231.
Russo G.I., Bier S., Hennenlotter J., Beger G., Pavlenco L., van de Flierdt J., Hauch S., Maas M., Walz S., Rausch S., et al. Expression of tumour progression-associated genes in circulating tumour cells of patients at different stages of prostate cancer. BJU Int. 2018;122:152-159.
Not in our library10.1111/bju.14200
232.
Agnoletto C., Minotti L., Brulle-Soumare L., Pasquali L., Galasso M., Corrà F., Baldassari F., Judde J.-G., Cairo S., Volinia S. Heterogeneous expression of EPCAM in human circulating tumour cells from patient-derived xenografts. Biomark. Res. 2018;6:31.
Not in our library10.1186/s40364-018-0145-8
233.
Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study · 2019
No notice
234.
Antolovic D., Galindo L., Carstens A., Rahbari N., Büchler M.W., Weitz J., Koch M. Heterogeneous detection of circulating tumor cells in patients with colorectal cancer by immunomagnetic enrichment using different EpCAM-specific antibodies. BMC Biotechnol. 2010;10:35.
Not in our library10.1186/1472-6750-10-35
235.
Gradilone A., Petracca A., Nicolazzo C., Gianni W., Cortesi E., Naso G., Vincenzi B., Cristini C., De Berardinis E., Di Silverio F., et al. Prognostic significance of survivin-expressing circulating tumour cells in T1G3 bladder cancer. BJU Int. 2010;106:710-715.
Not in our library10.1111/j.1464-410x.2009.09130.x
236.
Nicolazzo C., Busetto G.M., Del Giudice F., Sperduti I., Giannarelli D., Gradilone A., Gazzaniga P., de Berardinis E., Raimondi C. The long-term prognostic value of survivin expressing circulating tumor cells in patients with high-risk non-muscle invasive bladder cancer (NMIBC). J. Cancer Res. Clin. Oncol. 2017;143:1971-1976.
Not in our library10.1007/s00432-017-2449-8
237.
Palmirotta R., Lovero D., Silvestris E., Felici C., Quaresmini D., Cafforio P., Silvestris F. Next-generation Sequencing (NGS) Analysis on Single Circulating Tumor Cells (CTCs) with No Need of Whole-genome Amplification (WGA). Cancer Genomics Proteomics. 2017;14:173-179.
Not in our library10.21873/cgp.20029
238.
Effenberger K.E., Schroeder C., Hanssen A., Wolter S., Eulenburg C., Tachezy M., Gebauer F., Izbicki J.R., Pantel K., Bockhorn M. Improved Risk Stratification by Circulating Tumor Cell Counts in Pancreatic Cancer. Clin. Cancer Res. 2018;24:2844-2850.
Not in our library10.1158/1078-0432.ccr-18-0120
239.
Ramsköld D., Luo S., Wang Y.-C., Li R., Deng Q., Faridani O.R., Daniels G.A., Khrebtukova I., Loring J.F., Laurent L.C., et al. Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. Nat. Biotechnol. 2012;30:777-782.
Not in our library10.1038/nbt.2282
240.
Rolle A., Günzel R., Pachmann U., Willen B., Höffken K., Pachmann K. Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC(R) is a predictor for relapse: A preliminary report. World J. Surg. Oncol. 2005;3:18.
Not in our library10.1186/1477-7819-3-18
241.
Influence of endocrine therapy on the ratio of androgen receptor (AR) to estrogen receptor (ER) positive circulating epithelial tumor cells (CETCs) in breast cancer · 2018
Not checked
242.
Naume B., Borgen E., Tøssvik S., Pavlak N., Oates D., Nesland J.M. Detection of isolated tumor cells in peripheral blood and in BM: evaluation of a new enrichment method. Cytotherapy. 2004;6:244-252.
Not in our library10.1080/14653240410006086
243.
Full-length cytokeratin-19 is released by human tumor cells: a potential role in metastatic progression of breast cancer · 2009
No notice
244.
Alix-Panabières C. EPISPOT assay: detection of viable DTCs/CTCs in solid tumor patients. Recent Results Cancer Res. 2012;195:69-76.
Not in our library10.1007/978-3-642-28160-0_6
245.
Tulley S., Zhao Q., Dong H., Pearl M.L., Chen W.-T. Vita-AssayTM Method of Enrichment and Identification of Circulating Cancer Cells/Circulating Tumor Cells (CTCs). Methods Mol. Biol. 2016;1406:107-119.
Not in our library10.1007/978-1-4939-3444-7_9
246.
