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Jotzu, Constantin (2014): Differentiation of mesenchymal stem cells from the adipose tissue into carcinoma-associated myofibroblasts in interaction with human breast cancer cells. Dissertation, LMU München: Faculty of Medicine



Major advances in understanding and treating breast cancer have been made in the last two decades, yet it remains a significant problem with breast cancer being the most commonly identified cancer and the leading cause of cancer death among women worldwide. For many years breast cancer research has mainly focused on genetically changed cancer cells. However, recently the importance of the stromal compartment surrounding cancer cells in facilitating tumor growth, invasion and metastasis has been widely recognized. Cumulating evidence suggests that in particular carcinoma-associated myofibroblasts play a key role within the tumor stroma and influence many aspects of carcinogenesis. Nevertheless, the cell type of origin as well as the precise mechanisms by which these cells develop has not been conclusively established and remains controversial. The role of human adipose tissue derived stem cells (hASCs) in this context has not been studied so far. hASCs are locally adjacent to epithelial breast cancer cells and might represent early response cells within the tumor stroma. Hence, the aim of this study was to investigate whether carcinoma-associated myofibroblasts may originate from hASCs. The present study revealed that a significant percentage of hASCs differentiate into myofibroblast-like cells expressing alpha smooth muscle actin (α-SMA) and tenascin-C when exposed to conditioned medium from the human epithelial breast cancer cell lines MDMAB231 and MCF7. This process is induced by transforming growth factor beta 1 (TGFβ1) secreted from breast cancer cells. It was shown that conditioned medium from MDMAB231 and MCF7 contains significant amounts of TGFβ1. It could further be demonstrated that the differentiation of hASCs towards myofibroblasts is dependent on TGFβ1 signaling via phosphorylation of Smad2 and Smad3 in hASCs. The induction of myofibroblasts can be abolished using a neutralizing antibody to TGFβ1 as well as by pretreatment of hASCs with SB431542, a selective inhibitor of the TGFβ1 activin receptor-like kinases 4, 5 and 7. Additionally, hASC-derived myofibroblasts exhibit functional properties of carcinoma-associated myofibroblasts such as the increased secretion of the tumor-promoting soluble factors SDF-1α and CCL5. Furthermore hASC-derived myofibroblasts as well as conditioned medium from these cells promote the in vitro invasion of MDAMB231 breast cancer cells. Moreover inhibition of the TGFβ1 signaling pathway in hASCs reduces the potential of these cells to enhance the invasion of breast cancer cells. Overall, the data of the present study suggest that human adipose tissue derived stem cells can differentiate into carcinoma-associated myofibroblast under the influence of TGFβ1 secreted from breast cancer cells in vitro. The differentiation of hASCs towards these tumor-promoting cells can be abolished by targeting the TGFβ1 signaling pathway. Hence, inhibition of the TGFβ1 signaling pathway may prove to be an interesting target for breast cancer therapies. In vivo studies on the cancer microenvironment under special consideration of the interactions between hASCs and cancer cells should be of interest for breast cancer research in the future.