Loss of TGFβ signaling promotes colon cancer progression and tumor-associated inflammation

TGF beta has both tumor suppressive and tumor promoting effects in colon cancer. Also, TGF beta can affect the extent and composition of inflammatory cells present in tumors, contextually promoting and inhibiting inflammation. While colon tumors display intratumoral inflammation, the contributions of TGF beta to this process are poorly understood. In human patients, we found that epithelial loss of TGF beta signaling was associated with increased inflammatory burden; yet overexpression of TGF beta was also associated with increased inflammation. These findings were recapitulated in mutant APC models of murine tumorigenesis, where epithelial truncation of TGFBR2 led to lethal inflammatory disease and invasive colon cancer, mediated by IL8 and TGF beta 1. Interestingly, mutant APC mice with global suppression of TGF beta signals displayed an intermediate phenotype, presenting with an overall increase in IL8-mediated inflammation and accelerated tumor formation, yet with a longer latency to the onset of disease observed in mice with epithelial TGFBR-deficiency. These results suggest that the loss of TGF beta signaling, particularly in colon epithelial cells, elicits a strong inflammatory response and promotes tumor progression. This implies that treating colon cancer patients with TGF beta inhibitors may result in a worse outcome by enhancing inflammatory responses.