Altered TGF-beta Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis

作者：Franco Omar E; Jiang Ming; Strand Douglas W; Peacock James; Fernandez Suzanne; Jackson Roger S II; Revelo Monica P; Bhowmick Neil A; Hayward Simon W^*

来源：Cancer Research, 2011, 71(4): 1272-1281.

DOI：10.1158/0008-5472.CAN-10-3142

Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-beta receptor II (TGF beta R2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGF beta R2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-beta) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGF beta R2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGF beta R2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (alpha SMA)] through elevation of TGF-beta 1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGF beta R2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-beta 1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-beta 1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-beta signaling to tumor promotion by tumor stromal cells. Cancer Res; 71(4); 1272-81.

• 出版日期2011-2-15