| Summary: | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2011. === This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. === Cataloged from student submitted PDF version of thesis. === Includes bibliographical references. === Gastric cancer is the 2nd leading cause of cancer death worldwide and the 4th most commonly diagnosed cancer worldwide. Helicobacter pylori infection is the major risk factor of gastric cancer, and as such, this bacterium has been classified as a type 1, or definite, carcinogen by the International Agency for Research on Cancer. H. pylori infects the gastric mucosa of more than half of the world's population and promotes gastric carcinogenesis by inducing chronic inflammation. Over decades of persistent H. pylori infection and chronic inflammation, the stomach goes through a well characterized pathological progression involving chronic gastritis, atrophy, intestinal metaplasia, dysplasia, and ultimately cancer. Interestingly, there are strong gender differences in the development of gastric cancer, as men are twice as likely to develop the disease than women. Given the importance of H. pylori and chronic inflammation in gastric carcinogenesis, this thesis investigated the role of gender in modulating host immune responses to H. pylori. The aims of this thesis explored 1) the effect of gender on H. pylori's ability to induce mutations and 2) the effect of estrogen and the anti-estrogen, Tamoxifen, on H. pyloriinduced gastric cancer. For the first aim, the gpt delta mouse model, a murine mutational analysis model, was used to study chronic infection with H. pylori. Increased frequency of point mutations was observed in infected female mice at 12 months post infection. These mutations were not observed in infected male mice. Further analysis revealed that H. pylori induced a greater immune response in female mice in this model, as measured by increased severity of gastric lesions, decreased bacterial counts and the higher levels of Th1 antibodies for H. pylori. The spectra of mutations pointed towards oxidative damage as the underlying cause of induction. This study revealed that gender differences in mutagenesis were mediated by the severity and duration of the immune response. In the second aim, 17[beta]-estradiol prevented the formation of gastric cancer in the INSGAS mouse model, which develops gastric cancer in a male-predominant manner. Unexpectedly, this study led to the discovery that Tamoxifen may act as an agonist in this model of gastric cancer, as it was able to prevent gastric cancer using mechanisms similar to 17[beta]- estradiol. Both compounds downregulated pathways associated with cellular movement and cancer. CXCL1, a murine homolog of IL-8, was downregulated by treatment at both local and systemic levels, which led to a decreased neutrophilic infiltrate. 17[beta]-estradiol and Tamoxifen mediated the disruption of a positive feedback loop coupling CXCL1 secretion with neutrophil recruitment, which dampened the activation of proinflammatory and oncogenic pathways, leading to protection against gastric cancer. In conclusion, these studies provide further insight into the role of gender modulation of host immune response in H. pylori-induced mutagenesis and carcinogenesis. === by Alexander Sheh. === Ph.D.
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