BACTERIAL & CHEMICAL CARCINOGENS IN GASTRIC ONCOGENESIS

描述（由申请人提供）：胃癌（GC）是全球第二大癌症死亡原因。它被认为是由饮食中的亚硝胺和幽门螺杆菌感染共同致癌的结果。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。在本资助的当前周期中，我们按计划研究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DNA修复基因的表达，从而可能促进暴露于亚硝胺致癌物质的细胞转化。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：

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.