BACTERIAL & CHEMICAL CARCINOGENS IN GASTRIC ONCOGENESIS

描述（由申请人提供）：胃癌（GC）是全球癌症死亡的第二大原因。它被认为是由饮食中的亚硝胺和幽门螺杆菌感染的共同致癌作用引起的。H.尽管有强烈的免疫和炎症反应、胃酸、胃粘膜炎和上皮更新，但幽门螺杆菌在全世界>50%的人的胃粘膜中持续存在，直至宿主的一生。在本资助周期内，我们按计划调查了H。幽门螺杆菌感染对恒河猴胃粘膜的影响。我们证明了H.幽门螺杆菌感染和/或相关的炎症反应抑制DNA修复基因的表达，从而可能在暴露于亚硝胺致癌物时促进细胞转化。这些结果说明了这些细菌和饮食因素共同致癌作用的复杂性。基于这些发现和文献，我们提出了以下假设： (1)H.幽门螺杆菌引起炎性介质和氧自由基的释放，这些介质和氧自由基使DNA修复基因和肿瘤抑制基因（TSG）沉默，削弱上皮细胞的正常修复机制，从而增强化学致癌物如N-乙基-N ′-硝基-N-亚硝基胍（ENNG）的作用; pylori基因组，并可能增加其毒力; pylori是必要的，但不足以引起GC，并去除H。pylori可预防胃癌。我们的恒河猴模型特别适合于检验这些假设，并实现以下特定目标：（1）表征细菌致癌物H的作用。pylori感染和化学致癌物ENNG对胃粘膜炎症和DNA损伤的影响：（2）探讨ENNG和宿主反应对输入H. pylori基因组中的基因组差异。这部分研究将确定胃环境中致癌物的存在是否可以改变H。pylori基因组;（3）在发生GC的动物中，研究单独或与H.幽门螺杆菌根除对随后GC复发的影响。这些研究将允许在早期和晚期阶段的致癌化学和细菌致癌物的组织学和分子效应的前瞻性研究。

DESCRIPTION (provided by applicant): Gastric Carcinoma (GC) is the second leading cause of cancer death worldwide. It is believed to result from the co-carcinogenic effects of dietary nitrosamines and Helicobacter pylori infection. 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. During the current cycle of this grant, as planned, we investigated the effect of H. pylori infection on the gastric mucosa of the rhesus monkey. We demonstrated that H. pylori infection and/or the associated inflammatory response inhibit the expression of a DNA repair gene and thereby may promote cell transformation upon exposure to nitrosamine carcinogens. These results illustrate the complexity of the co-carcinogenenic effects of these bacterial and dietary factors. Based on these findings and on the literature, we formulated the following hypotheses: (1) H. pylori causes the release of inflammatory mediators and free oxygen radicals that silence DNA repair genes and tumor suppressor genes (TSG), weaken the normal repair mechanisms of epithelial cells and thereby potentiate the effects of chemical carcinogens such as N-ethyl-N'-nitro-N-nitroso-guanidine (ENNG); (2) ENNG in the gastric milieu promotes alterations of the H. pylori genome and may increase its virulence; and (3) H. pylori is necessary, but not sufficient to cause GC, and removal of H. pylori can prevent GC. Our 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 and of the chemical carcinogen ENNG on gastric inflammation and DNA damage at the macroscopic, microscopic and molecular level; (2) to explore the effect of ENNG and of the host's responses on the input H. pylori genome in placebo- vs. ENNG-treated animals. This portion of the study will determine whether the presence of a carcinogen in the gastric milieu can modify H. pylori genome; and (3) to study, in animals that develop GC, the effect of endoscopic mucosal resection alone or combined with H. pylori eradication on subsequent GC recurrence. These studies will permit a prospective study of the histological and molecular effects of chemical and bacterial carcinogens during the early and late stages of carcinogenesis.