BACTERIAL & CHEMICAL CARCINOGENS IN GASTRIC ONCOGENESIS

细菌

• 批准号: 6867722
• 负责人: ANDRE T DUBOIS
• 金额: $ 33.89万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867722
• 关键词: Helicobacter; Macaca mulatta; chemical carcinogen; chemical carcinogenesis; neoplasm /cancer genetics; nitrosoguanidines; nutrition related neoplasm /cancer; nutrition related tag; oncogenes; parasite /microorganism carcinogen; stomach neoplasms; tumor suppressor genes

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.

描述（由申请人提供）：胃癌（GC）是全世界癌症死亡的第二大原因。据信，这是由膳食亚硝胺和幽门螺杆菌感染的共同致癌作用引起的。尽管存在强烈的免疫和炎症反应、胃酸度、蠕动和上皮更新，但幽门螺杆菌在全球超过 50% 的人的胃粘膜中持续存在。在本次资助的当前周期中，我们按照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/或相关的炎症反应会抑制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。根据这些发现和文献，我们提出以下假设： (1)幽门螺旋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，从而增强N-乙基-N'-硝基-N-亚硝基胍(ENNG)等化学致癌物质的作用； (2) 胃环境中的 ENNG 促进幽门螺杆菌基因组的改变，并可能增加其毒力； (3)H.pylori是GC所必需的，但不足以引起GC，去除H.pylori可以预防GC。我们的恒河猴模型特别适合测试这些假设并实现以下具体目标：（1）在宏观、微观和分子水平上表征细菌致癌物幽门螺杆菌和化学致癌物 ENNG 对胃炎症和 DNA 损伤的影响； (2) 探讨 ENNG 和宿主反应对安慰剂与 ENNG 治疗动物输入幽门螺杆菌基因组的影响。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基因组； (3) 在发生GC的动物中研究单独内镜下粘膜切除术或联合根除幽门螺杆菌对随后GC复发的影响。这些研究将允许对化学和细菌致癌物在致癌作用的早期和晚期阶段的组织学和分子效应进行前瞻性研究。