Adipose tissue-derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor-derived factors.
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.
Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA.
Constantin
C
Jotzu
Eckhard
E
Alt
Gabriel
G
Welte
Jie
J
Li
Bryan T
BT
Hennessy
Eswaran
E
Devarajan
Srinivasalu
S
Krishnappa
Severin
S
Pinilla
Lilly
L
Droll
Yao-Hua
YH
Song
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism