Induction of EMT and expansion of breast CSCs by MSCs

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part II. Cancer stem cells

Epithelial – mesenchymal transition (EMT) is a form of cell plasticity in which epithelial cells acquire mesenchymal phenotypes. This process is an important component of embryogenesis. During EMT, cells lose their epithelial characteristics, cell – cell adhesion and their basal – apical polarity and experience simultaneous remodelling of their cytoskeletal structures. Furthermore, the expression of epithelial markers such as keratin switches to vimentin-type intermediate filaments and becomes motile and resistant to anoikis (Valdes et al., 2002; Klymkowsky and Savagner, 2009). A number of antiapoptotic transcription factors, such as Twist and Snail, and mesenchymal protein markers, such as vimentin and N-cadherin, have been consistently associated with EMT (Mani et al., 2008), and it has been demonstrated that other transcription factors, such as Snail, Slug and E47, are concomitantly expressed in nascent branches of mammary ducts and activate the EMT programme during morphogenesis and pathogenesis (Lee et al., 2011). Decreased expression of E-cadherin, and the resultant cellular dissociation, is another hallmark of EMT in breast cancer cells (Hombauer and Minguell, 2000; Fierro et al., 2004; Thiery and Sleeman, 2006; Martin et al., 2010). It has been reported that EMT, like invasive basal cancer subtypes, is characterized by vimentin upregulation and has been positively correlated with poor prognosis in breast cancer patients (Yamashita et al., 2013).

The EMT programme has been reported to endow cancer cells with certain stem cell-like properties thought to be necessary for metastatic process (Chaffer and Weinberg, 2011). Breast cancer cells were prompted to undergo EMT in order to acquire certain stem cell characteristics, such as the ability to form mammospheres and an increased capacity to form tumours upon serial transplantation into immune-suppressed mice (Morel et al., 2008). The tumour-promoting effects of the MSCs were also attributed to the induction of EMT, in which MSCs play a central role. The first evidence of the role of MSCs in mesenchymal transition was demonstrated in breast cancer (Martin et al., 2010). Breast cancer cells expressed elevated levels of oncogenes (NCOA4, FOS), proto-oncogenes (FYN, JUN), genes associated with invasion (MMP11), angiogenesis (VEGF) and antiapoptosis (IGF1R, BCL2), as well as downregulation of genes associated with proliferation (Ki67, MYBL2), following direct co-culture with MSCs. At the same time, significant upregulation of EMT specific markers (N-cadherin, vimentin, Twist and Snail) was also observed following co-culture with MSCs, with a reciprocal downregulation in the expression of E-cadherin protein. These changes were predominantly cell contact-mediated and regulated by MSCs.

MCSs have been shown to localize to breast carcinomas, where they integrate into the tumour-associated stroma and trigger EMT-mediated metastasis. It has been shown that bone marrow-derived human MSCs, when mixed with human breast carcinoma cells with low metastatic potential, cause the cancer cells to increase their metastatic potency (Karnoub et al., 2007). Studies suggest that breast cancer cells stimulate de novo secretion of the chemokine CCL5 (RANTES) from MSCs, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. ALDH1-positive breast cancer cells are enriched for CSCs. The enzymatic activity of ALDH1 is used for the identification and isolation of stem cells from a number of malignancies (Ginestier et al., 2007; Douville et al., 2009). We have recently shown that MSCs are able to promote a fourfold increase in the ALDH1-positive CSC population when co-cultured with MSCs (Korkaya et al., 2011b). Similarly, with MDA-MB-231 and MCF7/Ras cells, MSCs cause a multifold increase in the ALDH1 positivity in breast CSCs when co-cultured with a phenotype mediated by MSCs through contact-dependent mechanisms (El-Haibi et al., 2012). Our study also shows that breast CSCs co-cultured with MSCs exhibit a twoto twelvefold increase in primary and secondary mammosphere-forming capacities, which is consistent with the acquisition of CSC properties (Korkaya et al., 2011b). Bone marrow-derived human MSCs induce the production of lysyl oxidase when co-cultured with human breast carcinoma cells, which in turn enhances metastasis to the lung and bone. Lysyl oxidase produced by MSCs stimulates twist transcription in breast cancer cells via paracrine action, thereby mediating MSC-triggered EMT and metastasis (El-Haibi et al., 2012).

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