Helicobacter pylori is a gram-negative microaerophilic bacterium which causes active chronic gastritis and is associated with peptic ulcer disease (1-3). Epidemiologic studies have demonstrated a strong association between H. pylori infection and gastric cancer (reviewed in ref. 4) and gastric lymphoma (5-7). Correa and co-workers have proposed that the intestinal type of gastric carcinoma is preceded by a sequential chain of events including superficial gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia. While several oncogenes (tpr-met, K-ras, DCC and C-erb-2) have been analyzed, there is no consensus regarding their association with pre-malignant and malignant gastric lesions (8-IS). In contrast, there is extensive evidence that mutations of the pS3 tumor-suppressor gene precede, hence may be essential to, development of gastric cancer (16-19). However, it is not known whether alterations in the p53 tumor suppressor gene alone are sufficient to allow development of gastric cancer. The primary purpose of this proposal is to directly test the hypothesis that alterations of the p53 tumor suppressor gene are sufficient to allow experimentally-induced Helicobacter gastritis to progress into gastric carcinoma or lymphoma using a transgenic p53-deficient mouse model. We propose to determine whether experimental infection of transgenic homozygous and heterozygous p53-deficient mice with H. felis leads to pre- malignant or malignant gastric neoplasms. Although homozygous p53- deficient mice are otherwise developmentally normal, a wide variety of lymphomas and carcinomas is observed by six months of age (14,15). In contrast, heterozygous p53-deficient mice have a low (< 2% in nine months) spontaneous level of tumorigenesis. To our knowledge, neither gastric carcinoma nor gastric lymphoma have been reported in p53-deficient mice. The studies we propose should help to clarify the role of p53 gene mutations in development of gastric carcinoma. In addition, these studies may lead to development of a short-term animal model for analyzing the effects of vaccination against Helicobacter infection on prevention of gastric carcinoma or lymphoma.
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