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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