title: Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis.
abstract: Inflammatory bowel disease causes chronic, relapsing intestinal inflammation that can lead to the development of colorectal cancer. Members of the TNF superfamily are key regulators of intestinal inflammation. In particular, TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are involved in normal and pathologic intestinal tissue remodeling. In this study, we show that the TWEAK/Fn14 signaling complex plays a protective role during the acute stage of intestinal inflammation and contributes to the prevention of colitis-associated cancer during chronic inflammation through its proapoptotic effects. Colitis was induced in Fn14-/-and Fn14+/+wild-type littermates by administering 3% dextran sodium sulfate (DSS) for 7 days followed by 2-week recovery; azoxymethane (AOM) administration followed by two cycles of DSS/recovery was used to induce tumors. Reciprocal bone marrow chimeric mice were generated to compare hematopoietic and nonhematopoietic-specific effector tissues. Fn14-/-mice had enhanced susceptibility to colitis compared with Fn14+/+controls as assessed by endoscopic and histologic inflammatory scores, daily weight loss, and mortality rates during recovery after DSS administration. Bone marrow transfer experiments showed that both hematopoietic and nonhematopoietic components are involved in protection against colitis. Tumor lesions were found in the colons of most Fn14-/-mice, but not Fn14+/+controls. AOM/DSS administration enhanced susceptibility to tumorigenesis in Fn14-/-mice. Overall, these findings show that Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer. Cancer Res; 76(22); 6533-42. ©2016 AACR.
authors.affiliation: Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio.|Department of Medicine, Case Western University School of Medicine, Cleveland, Ohio.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Martino
authors.affiliation: Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio.|Department of Medicine, Case Western University School of Medicine, Cleveland, Ohio.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Dave
authors.affiliation: Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio.|Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio.
authors.forename: Paola
authors.initials: P
authors.lastname: Menghini
authors.affiliation: Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio.|Department of Pathology, Case Western University School of Medicine, Cleveland, Ohio.
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.affiliation: Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio.|Department of Medicine, Case Western University School of Medicine, Cleveland, Ohio.
authors.forename: Kristen O
authors.initials: KO
authors.lastname: Arseneau
authors.affiliation: Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio.|Department of Pathology, Case Western University School of Medicine, Cleveland, Ohio.
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
authors.affiliation: Case Digestive Health Research Institute, Case Western University School of Medicine, Cleveland, Ohio. fabio.cominelli@uhhospitals.org.|Department of Medicine, Case Western University School of Medicine, Cleveland, Ohio.|Department of Pathology, Case Western University School of Medicine, Cleveland, Ohio.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D003092:Colitis / Q000235:genetics* / Q000473:pathology; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D004724:Endoscopy / Q000379:methods*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007422:Intestines / Q000473:pathology*; D008297:Male; D051379:Mice; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000074049:Cytokine TWEAK; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors