Abstract
Simple SummaryCirculating tumor cells (CTCs) are the seeds that spread through the circulatory system and generate the metastatic sites. Among the various phenotypes exhibited by CTCs, epithelial-to-mesenchymal transition (EMT) has extensively gained attention because of its contribution to the acquisition of invasiveness and motility of CTCs, which is critical for the successful metastasis process. So far, many clinical studies have demonstrated that expressions of mesenchymal features in CTCs are associated with poor clinical outcomes in many types of solid cancer. In this review, the clinical significance of CTCs as a liquid biopsy is described in terms of the mesenchymal characteristics, expression of predictive biomarkers, and their correlations. Detailed analysis of these multivariate targets in CTCs could improve therapeutic decision-making.Metastasis-related events are the primary cause of cancer-related deaths, and circulating tumor cells (CTCs) have a pivotal role in metastatic relapse. CTCs include a variety of subtypes with different functional characteristics. Interestingly, the epithelial–mesenchymal transition (EMT) markers expressed in CTCs are strongly associated with poor clinical outcome and related to the acquisition of circulating tumor stem cell (CTSC) features. Recent studies have revealed the existence of CTC clusters, also called circulating tumor microemboli (CTM), which have a high metastatic potential. In this review, we present current opinions regarding the clinical significance of CTCs and CTM with a mesenchymal phenotype as clinical surrogate markers, and we summarize the therapeutic strategy according to phenotype characterization of CTCs in various types of cancers for future precision medicine.
Highlights
The concordance of Programmed death-ligand 1 (PD-L1) expression between tumor tissues and circulating tumor cells (CTCs) is not high [169,170,171]. This might support the conclusion that the presence of PD-L1+ CTC is not significantly correlated with the treatment outcomes of nivolumab, a PD-1 inhibitor, and a higher baseline PD-L1+ CTC number does not lead to a response in patients with advanced non-small cell lung cancer (NSCLC) [172]
CTCs have a diverse and heterogeneous phenotype, and the clinical value of CTCs and circulating tumor microemboli (CTM) with mesenchymal phenotype still does not translate into clinical applications
The expression of some pharmaco-molecular targets in CTCs is different from that in primary tumors, making it difficult to standardize the role of CTCs as a companion diagnostic tool
Summary
The major cause of death in ~80% of cancer cases is a metastatic cancer lesion-related complication. CTC detection by the CellSearch® system (generally two or more CTCs/7.5 mL blood as positive) does not have a high sensitivity in non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC), giving a result of only 20% even in the advanced metastatic stage [21] This contributes to the underestimation of CTC number and could be, in part, due to the high number of CTCs with a mesenchymal phenotype undergoing EMT (i.e., from hybrid CTCs to EMT-CTCs) [22,23]. Recent CTC-related studies focused on further detailed approaches, including phenotypic characterization of predictable therapeutic response markers through genotypic and immunophenotypic analysis These approaches can provide useful predictive information for the decision-making in precision medicine, but CTCs represent a heterogeneous population of tumor cells with the potential for metastases [35]. We summarize the clinical significance of CTCs, including the mesenchymal phenotype and the potential treatment response markers for future precision medicine
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