TGF-Beta and Inflammation in Gastric Cancer

性状（由申请人提供）：TGF-？，一个主要的调节细胞生长和炎症，分泌主要作为一个大的潜伏复合物（LLC）组成的TGF-？同源二聚体，TGF-？前肽二聚体，和一个潜在的TGF-？结合蛋白（LTBP），其与每个前肽链二硫键结合。前肽与TGF-？尽管前肽和TGF-？已被切割，使TGF-？潜伏的TGF-？必须从LLC中释放出来才能与其受体结合。一小部分潜在的TGF-？在不存在LTBP的情况下分泌复合于其前肽，并被称为小潜伏复合物（SLC）。要检查的影响，减少生产的活性TGF-？对炎症和肿瘤产生的影响，我们产生了突变小鼠（Tgfb 1C 33 S/C33 S和Tgfb 1-/C33 S），其中TGF-？结合LTBP的1个前肽被丝氨酸取代。这个突变的TGF-？1前肽不能与LTBP结合。因此，没有分泌的潜伏TGF-？1与LTBP结合，但LTBP和SLC均正常分泌。Tgfb 1C 33 S/C33 S小鼠具有多器官炎症，发生胃、直肠和肛门肿瘤，并在3-4个月内死亡。该表型类似于Tgfb 1-/-小鼠的表型，除了Tgfb 1C 33 S/C33 S炎性表型比Tgfb 1-/-表型更温和，但肿瘤表型比Tgfb 1-/-表型更强。100%的Tgfb 1-/C33 S小鼠在12周龄时发生胃腺癌，并且与Tgfb 1C 33 S/C33 S小鼠相比具有更强的炎症反应。我们的小鼠也感染了螺杆菌，这是人类胃癌发展的主要风险因素。因此，Tgfb 1-/C33 S小鼠提供了一种新的模型系统，以研究胃腺癌的诱导以及炎症反应在肿瘤发生中的参与。使用本申请中所述的Tgfb 1-/C33 S小鼠，我们将确定炎症对肿瘤产生的贡献-特别是胃腺癌、GI上皮细胞增殖和凋亡的变化、炎症反应在肿瘤诱导中的作用、螺杆菌感染对肿瘤产生的潜在需求以及肿瘤细胞的来源。我们将结合小鼠遗传学、细胞生物学和生物化学来回答这些问题。所提出的实验的成功完成将为理解胃肿瘤的产生提供关键信息。这些信息可能会产生对胃肿瘤的治疗干预或预防的见解。公共卫生相关性：胃肿瘤是全球癌症死亡的第二大原因，了解潜在的TGF-？有助于这种肿瘤的产生，可能对诊断和治疗产生影响。我们所生产的突变小鼠为研究胃腺癌的快速形成提供了一个新的系统。此外，这些小鼠可能是有用的研究炎症性肠病以及其他方面的TGF-？生物学

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.