Carcinoma-Associated Fibroblast–Like Differentiation of Human Mesenchymal Stem Cells

Abstract

Carcinoma-associated fibroblasts (CAF) have recently been implicated in important aspects of epithelial solid tumor biology, such as neoplastic progression, tumor growth, angiogenesis, and metastasis. However, neither the source of CAFs nor the differences between CAFs and fibroblasts from nonneoplastic tissue have been well defined. In this study, we show that human bone marrow-derived mesenchymal stem cells (hMSCs) exposed to tumor-conditioned medium (TCM) over a prolonged period of time assume a CAF-like myofibroblastic phenotype. More importantly, these cells exhibit functional properties of CAFs, including sustained expression of stromal-derived factor-1 (SDF-1) and the ability to promote tumor cell growth both in vitro and in an in vivo coimplantation model, and expression of myofibroblast markers, including A-smooth muscle actin and fibroblast surface protein. hMSCs induced to differentiate to a myofibroblast-like phenotype using 5-azacytidine do not promote tumor cell growth as efficiently as hMSCs cultured in TCM nor do they show increased SDF-1 expression. Furthermore, gene expression profiling revealed similarities between TCM-exposed hMSCs and CAFs. Taken together, these data suggest that hMSCs are a source of CAFs and can be used in the modeling of tumor-stroma interactions. To our knowledge, this is the first report showing that hMSCs become activated and resemble carcinoma-associated myofibroblasts on prolonged exposure to conditioned medium from MDAMB231 human breast cancer cells. [Cancer Res 2008;68(11):4331-9]

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

“…3). These findings emphasize the importance of soluble factors in interactions between MSCs and BCCs and may explain the attraction that exists between these cell types [32, 37]. Aside from their role in maintaining tumor survival, MSCs have been suspected to induce transformation in normal epithelial cells [42].…”

“…Depending on the metastatic site, the breast cancer microenvironment can contain a variety of cell types, such as endothelial cells, macrophages, pericytes, lymphocytes, and stromal cells [37, 38]. Local invasion of cancer cells into resident tissue creates a nurturing environment for cancer cells in which growth and progression can occur relatively easily [39].…”

“…CAFs and BCCs have a reciprocal relationship and are in constant interaction [41]. For example, the exposure of MSCs to conditioned media from BCCs can lead to MSC conversion into CAF-like cells expressing stromal cell-derived factor-1 (SDF-1), which has implications in BCC chemotaxis and metastasis to the bone marrow [37] (Fig. 3).…”

“…The markers for CAFs include, but are not limited to, α -smooth muscle actin, fibroblast surface protein, and calponin [38]. These components are thought to have contractile function [37, 38]. However, the research is complicated by the heterogeneity in CAFs as CAFs have been shown to demonstrate variable responses to chemotherapy [40].…”

“…Other explanations hold that mesenchymal precursors may be recruited to the sites of malignancy and may facilitate cellular growth and tumor progression [44]. MSCs, for example, have been suggested as the precursor for CAFs and myofibroblasts that interact with BCCs [37]. MSCs gain expression of fibroblast surface protein and α -smooth muscle actin after exposure to tumor-conditioned media [37].…”