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.
Highlights
Despite recent medical advances, metastasis, tumor relapse, a lack of effective therapies, and drug resistance remain the major causes of death for tumor patients [1,2,3,4,5]
A lot of evidence documents that circulating tumor cells (CTCs) represent a heterogeneous pool of tumor cells [8], with highly variable, but generally short, survival times; the pool of these cells in the bloodstream can be continuously replenished by the release of replicating tumor cells in metastatic foci, and relates to cancer dormancy [21,22]
Several 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 [14,49,52,53,54,55,56,57,58]
Summary
Metastasis, tumor relapse, a lack of effective therapies, and drug resistance remain the major causes of death for tumor patients [1,2,3,4,5]. Cancer metastasis occurs when tumor cells dissociate from a primary tumor and migrate to distant organs through the peripheral vasculature [1,9,10,11,12]. Cancers 2019, 11, 483 transition (EMT), leading to their intravasation and survival in blood or lymph vessels, and their extravasation at distant sites; here they are subjected to mesenchymal-to-epithelial transition (MET), and proliferate to establish metastatic lesions [12,13,14]. 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 [1,15].
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