Adipose tissue-derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor-derived factors

作者：Jotzu Constantin; Alt Eckhard; Welte Gabriel; Li Jie; Hennessy Bryan T; Devarajan Eswaran; Krishnappa Srinivasalu; Pinilla Severin; Droll Lilly; Song Yao Hua^*

来源：Analytical Cellular Pathology, 2010, 33(2): 61-79.

DOI：10.3233/ACP-CLO-2010-0535

• Breast cancer
• mesenchymal stem cells
• carcinoma-associated fibroblasts
• transforming growth factor-beta 1
• invasion

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 (TGF beta 1) and the differentiation of hASCs towards CAFs is dependent on TGF beta 1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGF beta 1 as well as by pretreatment of the hASCs with SB431542, a TGF beta 1 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.

• 出版日期2010