Loss of TGFβ signaling promotes colon cancer progression and tumor-associated inflammation
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Daniel R. Principe1, Brian DeCant2, Jonas Staudacher2, Dominic Vitello3, Riley J. Mangan2, Elizabeth A. Wayne2,3, Emman Mascariñas2, Andrew M. Diaz2, Jessica Bauer2, Ronald D. McKinney2, Khashayarsha Khazaie4, Boris Pasche5, David W. Dawson6, Hidayatullah G. Munshi3,7, Paul J. Grippo2,* and Barbara Jung2,*
1 University of Illinois College of Medicine, Urbana-Champaign, IL, USA
2 Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
3 Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
4 Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA
5 Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA
6 Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
7 Department of Medicine, Northwestern University, Chicago, IL, USA
* These authors have contributed equally to this manuscript and serve as joint senior authors
Paul J. Grippo, email:
Barbara Jung, email:
Keywords: colon cancer, Inflammation, TGF-beta
Received: May 02, 2016 Accepted: May 14, 2016 Published: June 04, 2016
TGFβ has both tumor suppressive and tumor promoting effects in colon cancer. Also, TGFβ 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 TGFβ to this process are poorly understood. In human patients, we found that epithelial loss of TGFβ signaling was associated with increased inflammatory burden; yet overexpression of TGFβ 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 TGFβ1. Interestingly, mutant APC mice with global suppression of TGFβ 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 TGFβ signaling, particularly in colon epithelial cells, elicits a strong inflammatory response and promotes tumor progression. This implies that treating colon cancer patients with TGFβ inhibitors may result in a worse outcome by enhancing inflammatory responses.
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