GASTRIC CANCER INDUCED BY H PYLORI IN P27 DEFICIENT MICE

描述(申请人提供)：胃癌是世界范围内死亡的主要原因。在大多数情况下，这种疾病是幽门螺杆菌数十年来胃部感染和相关的炎症反应的结果。胃癌发生的危险因素包括特定的幽门螺杆菌毒力决定因素和宿主因素的存在，如导致细胞因子和细胞因子受体表达和活性的基因多态性。长期以来，由于缺乏合适的啮齿动物模型，对根除幽门螺杆菌预防或减少胃癌发生的分子和细胞机制以及根除幽门螺杆菌的可能性的研究一直受到阻碍。我们最近建立了一种新的幽门螺杆菌相关性胃癌小鼠模型，基于以下发现：(1)幽门螺杆菌降低胃上皮细胞p27蛋白的表达，(2)p27具有肿瘤抑制蛋白的特性，(3)p27在胃癌中的低表达与预后不良有关。P27基因缺陷小鼠感染幽门螺杆菌SS1菌株后，58%的小鼠发生了显着的胃不典型增生或肿瘤，而野生型小鼠在感染60周后只有7%。在这些变化之前，有明显的胃炎症和早期的肠化生。我们建议验证以下假设：1.在p27-/-小鼠中，p27在骨髓来源的胃炎性细胞中的表达缺失，而不是胃上皮细胞，是导致幽门螺杆菌感染后发生胃癌的原因。2.在幽门螺杆菌感染的p27-/-小鼠模型中，在肠化生发生之前给予根除幽门螺杆菌治疗可以防止胃癌的发生。这些假设将通过两个特定的目标来验证：1.在幽门螺杆菌感染之前，p27-/-小鼠将接受来自ROSA 26野生型小鼠的骨髓移植(反之亦然)，并将确定骨髓移植对胃癌发生的影响。2.将幽门螺杆菌感染p27-/-小鼠，观察根除幽门螺杆菌对胃癌发病率的影响。在这个模型中，幽门螺杆菌根除治疗的干预将在频繁的肠化生发生前后进行比较。这些研究将有助于更好地理解与幽门螺杆菌感染相关的胃癌发生机制，并将评估一种新的幽门螺杆菌相关胃癌发生的小鼠模型，用于临床前测试。由于世界卫生组织将幽门螺杆菌列为全球第二大癌症死亡原因的病因学中的I类(明确的)致癌物，这项工作对一个重大的全球公共卫生问题具有影响。我们的总体长期目标是为制定预防、诊断和治疗胃癌的新的临床策略作出贡献。 胃(胃)癌是世界上第二大癌症死亡原因，通常是由于感染幽门螺杆菌引起的慢性胃炎引起的。由于缺乏合适的动物模型，研究幽门螺杆菌是如何促进胃癌的，以及抗生素治疗是否能预防人类的胃癌的研究一直受到阻碍。为了解决这些重要问题，我们建议评估我们建立的一种新的幽门螺杆菌诱导的胃癌小鼠模型。

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.