Role of TGF-beta in Prostate Cancer Progression

Carcinoma arises from epithelium, however, there is growing evidence that inflammation and interactions with the surrounding stromal microenvironment are critical for cancer initiation and progression. Stromal alterations during tumorigenesis have been shown in prostate cancer and many other tumors. As a major component of the stroma, fibroblasts are recognized as prominent modifiers of cancer progression. The contribution of carcinoma associated fibroblasts CAF to cancer has been demonstrated and become accepted, research has been conducted to understand the mechanisms underlying this stromal-epithelial interaction. In the last year, we aimed to identify pathways which could elicit tumor-promoting paracrine effects and whose expression patterns correlated with those seen in human disease. We found that although BPH-1 cells showed growth inhibition upon TGF-Beta treatment, the tumorigenic derivative BPH-1CAFTD lines skipped such inhibition via the effects of elevated levels of constitutively active Akt expression, which blocked nuclear translocation of Smad3 and p21. We also demonstrated that elevated stromal TGF-Beta signaling is essential for CAF to induce tumor from BPH-1 cells in vivo and in vitro. To explain the paradox, we conducted further work and delineated that CAF secrets elevated level of TGF-Beta and SDF1 in parallel. TGF-Beta was shown be able to induce the specific receptor of SDF1, SDF1 signaling contributes significantly to the elevation of phosphorylated Akt in the target epithelial cells. The data generated here demonstrate synergistic links between these TGF-Beta and CXCL12SDF1 pathways acting as critical components of CAF-driven tumorigenesis in vivo.