BACTERIAL & 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。它被认为是由于饮食亚硝胺和幽门螺杆菌感染的共同致癌作用造成的。幽门螺杆菌在全世界50%的人的胃粘膜中持续存在，尽管有强烈的免疫和炎症反应，胃酸，蠕动和上皮细胞的更替。在这笔赠款的当前周期中，我们按计划调查了幽门螺杆菌感染对恒河猴胃粘膜的影响。我们证明，幽门螺杆菌感染和/或相关的炎症反应抑制了DNA修复基因的表达，从而可能促进亚硝胺致癌物暴露后的细胞转化。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)幽门螺杆菌引起炎症介质和自由基的释放，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，从而加强化学致癌物如N-乙基-N‘-硝基-N-亚硝基-胍(ENNG)的作用；(2)胃环境中的ENNG促进幽门螺杆菌基因组的变化，并可能增加其毒力；以及(3)幽门螺杆菌是必要的，但不足以引起GC，清除H.Pylori可以防止GC。我们的恒河猴模型特别适合测试这些假设，并实现下列特定目标：(1)在宏观、微观和分子水平上表征细菌致癌物H.Pylori和化学致癌物ENNG对胃炎症和DNA损伤的影响；(2)在安慰剂对照组和ENNG组动物中探讨ENNG以及宿主反应对H.Pylori输入基因组的影响。这部分研究将确定胃环境中致癌物的存在是否会改变幽门螺杆菌的基因组；以及(3)在发生胃癌的动物中，研究单独或联合根除幽门螺杆菌对随后胃癌复发的影响。这些研究将允许对化学致癌物和细菌致癌物在致癌早期和晚期的组织学和分子效应进行前瞻性研究。

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.