Loss of TGFβ signaling promotes colon cancer progression and tumor-associated inflammation.
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.
University of Illinois College of Medicine, Urbana-Champaign, IL, USA.
Daniel R
DR
Principe
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Brian
B
DeCant
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Jonas
J
Staudacher
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Dominic
D
Vitello
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Riley J
RJ
Mangan
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Elizabeth A
EA
Wayne
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Emman
E
Mascariñas
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Andrew M
AM
Diaz
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Jessica
J
Bauer
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Ronald D
RD
McKinney
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA.
Khashayarsha
K
Khazaie
Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.
Boris
B
Pasche
Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
David W
DW
Dawson
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Department of Medicine, Northwestern University, Chicago, IL, USA.
Hidayatullah G
HG
Munshi
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Paul J
PJ
Grippo
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Barbara
B
Jung
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; C000613192:adenomatous polyposis coli protein, mouse
TGF-beta; colon cancer; inflammation