Abstract
Solid tumors comprise of maturated cancer cells and self-renewing cancer stem-like cells (CSCs), which are associated with various other nontumorigenic cell populations in the tumor microenvironment. In addition to immune cells, endothelial cells, fibroblasts, and further cell types, mesenchymal stroma/stem-like cells (MSC) represent an important cell population recruited to tumor sites and predominantly interacting with the different cancer cells. Breast cancer models were among the first to reveal distinct properties of CSCs, however, the cellular process(es) through which these cells are generated, maintained, and expanded within neoplastic tissues remains incompletely understood. Here, we discuss several possible scenarios that are not mutually exclusive but may even act synergistically: fusion of cancer cells with MSC to yield hybrid cells and/or the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells by MSC, which can relay signals for retrodifferentiation and eventually, the generation of breast CSCs (BCSCs). In either case, the consequences may be promotion of self-renewal capacity, tumor cell plasticity and heterogeneity, an increase in the cancer cells’ invasive and metastatic potential, and the acquisition of resistance mechanisms towards chemo- or radiotherapy. While specific signaling mechanisms involved in each of these properties remain to be elucidated, the present review article focusses on a potential involvement of cancer cell fusion and EMT in the development of breast cancer stem cells.
Highlights
Tumor tissue and its microenvironment harbors a variety of different cell types which are interacting, proliferating, and differentiating
It is commonly accepted that breast CSCs (BCSCs) are crucially involved in driving tumor progression and resistance mechanistic insights how these cells are generated maintained in toit therapy, is commonly accepted thatinto
Elucidating the precise role of or cell fusion self-renewal, metastasis, and therapy resistance on the other hand, it is still a matter of in debate whether epithelial-mesenchymal transition (EMT) is a prerequisite for metastasis to occur
Summary
Tumor tissue and its microenvironment harbors a variety of different cell types which are interacting, proliferating, and differentiating. An important cell type in the tumor microenvironment is mesenchymal stroma/stem-like cells (MSC), termed multipotent mesenchymal stromal cells or medicinal signaling cells [3,4]. These cells relay transcellular signaling among the different tumor-associated cell populations by the production and release of trophic factors. MSC support neovascularization of the tumor tissue [21] via the release of transforming growth factor beta (TGFβ) This growth factor is known to promote invasion and metastasis through the induction of epithelial-mesenchymal transition (EMT), a morphogenetic program during which the epithelial phenotype of the carcinoma cells is lost and replaced with a mesenchymal one [22]. Enhanced recruitment of MSC and localization in a tumorigenic microenvironment contribute to immune modulation [25], tumor angiogenesis, and various modes of direct and indirect interactions of MSC with tumor cells followed by mutual alterations of their functionalities [26,27,28,29,30]
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