title: Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-β in gastric tissue.
abstract: The contributions of TGF-β signaling to cancer are complex but involve the inflammatory microenvironment as well as cancer cells themselves. In mice encoding a TGF-β mutant that precludes its binding to the latent TGF-β binding protein (Tgfb1(-/C33S)), we observed multiorgan inflammation and an elevated incidence of various types of gastrointestinal solid tumors due to impaired conversion of latent to active TGF-β1. By genetically eliminating activators of latent TGF-β1, we further lowered the amount of TGF-β, which enhanced tumor frequency and multiorgan inflammation. This model system was used to further investigate the relative contribution of TGF-β1 to lymphocyte-mediated inflammation in gastrointestinal tumorigenesis. Toward this end, we generated Tgfb1(-/C33S);Rag2(-/-) mice that lacked adaptive immune function, which eliminated tumor production. Analysis of tissue from Tgfb1(-/C33S) mice indicated decreased levels of P-Smad3 compared with wild-type animals, whereas tissue from Tgfb1(-/C33S);Rag2(-/-) mice had normal P-Smad3 levels. Inhibiting the inflammatory response normalized levels of interleukin (IL)-1β and IL-6 and reduced tumor cell proliferation. In addition, Tgfb1(-/C33S);Rag2(-/-) mice exhibited reduced paracrine signaling in the epithelia, mediated by hepatocyte growth factor produced by gastric stroma. Together, our results indicate that many of the responses of the gastric tissue associated with decreased TGF-β1 may be directly or indirectly affected by inflammatory processes, which accompany loss of TGF-β1, rather than a direct effect of loss of the cytokine.
authors.affiliation: Authors' Affiliations: Departments of Cell Biology, Pathology, Medicine, and Dermatology; Office of Collaborative Science, New York University Langone School of Medicine, New York, New York; and Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ota
authors.forename: Masahito
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Victoria
authors.initials: V
authors.lastname: Fang
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shibahara
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.forename: Cynthia
authors.initials: C
authors.lastname: Loomis
authors.forename: Michael
authors.initials: M
authors.lastname: Cammer
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism; D005756:Gastritis / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019899:Paracrine Communication; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met