TGF-?, a major regulator of cell growth and inflammation, is secreted primarily as a large latent complex (LLC) consisting of the TGF-? homodimer, the TGF-? propeptide dimer, and a single molecule of the latent TGF-? binding protein (LTBP), which is disulfide bonded to each of the propeptide chains. Association of the propeptide with TGF-? even though the bond between propeptide and TGF-? has been cleaved, renders the TGF-? latent. TGF-? must be freed from the LLC to bind to its receptors. A minor fraction of the latent TGF-? is secreted complexed to its propeptide in the absence of LTBP and is called the small latent complex (SLC). To examine the effect of decreased production of active TGF-? on inflammation and tumor production, we generated mutant mice (Tgfb1C33S/C33S and Tgfb1-/C33S) in which the cysteines in the TGF-?1 propeptide that bind to LTBP were replaced by serines. This mutant TGF-?1 propeptide cannot bind to LTBP. Thus, none of the secreted latent TGF-?1 is bound to an LTBP, but both LTBP and SLC are secreted normally. Tgfb1C33S/C33S mice have multi-organ inflammation, develop tumors of the stomach, rectum and anus, and die by 3-4 months. This phenotype resembles that of the Tgfb1-/- mouse except that the Tgfb1C33S/C33S inflammatory phenotype is milder but the tumor phenotype stronger than the Tgfb1-/- phenotypes. 100% of Tgfb1-/C33S mice develop gastric adenocarcinomas by 12 weeks of age and have a stronger inflammatory response compared to Tgfb1C33S/C33S mice. Our mice are also infected with Helicobacter, a major risk factor for the development of gastric cancer in humans. Thus, Tgfb1-/C33S mice provide a new model system to study gastric adenocarcinoma induction as well as the participation of the inflammatory response in tumorigenesis. Using Tgfb1-/C33S mice as described in this application, we will establish the contribution of inflammation to tumor production - specifically gastric adenocarcinomas, the changes in cell proliferation and apoptosis in the GI epithelium, the role of the inflammatory response in tumor induction, the potential requirement for Helicobacter infection for tumor production, and the source of the tumor cells. We will use a combination of mouse genetics, cell biology, and biochemistry to answer these questions. The successful completion of the proposed experiments will provide information critical to the understanding of the generation of gastric tumors. Such information may yield insights for therapeutic intervention or prevention of gastric tumors.
Gastric tumors are the second leading cause of cancer death worldwide and understanding how the activation of latent TGF-? contributes to the generation of this tumor may have impact for diagnosis and treatment. The mutant mice we have produced provide a novel system for the study of the rapid formation of gastric adenocarcinomas. In addition, these mice may be useful for the study of inflammatory bowel disease as well as other aspects of TGF-? biology.
| Ota, Mitsuhiko; Horiguchi, Masahito; Fang, Victoria et al. (2014) Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-? in gastric tissue. Cancer Res 74:2642-51 |
| Shibahara, Kotaro; Ota, Mitsuhiko; Horiguchi, Masahito et al. (2013) Production of gastrointestinal tumors in mice by modulating latent TGF-?1 activation. Cancer Res 73:459-68 |
