| First Author | Principe DR | Year | 2016 |
| Journal | Cancer Res | Volume | 76 |
| Issue | 9 | Pages | 2525-39 |
| PubMed ID | 26980767 | Mgi Jnum | J:231759 |
| Mgi Id | MGI:5774897 | Doi | 10.1158/0008-5472.CAN-15-1293 |
| Citation | Principe DR, et al. (2016) TGFbeta Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res 76(9):2525-39 |
| abstractText | In early pancreatic carcinogenesis, TGFbeta acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFbeta appears to promote tumor progression. Therefore, to better understand the contributions of TGFbeta signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFbeta signals facilitated pancreatic tumorigenesis, whereas global loss of TGFbeta signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFbeta1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFbeta-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8(+) T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFbeta expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFbeta may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFbeta signals in the epithelium. Cancer Res; 76(9); 2525-39. (c)2016 AACR. |
