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
In order to generate metastasies, cancer cells at the primary tumour and distant organ sites must undergo transient activation of reversible embryonic programmes of EMT and mesenchymal – epithelial transition (MET), respectively. In contrast to EMT, in which the loss of epithelial characteristics is followed by the acquisition of a mesenchymal phenotype, MET is characterized by E-cadherin expression and the acquisition of cell – cell contacts and cellular polarity. Activation of EMT in cells at primary tumour sites promotes their motility, invasive capacity and ability to survive in the circulation. These EMT-like CSCs form micrometastasis at distant sites, but may remain dormant until they undergo an MET conversion, which is associated with self-renewal as well as differentiation. This generates metastases which display a hierarchical organization, resembling that found in the primary tumour. Recent studies have shown that the processes of EMT and MET are both required driving forces for tumour metastasis. In the case of colorectal cancer, a characteristic phenotypic change in the cells at the invasive tumour front and the metastatic site have been reported (Brabletz et al., 2001). Brabletz et al. (2001) showed that cells at the invasive front of the primary tumour site are often associated with the loss of epithelial differentiation and acquisition of a mesenchyme-like phenotype, which later grow and colonize as epithelial-like tumours at the site of metastasis. They showed invasive EMT stem-like cells to be growth-arrested while MET cells were highly proliferative, generating tumours at metastatic sites (Brabletz et al., 2001). While several studies have revealed an association between EMT and the acquisition of CSC properties (Mani et al., 2008; Wellner et al., 2009), a few recent reports have described the gain of stem cell characteristics in MET cells, which are requisite for the initiation of secondary tumours (Chaffer et al., 2006; Brabletz, 2012; Celia-Terrassa et al., 2012). A recent study has shown that breast CSCs exist in alternative EMT and MET states, characterized by the expression of different CSC markers (Liu et al., 2014). Furthermore, high concordance was found in the gene expression profile of CD24CD44+ EMT CSCs and ALDH+ MET CSCs isolated from genetically distinct tumour subtypes, suggesting shared CSC properties across the molecular subtypes of breast cancer. Based on the gene expression profiles, we found that mesenchymal-like breast CSCs resemble basal stem cells, whereas the profiles of epithelial-like breast CSCs resemble those of luminal stem cells in the normal breast. Furthermore, we found that breast CSC plasticity enables CSCs to transition between these EMT and MET states, and that this transition may be regulated by the tumour microenvironment. Activation of several stem cell pathways, including Hedgehog (Hh), Wnt and transforming growth factor beta (TGF-β), has been shown to be involved in the regulation of EMT (Shin et al., 2010; Takebe et al., 2011; Yoo et al., 2011). Other stem cell-regulating pathways, including bone morphogenetic protein (BMP) and human epidermal growth factor receptor 2 (HER2) signalling, have also been shown to promote MET. Recently studies have interrogated the role of transcription factors and other signaling molecules involved in the switching of EMT/MET states during metastasis. Ocana et al. (2012) showed that the loss of the homeobox factor PRRX1 plays an essential role in the stemness of MET cells, favouring metastatic progression, while Stankic et al. (2013) demonstrated an important role of Id1, along with TGF-β, in the transition of EMT to MET CSCs during lung metastatic colonization. The latter group also demonstrated that TGF-β-induced Id1 acts on EMT CSCs to promote their transition into MET CSCs during lung colonization. MSCs found in secondary tumour sites are known to play a vital role in the promotion of metastasis through cell – cell contact and the secretion of several growth factors and cytokines. A functional interaction between human MSCs and lung adenocarcinoma (LAC) cells shows that MSCs effectively inhibit the migration and invasion of several LAC cell lines and enhance the MET phenotype (Wang et al., 2012). The role of MSCs in MET plasticity is not well characterized. The interaction of MSCs with breast CSCs may depend on the expression of receptors, the degree of differentiation and the type of tumour cells with which they are interacting.
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