Abstract
To date, there is indisputable evidence of significant CTC heterogeneity in carcinomas, in particular breast cancer. The heterogeneity of CTCs is manifested in the key characteristics of tumor cells related to metastatic progression – stemness and epithelial–mesenchymal (EMT) plasticity. It is still not clear what markers can characterize the phenomenon of EMT plasticity in the range from epithelial to mesenchymal phenotypes. In this article we examine the manifestations of EMT plasticity in the CTCs in breast cancer. The prospective study included 39 patients with invasive carcinoma of no special type. CTC phenotypes were determined by flow cytometry before any type of treatment. EMT features of CTC were assessed using antibodies against CD45, CD326 (EpCam), CD325 (N-cadherin), CK7, Snail, and Vimentin. Circulating tumor cells in breast cancer are characterized by pronounced heterogeneity of EMT manifestations. The results of the study indicate that the majority of heterogeneous CTC phenotypes (22 out of 24 detectable) exhibit epithelial–mesenchymal plasticity. The variability of EMT manifestations does not prevent intravasation. Co-expression of EpCAM and CK7, regardless of the variant of co-expression of Snail, N-cadherin, and Vimentin, are associated with a low number of CTCs. Intrapersonal heterogeneity is manifested by the detection of several CTC phenotypes in each patient. Interpersonal heterogeneity is manifested by various combinations of CTC phenotypes in patients (from 1 to 17 phenotypes).
Highlights
In breast cancer patients, the cases with the CD45–EpCAM+CK7+N-cadherin– circulating tumor cells (CTCs) phenotype is significantly less than cases with the CD45–EpCAM+CK7–N-cadherin– CTCs
Depending on the expression of EpCAM, CK7, Snail, N-cadherin, and Vimentin, we considered the probability of 24 CTC phenotypes in breast cancer patients
Taking into account the presence or absence of epithelial and mesenchymal markers used in our study, most of the detected CTC phenotypes can be attributed to hybrid ones
Summary
Phenotypic heterogeneity of CTCs is already a well-known phenomenon. Among the many CTC phenotypes, only a few can possess the properties of “seeds”, namely, resistance to anoikis, the ability to extravasate, to transform into disseminated cells, high adaptability to the premetastatic niche, and the ability to induce angiogenesis and stromal formation in metastasis. These cells should be considered as the primary targets of chemotherapy. In connection with the obviousness of such an approach to the prevention of metastases, the task of determining the phenotypic portrait of “seeds” is urgent. One of the most important characteristics of CTCs, ensuring their ability to become metastatic seeds, is the phenotypic heterogeneity of epithelial–mesenchymal (EMT) manifestations [5]
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