The etiology of H. pylori-induced gastric cancer is multifactorial, but one important component is the dysregulated immune response that leads to chronic inflammation and resulting cellular damage. Our lab has discovered a novel pathway for the generation of oxidative stress-induced DNA damage in H. pylori- iniected gastric epithelial cells that results from oxidation of the polyamine spermine by the enzyme spermine oxidase (SMO), producing hydrogen peroxide (H2O2). Increased substrate for SMO is generated by synthesis of polyamines from L-ornithine by the enzyme ornithine decarboxylase (ODC). We have also previously implicated nitric oxide (NO), reporting that the enzyme inducible NO synthase (INOS) that produces high levels of NO, a known mutagen, is upregulated by H. pylori in vitro and in vivo. Work supported by this P01 has demonstrated dramatically different rates of gastric cancer in Colombia, such that individuals from the high risk region of the Andean mountains have a 25-fold greater risk of developing cancer than those from the low risk coastal region, despite identical prevalence rates of H. pylori infection. Our preliminary studies using genotype-matched H. pylori clinical isolates indicate that when compared to strains from the low risk region, strains from the high risk region induce significantly more SMO and oxidative DNA damage in gastric epithelial cells in vitro that correlates with similar findings in the gastritis tissues from the source patients for these strains. We also found that high risk strains induce more INOS in vitro and in vivo. Importantly, we show that Colombian clinical isolates can infect mice and gerbils, and that a high risk strain induces dyplasia in gerbils. Evolutionary analysis of 6 strains by multi-locus sequence typing revealed that the 3 strains from the high risk region clustered together and with reference strains of European origin and the 3 strains from the low risk region clustered together and with strains of African origin. Our hypothesis is that oxidative stress from SMO, and nitrosative stress from iNOS are determinants of neoplastic risk in H. pylori infection, and these pathways are differentially modulated by H. pylori strains from regions of high vs. low gastric cancer risk.
Our Specific Aims are: 1.) To demonstrate that H. pylori strains from the high vs. low gastric cancer risk region exhibit increased ability to induce responses that lower the threshold for carcinogenesis;2.) To demonstrate that polyamine synthesis by ODC, oxidation of spermine by SMO, and generation of NO by INOS are mediators of gastric cancer risk in vivo;and 3.) To define microbial determinants of oxidative and nitrosative stress, and gastric cancer risk by studying H. pylori strains from longitudinal Colombian cohorts in adults and children. The studies proposed are innovative and tightly ntegrated with this P01 as a whole, as they seek to define specific mechanisms of gastric carcinogenesis induced by H. pylori strains from regions of divergent cancer risk in the Colombian natural laboratory.
(See Instructions): This project examines damage to the stomach lining caused by oxygen radicals and nitric oxide in order to determine if these agents have a causal role in the gastric cancer induced by H. pylori.
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