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

Agnoletto, Chiara; Corrà, Fabio; Minotti, Linda; Baldassari, Federica; Crudele, Francesca; Cook, William Joseph James; Di Leva, Gianpiero; Pio d’Adamo, Adamo; Gasparini, Paolo; Volinia, Stefano

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Chiara Agnoletto

Fabio Corrà

Linda Minotti

Federica Baldassari

Francesca Crudele

William Joseph James Cook

Adamo Pio d’Adamo

Paolo Gasparini

Stefano Volinia


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.

Journal Article Type Article
Acceptance Date Mar 30, 2019
Publication Date Apr 5, 2019
Journal Cancers (Basel)
Print ISSN 2072-6694
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 11
Issue 4
Article Number 483
Keywords CTC, EMT, stemness, CSC
Publisher URL


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