BACTERIAL & CHEMICAL CARCINOGENS IN GASTRIC ONCOGENESIS

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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.