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

TLDR

Carcinoma‑associated fibroblasts drive tumor progression, angiogenesis, and metastasis, yet their cellular origin and distinctions from normal fibroblasts remain unclear. Human bone marrow–derived mesenchymal stem cells exposed to tumor‑conditioned medium differentiate into CAF‑like myofibroblasts that express SDF‑1, α‑SMA, and FSP‑1, promote tumor growth in vitro and in vivo, and exhibit gene expression profiles similar to CAFs, indicating that hMSCs can serve as a source of CAFs for tumor‑stroma studies.

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 alpha-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.