Contribution of transforming growth factor-β signaling to intestinal cancer development

Abstract

Transforming Growth Factor-β (TGF-β) is a cytokine involved in the regulation of multiple cellular responses, and it is accepted that the TGF-β signaling pathway is implicated in both tumor-suppressing and tumor-promoting processes. To assess the role of TGF-β signaling in intestinal cancer, we generated a mouse model that recapitulates two common genetic events observed in colon cancer. Hence, we mated Apc1638N/wt mice with mice that are null for Tgfbr2 in the intestinal epithelium, here called Tgfbr2IEKO. We observed a dramatic increase in the number of intestinal adenocarcinomas in the Apc1638N/wt; Tgfbr2IEKO mice compared to those mice with intact Tgfbr2. Additionally, analyses of tumor-derived epithelial cells and primary tumor tissues showed elevated amounts of TGF-β1 as well as higher MMP-2 activity in specimens from Apc1638N/wt; Tgfbr2IEKO mice in comparison to those that maintained Tgfbr2. These results indicate that inactivation of TGFBR2 in intestinal epithelial cells promotes the malignant transformation of neoplasms initiated by Apc mutation, thus providing in vivo evidence of cooperation between canonical Wnt signaling upregulation and TGF-β signaling inactivation to drive tumor progression. We also evaluated the effects of TGF-β signaling on advanced colorectal cancer, particularly on the acquisition of resistance to anoikis or cell death induced by inappropriate cell-cell or cell-extracellular matrix attachment. Thus, we assessed the effect of TGF-β1 on anoikis in established colorectal human cancer cell lines. We found that TGF-β1-treated HCT116+Chr3 and CBS showed a significant reduction of cell death upon loss of anchorage, and that suppression of autocrine TGF-β signaling in HCT116+Chr3 inhibited this effect. We found that TGF-β1 can promote the activation of the PIK3/AKT and MAPK/ERK pathways, and it modulates the expression of Bim and Bcl-2. Therefore, TGF-β paradoxically promotes the malignant behavior of a subset of TGF-β responsive colon cancer cell lines by blocking anoikis through cell-autonomous mechanisms. In aggregate, these studies show that TGF-β signaling plays a complex and context-dependent role in intestinal cancer development. TGF-β's cell-autonomous and non-autonomous functions are involved in intestinal tumor progression and should be thoroughly considered when planning therapeutic intervention through TGF-β signaling manipulation.