GASTRIC CANCER INDUCED BY H PYLORI IN P27 DEFICIENT MICE

描述（由申请人提供）：胃癌是全球死亡的主要原因之一。在大多数情况下，这种疾病是几十年的胃幽门螺杆菌感染和相关的炎症反应的结果。胃癌发展的危险因素包括特定幽门螺杆菌毒力决定因素和宿主因素的存在，如细胞因子和细胞因子受体表达和活性的多态性。长期以来，由于缺乏合适的啮齿动物模型，对幽门螺杆菌的分子和细胞机制以及根除幽门螺杆菌以预防或减少胃癌发生的可能性的研究一直受到阻碍。我们最近在p27缺陷小鼠中开发了一种新的幽门螺杆菌相关胃癌小鼠模型，基于以下发现：(i)幽门螺杆菌降低胃上皮细胞p27蛋白表达，（ii） p27具有肿瘤抑制蛋白的特性，以及（iii）胃癌中p27的低表达与预后不良相关。p27缺陷小鼠感染SS1型幽门螺杆菌导致58%的小鼠发生明显的胃发育不良或胃癌，而感染60周后，野生型小鼠只有7%发生胃癌。这些变化之前是明显的胃炎症和肠化生的早期发展。我们建议检验以下假设：1。p27-/-小鼠在幽门螺杆菌感染后胃癌发生的原因是p27-/-在骨髓源性胃炎症细胞而不是胃上皮细胞中的表达缺失。2. 在幽门螺杆菌感染的p27-/-小鼠模型中，在肠化生发生前给予幽门螺杆菌根除治疗可预防胃癌的发生。这些假设将通过两个具体目标来检验：1。p27-/-小鼠在幽门螺杆菌感染前接受ROSA 26野生型小鼠的骨髓移植（反之亦然），并确定骨髓移植对胃癌发展的影响。2. 将p27-/-小鼠感染幽门螺杆菌，并评价根除幽门螺杆菌对胃癌发病率的影响。在本模型中，将对发生频繁肠化生的前后进行幽门螺杆菌根除治疗的干预进行比较。这些研究将有助于提高对幽门螺杆菌感染相关胃癌发生机制的理解，并将评估一种新的幽门螺杆菌相关胃癌发生的小鼠模型，用于临床前试验。由于幽门螺杆菌被世界卫生组织指定为第一类（明确的）致癌物，在世界范围内癌症死亡的第二大常见原因的病因学中，这项工作对一个主要的全球公共卫生问题有影响。我们的长期目标是为胃癌的预防、诊断和治疗提供新的临床策略。公共卫生相关性

DESCRIPTION (provided by applicant): Gastric cancer is a major cause of worldwide mortality. In most cases, this disease is the consequence of decades of gastric infection by Helicobacter pylori and the associated inflammatory response. Risk factors for gastric cancer development include the presence of specific H. pylori virulence determinants and host factors, such as polymorphisms responsible for cytokine and cytokine receptor expression and activity. Research into both the molecular and cellular mechanisms responsible and the possibility of eradicating H. pylori to prevent or decrease gastric carcinogenesis has long been hampered by the paucity of suitable rodent models. We have recently developed a novel murine model of H. pylori-associated gastric cancer in the p27-deficient mouse, based on the following findings: (i) H. pylori decreases gastric epithelial cell p27 protein expression, (ii) p27 has the properties of a tumor suppressor protein, and (iii) low expression of p27 in gastric cancers is associated with poor prognosis. Infection of p27-deficient mice with the SS1 strain of H. pylori resulted in the development of significant gastric dysplasia or carcinoma in 58% of these mice compared with only 7% of wild- type mice after 60 weeks infection. These changes were preceded by marked gastric inflammation and the early development of intestinal metaplasia. We propose to test the following hypotheses: 1. That loss of p27 expression in bone marrow-derived gastric inflammatory cells, rather than gastric epithelial cells, is responsible for gastric carcinogenesis following H. pylori infection in p27-/- mice. 2. That H. pylori eradication therapy given prior to the development of intestinal metaplasia will prevent gastric cancer development in the H. pylori-infected p27-/- mouse model. These hypotheses will be tested by 2 specific aims: 1. p27-/- mice will receive a bone marrow transplantation from ROSA 26 wild type mice (and vice-versa) prior to H. pylori infection, and the effects of bone marrow transplantation on gastric cancer development will be determined. 2. p27-/- mice will be infected with H. pylori and the effect of eradication of H. pylori on gastric cancer incidence will be evaluated. Intervention with H. pylori eradication therapy will be compared before and after the development of frequent intestinal metaplasia in this model. These studies will lead to improved understanding of the mechanisms of gastric carcinogenesis associated with H. pylori infection and will evaluate a novel mouse model of H. pylori-associated gastric carcinogenesis for preclinical testing. Because of the designation of H. pylori by the World Health Organization as a class I (definite) carcinogen in the etiology of the second most frequent cause of worldwide cancer mortality, this work has implications for a major global public health problem. Our overall long-term goal is to contribute to the development of new clinical strategies for the prevention, diagnosis and treatment of gastric cancer.Public Health Relevance Gastric (stomach) cancer is the second most common cause of cancer death in the world, usually arising as a consequence of chronic gastritis caused by infection with Helicobacter pylori bacteria. Research to investigate how H. pylori promotes gastric cancer and whether antibiotic therapy will prevent gastric cancer in humans, has been hampered by a lack of suitable animal models. We propose to evaluate a new mouse model of H. pylori-induced gastric cancer that we have developed, in order to address these important questions.