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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cancer+Res 2016 ; 76 (9): 2525-39 Nephropedia Template TP
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TGF? signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis #MMPMID26980767
Cancer Res 2016[May]; 76 (9): 2525-39 PMID26980767show ga
In early pancreatic carcinogenesis, TGF? acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGF? appears to promote tumor progression. Therefore, to better understand the contributions of TGF? signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGF? signals facilitated pancreatic tumorigenesis, whereas global loss of TGF? signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGF?1 production, and the resultant restoration of anti-tumor immune function. Similarly, TGFBR-deficient T cells resisted TGF?-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8+ T cells led to enhanced infiltration and GranzymeB-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGF? expression correlated with increased fibrosis and associated negatively with expression of GranzymeB. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGF? 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 TGF? signals in the epithelium.