Affiliations: Department of Molecular Pathology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA | Department of Systems Biology and Gynecologic Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
Note: [] These authors contributed equally to this work.
Note: [] Corresponding author: Yao-Hua Song, MD, PhD, University of Texas, M.D. Anderson Cancer Center, 2SCR3.3024, Box 0951, 7435 Fannin Street, Houston, TX 77054, USA. Tel.: +1 713 834 6117; Fax: +1 713 834 6105; E-mail: [email protected].
Abstract: Carcinoma-associated fibroblasts (CAF) are considered to contribute to tumor growth, invasion and metastasis. However, the cell type of origin remains unknown. Since human adipose tissue-derived stem cells (hASCs) are locally adjacent to breast cancer cells and might directly interact with tumor cells, we investigated whether CAFs may originate from hASCs. We demonstrated that a significant percentage of hASCs differentiated into a CAF-like myofibroblastic phenotype (e.g., expression of alpha smooth muscle actin and tenascin-C) when exposed to conditioned medium from the human breast cancer lines MDAMB231 and MCF7. The conditioned medium from MDAMB231 and MCF7 contains significant amounts of transforming growth factor-beta 1 (TGFβ1) and the differentiation of hASCs towards CAFs is dependent on TGFβ1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGFβ1 as well as by pretreatment of the hASCs with SB431542, a TGFβ1 receptor kinase inhibitor. Additionally, we found that these hASC-derived CAF-like cells exhibit functional properties of CAFs, including the ability to promote tumor cell invasion in an in vitro invasion assay, as well as increased expression of stromal-cell-derived factor 1 (SDF-1) and CCL5. Taken together, these data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion.
