Recent epidemiologic studies have indicated an association between Helicobacter pylori and gastric cancer. However, direct experimental evidence demonstrating a causal role for Helicobacter in carcinogenesis has been lacking. Our group has developed a mouse model of chronic Helicobacter felis (H. felis) infection in which bacterial gastritis progresses to active chronic inflammation but not to cancer. Taken together, these observations suggest that Helicobacter infection alone is not sufficient for malignant transformation. Therefore, in order to demonstrate in vivo a role for Helicobacter in gastric cancer, we propose to examine the effect of chronic H. felis infection in combination with other factors, including known chemical carcinogens, dietary alterations and a genetic predisposition. Recent studies have shown that the administration of N-methyl-N-nitrosourea (MNU) reproducibly induces cancer in the glandular stomach of a high percentage of mice. We plan to determine whether H. felis infection can increase the incidence or reduce the latency period of stomach cancer induced by MNU. Using this H. felis/MNU model, we will then examine the role of a high salt (8%) diet as a risk factor for gastric cancer, as well as the effect of treatment of H. felis. In addition, we will determine whether known oncogenes and tumor suppressor genes can interact with H. felis infection, through the employment of genetically altered mice. In preliminary studies, we have generated metallothionein-TPR-MET transgenic mice, and we have inoculated p53 knockout mice with H. felis. Finally, the tumors arising in the H. felis/MNU treated mice will be examined for oncogene activation, tumor suppressor gene inactivation, and microsatellite DNA alterations. Thus, the H. felis/MNU model offers an opportunity to demonstrate a role for Helicobacter as a tumor promoter agent in gastric cancer, and to examine the mechanisms by which Helicobacter spp. might contribute to the malignant process.

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National Cancer Institute (NCI)
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Massachusetts General Hospital
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Seo, Ji Hye; Fox, James G; Peek Jr, Richard M et al. (2011) N-methyl D-aspartate channels link ammonia and epithelial cell death mechanisms in Helicobacter pylori Infection. Gastroenterology 141:2064-75
Hagen, Susan J; Ohtani, Masa; Zhou, Jin-Rong et al. (2009) Inflammation and foveolar hyperplasia are reduced by supplemental dietary glutamine during Helicobacter pylori infection in mice. J Nutr 139:912-8
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Wang, T C; Dockray, G J (1999) Lessons from genetically engineered animal models. I. Physiological studies with gastrin in transgenic mice. Am J Physiol 277:G6-11
Lichtenberger, L M; Dial, E J; Ottlecz, A et al. (1999) Attenuation of hydrophobic phospholipid barrier is an early event in Helicobacter felis-induced gastritis in mice. Dig Dis Sci 44:108-15
Fox, J G (1998) Review article: Helicobacter species and in vivo models of gastrointestinal cancer. Aliment Pharmacol Ther 12 Suppl 1:37-60
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Fox, J G; Dangler, C A; Sager, W et al. (1997) Helicobacter mustelae-associated gastric adenocarcinoma in ferrets (Mustela putorius furo). Vet Pathol 34:225-9

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