The role of MSCs in breast cancer

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

MSCs have been increasingly recognized as an important population of cells within the tumour microenvironment, where they modulate tumour progression and drug sensitivity (Albini and Sporn, 2007). Several recent studies suggest that the tumour microenvironment can modify the proliferation, survival, polarity, differentiation, invasiveness and metastatic capacity of cancer cells (Frisch and Francis, 1994; Weaver et al., 1996; Aboseif, 1999). Furthermore, the proximity of MSCs and CSCs in biopsies obtained from cancer patients has been confirmed by immunohistochemical analysis, raising the possibility that MSCs may influence the clinical course of human malignancies by regulating CSC functions (Corre et al., 2012). Proinflammatory cytokines, chemokines and other mediators secreted by tumours actively recruit various cells, including bone marrow-derived MSCs, into the tumour microenvironment (Dvorak, 1986). These cells respond to signals and factors produced by the tumour cells and support CSC self-renewal, invasion and metastasis (Hu and Polyak, 2008; Korkaya et al., 2011a). The homing capacity of MSCs has been demonstrated in a number of human cancers, including lung cancer (Loebinger et al., 2009), malignant glioma (Sonabend et al., 2008; Sasportas et al., 2009; Yang et al., 2009), Kaposi’s sarcomas (Khakoo et al., 2006), breast cancer (Kidd et al., 2009; Patel et al., 2010), colon carcinoma (Menon et al., 2007), melanoma (Studeny et al., 2002) and ovarian cancer (Kidd et al., 2009).

Accumulating evidence indicates that MSCs play a critical role in supporting breast tumour development (El-Haibi et al., 2012). The formation of breast carcinomas is often accompanied by responses that closely resemble a wound that won’t heal, and signals from these malignant cells may attract MSCs into the tumour stroma (El-Haibi and Karnoub, 2010). Breast cancer cells have been observed to have the capacity to chemo-attract MSCs in in vitro and in vivo experimental settings (Goldstein et al., 2010). These cells, like bone marrow-derived MSCs, migrate and become incorporated into the stroma of developing breast carcinomas (Karnoub et al., 2007; Goldstein et al., 2010). MSCs secrete a number of chemokines, including CCL5/RANTES, IL-17B, IL-6 and IL-8 (Karnoub et al., 2007; Goldstein et al., 2010; Liu et al., 2011), which may act on breast CSCs to mediate invasion, metastasis and therapeutic resistance (El-Haibi et al., 2012). Hypoxia-inducible factors (HIFs) mediate paracrine signalling between breast cancer cells and MSCs to promote metastasis. Co-culture of breast cancer cells and MSCs results in the increased expression of genes encoding proteins that promote metastasis by mediating tissue invasion and premetastatic niche formation (Chaturvedi et al., 2013).

Use of adipose-derived MSCs in in vitro experiments suggests that MSCs contribute to the progression of basal-like breast cancers by stimulating growth and invasion (Zhao et al., 2012). It has been demonstrated that MSCs promote the ability of breast CSCs to form spheres, as well as inducing a more mesenchymal phenotype. Furthermore, MSC-originating signals also decrease E-cadherin expression in oestrogen receptor-positive luminal breast cancers (Klopp et al., 2010). This has been convincingly demonstrated by co-culture with MSCs: the MSC-conditioned media promoted sphere formation of normal mammary epithelial cells and MCF7 and SUM149 breast cancer cells, suggesting that MSC-derived factors induce CSC self-renewal. In contrast to their tumour-promoting properties, there are few reports suggesting that MSCs play a role in tumour suppression of breast cancer cells. Co-culture of MDA-MB231 with human MSCs induced apoptosis in MDA-MB-231 cancer cells. The effect of human-derived MSCs on tumourigenesis in vivo was assessed by injection of MSCs into nonobese diabetic/severe combined immune-deficient mice following tumour establishment with MDA-MB-231, and it was found that MSCs were able to suppress breast cancer tumourigenesis in mice (Chao et al., 2012).

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