Premasekharan G., Gilbert E., Okimoto R.A., Hamirani A., Lindquist K.J., Ngo V.T., Roy R., Hough J., Edwards M., Paz R., et al. An improved CTC isolation scheme for pairing with downstream genomics: Demonstrating clinical utility in metastatic prostate, lung and pancreatic cancer. Cancer Lett. 2016;380:144-152.
Not in our library10.1016/j.canlet.2016.06.017
247.
Antibody-independent capture of circulating tumor cells of non-epithelial origin with the ApoStream® system. · 2017
Not checked
248.
Rugo H.S., Cortes J., Awada A., O’Shaughnessy J., Twelves C., Im S.-A., Hannah A., Lu L., Sy S., Caygill K., et al. Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol. Clin. Cancer Res. 2018;24:3348-3357.
Not in our library10.1158/1078-0432.ccr-17-3059
249.
Lara O., Tong X., Zborowski M., Chalmers J.J. Enrichment of rare cancer cells through depletion of normal cells using density and flow-through, immunomagnetic cell separation. Exp. Hematol. 2004;32:891-904.
Not in our library10.1016/j.exphem.2004.07.007
250.
Rosenberg R., Gertler R., Friederichs J., Fuehrer K., Dahm M., Phelps R., Thorban S., Nekarda H., Siewert J.R. Comparison of two density gradient centrifugation systems for the enrichment of disseminated tumor cells in blood. Cytometry. 2002;49:150-158.
Not in our library10.1002/cyto.10161
251.
Gerges N., Rak J., Jabado N. New technologies for the detection of circulating tumour cells. Br. Med. Bull. 2010;94:49-64.
Not in our library10.1093/bmb/ldq011
252.
Mascalchi M., Maddau C., Sali L., Bertelli E., Salvianti F., Zuccherelli S., Matucci M., Borgheresi A., Raspanti C., Lanzetta M., et al. Circulating tumor cells and microemboli can differentiate malignant and benign pulmonary lesions. J. Cancer. 2017;8:2223-2230.
Not in our library10.7150/jca.18418
253.
Yanagita M., Luke J.J., Hodi F.S., Jänne P.A., Paweletz C.P. Isolation and characterization of circulating melanoma cells by size filtration and fluorescent in-situ hybridization. Melanoma Res. 2018;28:89-95.
Not in our library10.1097/cmr.0000000000000431
254.
Lee Y., Guan G., Bhagat A.A. ClearCell® FX, a label-free microfluidics technology for enrichment of viable circulating tumor cells. Cytometry A. 2018;93:1251-1254.
Not in our library10.1002/cyto.a.23507
255.
Abouleila Y., Onidani K., Ali A., Shoji H., Kawai T., Lim C.T., Kumar V., Okaya S., Kato K., Hiyama E., et al. Live single cell mass spectrometry reveals cancer-specific metabolic profiles of circulating tumor cells. Cancer Sci. 2019;110:697-706.
Not in our library10.1111/cas.13915
256.
Fan X., Jia C., Yang J., Li G., Mao H., Jin Q., Zhao J. A microfluidic chip integrated with a high-density PDMS-based microfiltration membrane for rapid isolation and detection of circulating tumor cells. Biosens. Bioelectron. 2015;71:380-386.
Not in our library10.1016/j.bios.2015.04.080
257.
Kim Y.J., Kang Y.-T., Cho Y.-H. Poly(ethylene glycol)-Modified Tapered-Slit Membrane Filter for Efficient Release of Captured Viable Circulating Tumor Cells. Anal. Chem. 2016;88:7938-7945.
Not in our library10.1021/acs.analchem.5b04927
258.
Hong X., Sullivan R.J., Kalinich M., Kwan T.T., Giobbie-Hurder A., Pan S., LiCausi J.A., Milner J.D., Nieman L.T., Wittner B.S., et al. Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy. Proc. Natl. Acad. Sci. USA. 2018;115:2467-2472.
Not in our library10.1073/pnas.1719264115
259.
Andree K.C., Mentink A., Nguyen A.T., Goldsteen P., van Dalum G., Broekmaat J.J., van Rijn C.J.M., Terstappen L.W.M.M. Tumor cell capture from blood by flowing across antibody-coated surfaces. Lab Chip. 2019;19:1006-1012.
Not in our library10.1039/c8lc01158c
260.
Circulating tumor cells from prostate cancer patients interact with E-selectin under physiologic blood flow. · 2013
Not checked
261.
Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia · 2017
Not checked
262.
