Bacterial and 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, but its incidence is highly variable among different countries and populations. Whether GC occurs or not depends on a complex equilibrium between inflammation resulting from gastric bacterial flora (especially Helicobacter pylori), and intake of carcinogenic and protective nutrients. 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. We receltly demonstrated that H. pylori infection alone caused only a persistent inflammatory response and that a dietary carcinogen alone caused only angiodysplasia. In contrast, the association of the carcinogen and H. pylori infection for three years induced precancerous lesions that were replaced at 5-year by intraepithelial neoplasia in half of the animals. Array, real- time RT-PCR, and in situ hybridization analysis of gastric biopsies demonstrated molecular signatures that were specific to each of the monkey subgroups, including the three animals with intraepithelial neoplasia. Progress to date illustrates the complexity of the co-carcinogenenic effects of bacterial and dietary factors and the following hypotheses:: (1) H. pylori up-regulates pro-inflammatory genes and down-regulates DNA repair genes and tumor suppressor genes (TSG); the resulting weakening of normal repair mechanisms of epithelial cells may potentiate the effects of dietary carcinogens and be counteracted by protective dietary phytoestrogens; (2) an imbalance between the functions of effector and regulatory T cells may promote carcinogenesis; and (3) The gastric milieu promotes alterations of the H. pylori genome and modifies its virulence. The 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, of a dietary procarcinogen and of protective nutrients on gastric mucosa at the macroscopic, microscopic and molecular level; (2) to study the gastric mucosal cellular immune response in response to long term H. pylori infection and dietary factors; and (3) to explore the effect of diet and of the host's responses on H. pylori genome. Monkeys with and without H. pylori infection and/or administration of a dietary carcinogen will be exposed to an isoflavones-depleted diet and the gastric mucosa will be studied for precancerous and neoplasitc transformation This prospective study of histological and molecular effects of diet and bacterial carcinogens will provide novel and useful information regarding the early and late stages of carcinogenesis. PUBLIC HEALTH RELEVANCE: Gastric Carcinoma (GC) is the second leading cause of cancer death worldwide. Because survival at 5-year is very low, there is a need for a better understanding of the pathogenesis of the disease The proposed studies will permit a prospective analysis of the histological and molecular effects of dietary components and bacterial carcinogens during the early and late stages of carcinogenesis in a primate model.