Bacterial and Chemical Carcinogens in Gastric Oncogenesis

描述（申请人提供）：胃癌（GC）是全球第二大癌症死亡原因，但其发病率在不同国家和人群中差异很大。胃癌是否发生取决于胃菌群（尤其是幽门螺杆菌）引起的炎症与致癌和保护性营养物质的摄入之间的复杂平衡。尽管有强烈的免疫和炎症反应、胃酸、蠕动和上皮细胞转换，但幽门螺杆菌仍存在于世界上50%的人的胃粘膜中。我们最近证明单独幽门螺旋杆菌感染只引起持续的炎症反应，单独的饮食致癌物只引起血管发育不良。相比之下，致癌物和幽门螺杆菌感染的关联在3年内诱导癌前病变，在5年内被上皮内瘤变所取代。胃活检的阵列、实时RT-PCR和原位杂交分析显示了每个猴子亚群特有的分子特征，包括3只上皮内瘤变动物。迄今为止的进展说明了细菌和饮食因素共同致癌作用的复杂性和以下假设：(1)幽门螺杆菌上调促炎基因，下调DNA修复基因和肿瘤抑制基因（TSG）；由此导致的上皮细胞正常修复机制的减弱可能会增强膳食致癌物的作用，并被保护性膳食植物雌激素抵消；(2)效应T细胞和调节性T细胞功能失衡可能促进癌变；(3)胃环境促进幽门螺杆菌基因组的改变并改变其毒力。恒河猴模型特别适合于检验这些假设，并实现以下具体目标：(1)从宏观、微观和分子水平上表征细菌致癌物幽门螺杆菌、膳食致癌物和保护性营养素对胃粘膜的影响；(2)研究胃黏膜细胞免疫应答对长期幽门螺杆菌感染的影响及饮食因素；(3)探讨饮食和宿主反应对幽门螺杆菌基因组的影响。有或没有幽门螺杆菌感染和/或饮食致癌物的猴子将暴露于缺乏异黄酮的饮食中，并研究胃粘膜的癌前和肿瘤转化。这项关于饮食和细菌致癌物的组织学和分子效应的前瞻性研究将为癌变的早期和晚期提供新的有用信息。公共卫生相关性：胃癌（GC）是全球癌症死亡的第二大原因。由于5年生存率很低，因此有必要更好地了解该疾病的发病机制。拟议的研究将允许对灵长类动物模型中癌变早期和晚期饮食成分和细菌致癌物的组织学和分子效应进行前瞻性分析。

DESCRIPTION (provided by applicant): Gastric Carcinoma (GC) is the second leading cause of cancer death worldwide, but its incidence is highly variable among different countries and populations. Whether GC occurs or not depends on a complex equilibrium between inflammation resulting from gastric bacterial flora (especially Helicobacter pylori), and intake of carcinogenic and protective nutrients. H. pylori persists in the gastric mucosa of >50% of humans worldwide for the life of the host, despite intense immune and inflammatory responses, gastric acidity, peristalsis, and epithelial turnover. We receltly demonstrated that H. pylori infection alone caused only a persistent inflammatory response and that a dietary carcinogen alone caused only angiodysplasia. In contrast, the association of the carcinogen and H. pylori infection for three years induced precancerous lesions that were replaced at 5-year by intraepithelial neoplasia in half of the animals. Array, real- time RT-PCR, and in situ hybridization analysis of gastric biopsies demonstrated molecular signatures that were specific to each of the monkey subgroups, including the three animals with intraepithelial neoplasia. Progress to date illustrates the complexity of the co-carcinogenenic effects of bacterial and dietary factors and the following hypotheses:: (1) H. pylori up-regulates pro-inflammatory genes and down-regulates DNA repair genes and tumor suppressor genes (TSG); the resulting weakening of normal repair mechanisms of epithelial cells may potentiate the effects of dietary carcinogens and be counteracted by protective dietary phytoestrogens; (2) an imbalance between the functions of effector and regulatory T cells may promote carcinogenesis; and (3) The gastric milieu promotes alterations of the H. pylori genome and modifies its virulence. The rhesus monkey model is particularly well adapted to test these hypotheses and to fulfill the following specific aims: (1) to characterize the effect of the bacterial carcinogen H. pylori, of a dietary procarcinogen and of protective nutrients on gastric mucosa at the macroscopic, microscopic and molecular level; (2) to study the gastric mucosal cellular immune response in response to long term H. pylori infection and dietary factors; and (3) to explore the effect of diet and of the host's responses on H. pylori genome. Monkeys with and without H. pylori infection and/or administration of a dietary carcinogen will be exposed to an isoflavones-depleted diet and the gastric mucosa will be studied for precancerous and neoplasitc transformation This prospective study of histological and molecular effects of diet and bacterial carcinogens will provide novel and useful information regarding the early and late stages of carcinogenesis. PUBLIC HEALTH RELEVANCE: Gastric Carcinoma (GC) is the second leading cause of cancer death worldwide. Because survival at 5-year is very low, there is a need for a better understanding of the pathogenesis of the disease The proposed studies will permit a prospective analysis of the histological and molecular effects of dietary components and bacterial carcinogens during the early and late stages of carcinogenesis in a primate model.