Abstract
The presence of stem and epithelial–mesenchymal-transition (EMT) features in circulating tumor cells (CTCs) determines their invasiveness, adaptability to the microenvironment, and resistance to proapoptotic signals and chemotherapy. It also allows them to fulfil the role of metastatic “seeds”. We evaluated the heterogeneity of stem CTCs by their CD44, ALDH1, and CD133 expression depending on N-cadherin expression in breast-cancer patients. A total of 38 female patients were selected for this study. CTC phenotypes were determined by flow cytometry before any type of treatment. Multiplex immunofluorescence was used for the evaluation of tumor-cell heterogeneity in primary lesions. In patients who had CD44-CD24- CTCs, a subset of cells with the expression of other stem-cell markers (CD133 and ALDH1) were detected. Expression of CD133 and/or ALDH1 may be associated with expression of N-cadherin: all populations of N-cadherin+ CTCs demonstrate stem features; in the absence of N-cadherin expression, true nonstem (CD44-CD24-CD133-ALDH1-) cells are found. The heterogeneity of stem marker expression in CTCs was observed regardless of N-cadherin expression. In our study, stromal cell-derived factor-1 (SDF-1) receptor expression in CTCs did not depend on stemlike traits, but was instead associated with N-cadherin expression. Subpopulations of tumor cells, detected both in tumors and blood, were identified. Breast cancer was characterized by pronounced interpersonal and intrapersonal heterogeneity of CTCs by the presence and combination of various stem features and N-cadherin expression. To complete the characterization of stemlike features of CTCs, we suggest the simultaneous use of the three stem markers.
Highlights
Circulating tumor cells (CTCs) are essential and informative objects for understanding the metastasis of carcinomas [1]
We focused on the assessment of CTC heterogeneity in invasive-breast-cancer patients and the study of its stemlike features by the simultaneous usage of three markers (CD44 and CD24, ALDH1, or CD133), depending on N-cadherin expression
The primary goal of this study was the comparison of stem-marker (ALDH1 and CD133) expression in CD44-CD24- and CD44+CD24- CTC subsets depending on the presence of EMT features (N-cadherin expression)
Summary
Circulating tumor cells (CTCs) are essential and informative objects for understanding the metastasis of carcinomas [1]. They come in metastasis lesions and become, for an indefinite time, disseminated tumor cells (DTCs). DTCs produce metastasis if they possess all characteristics of “seed” cells, and if a functional premetastatic niche exists [2,3]. These cells become dormant if the triggers are absent or the microenvironment (niche) is deficient [4]. Disseminated dormant cells are often unavailable for research. It is necessary to pay attention to the study of biological characteristics of CTCs as archetypes of seed or dormant cells. Numerous data confirmed the significant heterogeneity of the CTCs and cells in primary tumors [5]
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