Sun Y.-F., Guo W., Xu Y., Shi Y.-H., Gong Z.-J., Ji Y., Du M., Zhang X., Hu B., Huang A., et al. Circulating Tumor Cells from Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma. Clin. Cancer Res. 2018;24:547-559.
Not in our library10.1158/1078-0432.ccr-17-1063
263.
Franken A., Driemel C., Behrens B., Meier-Stiegen F., Endris V., Stenzinger A., Niederacher D., Fischer J.C., Stoecklein N.H., Ruckhaeberle E., et al. Label-Free Enrichment and Molecular Characterization of Viable Circulating Tumor Cells from Diagnostic Leukapheresis Products. Clin. Chem. 2019;65:549-558.
Not in our library10.1373/clinchem.2018.296814
264.
Gkountela S., Castro-Giner F., Szczerba B.M., Vetter M., Landin J., Scherrer R., Krol I., Scheidmann M.C., Beisel C., Stirnimann C.U., et al. Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell. 2019;176:98.e14-112.e14.
Not in our library10.1016/j.cell.2018.11.046
265.
Carter L., Rothwell D.G., Mesquita B., Smowton C., Leong H.S., Fernandez-Gutierrez F., Li Y., Burt D.J., Antonello J., Morrow C.J., et al. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat. Med. 2017;23:114-119.
Not in our library10.1038/nm.4239
266.
Molecular characterization of breast cancer CTCs associated with brain metastasis · 2017
No notice
267.
Vishnoi M., Boral D., Liu H., Sprouse M.L., Yin W., Goswami-Sewell D., Tetzlaff M.T., Davies M.A., Oliva I.C.G., Marchetti D. Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow-Resident Melanoma CTCs. Cancer Res. 2018;78:5349-5362.
Not in our library10.1158/0008-5472.can-18-0644
268.
De Laere B., Oeyen S., Mayrhofer M., Whitington T., van Dam P.-J., Van Oyen P., Ghysel C., Ampe J., Ost P., Demey W., et al. TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer. Clin. Cancer Res. 2019;25:1766-1773.
Not in our library10.1158/1078-0432.ccr-18-1943
269.
Krivacic R.T., Ladanyi A., Curry D.N., Hsieh H.B., Kuhn P., Bergsrud D.E., Kepros J.F., Barbera T., Ho M.Y., Chen L.B., et al. A rare-cell detector for cancer. Proc. Natl. Acad. Sci. USA. 2004;101:10501-10504.
Not in our library10.1073/pnas.0404036101
270.
Somlo G., Lau S.K., Frankel P., Hsieh H.B., Liu X., Yang L., Krivacic R., Bruce R.H. Multiple biomarker expression on circulating tumor cells in comparison to tumor tissues from primary and metastatic sites in patients with locally advanced/inflammatory, and stage IV breast cancer, using a novel detection technology. Breast Cancer Res. Treat. 2011;128:155-163.
Not in our library10.1007/s10549-011-1508-0
271.
McDaniel A.S., Ferraldeschi R., Krupa R., Landers M., Graf R., Louw J., Jendrisak A., Bales N., Marrinucci D., Zafeiriou Z., et al. Phenotypic diversity of circulating tumour cells in patients with metastatic castration-resistant prostate cancer. BJU Int. 2017;120:E30-E44.
Not in our library10.1111/bju.13631
272.
Autio K.A., Dreicer R., Anderson J., Garcia J.A., Alva A., Hart L.L., Milowsky M.I., Posadas E.M., Ryan C.J., Graf R.P., et al. Safety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate-Specific Membrane Antigen for Patients With Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2018;4:1344-1351.
Not in our library10.1001/jamaoncol.2018.2168
273.
Ilie M., Hofman V., Leroy S., Cohen C., Heeke S., Cattet F., Bence C., Lalvée S., Mouroux J., Marquette C.-H., et al. Use of circulating tumor cells in prospective clinical trials for NSCLC patients - standardization of the pre-analytical conditions. Clin. Chem. Lab. Med. 2018;56:980-989.
Not in our library10.1515/cclm-2017-0764
274.
Kallergi G., Aggouraki D., Zacharopoulou N., Stournaras C., Georgoulias V., Martin S.S. Evaluation of α-tubulin, detyrosinated α-tubulin, and vimentin in CTCs: identification of the interaction between CTCs and blood cells through cytoskeletal elements. Breast Cancer Res. 2018;20:67.
Not in our library10.1186/s13058-018-0993-z

Cited by papers we hold 2

Emerging biomarkers for early cancer detection and diagnosis: challenges, innovations, and clinical perspectives · 2025
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New insights into the correlations between circulating tumor cells and target organ metastasis · 2023
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