Gastric cancer is a major cause of worldwide mortality. In most cases, this disease is the consequence of decades of gastric infection by Helicobacter pylori and the associated inflammatory response. Risk factors for gastric cancer development include the presence of specific H. pylori virulence determinants and host factors, such as polymorphisms responsible for cytokine and cytokine receptor expression and activity. Research into both the molecular and cellular mechanisms responsible and the possibility of eradicating H. pylori to prevent or decrease gastric carcinogenesis has long been hampered by the paucity of suitable rodent models. We have recently developed a novel murine model of H. pylori-associated gastric cancer in the p27-deficient mouse, based on the following findings: (i) H. pylori decreases gastric epithelial cell p27 protein expression, (ii) p27 has the properties of a tumor suppressor protein, and (iii) low expression of p27 in gastric cancers is associated with poor prognosis. Infection of p27-deficient mice with the SS1 strain of H. pylori resulted in the development of significant gastric dysplasia or carcinoma in 58% of these mice compared with only 7% of wild- type mice after 60 weeks infection. These changes were preceded by marked gastric inflammation and the early development of intestinal metaplasia. We propose to test the following hypotheses: 1. That loss of p27 expression in bone marrow-derived gastric inflammatory cells, rather than gastric epithelial cells, is responsible for gastric carcinogenesis following H. pylori infection in p27-/- mice. 2. That H. pylori eradication therapy given prior to the development of intestinal metaplasia will prevent gastric cancer development in the H. pylori-infected p27-/- mouse model. These hypotheses will be tested by 2 specific aims: 1. p27-/- mice will receive a bone marrow transplantation from ROSA 26 wild type mice (and vice-versa) prior to H. pylori infection, and the effects of bone marrow transplantation on gastric cancer development will be determined. 2. p27-/- mice will be infected with H. pylori and the effect of eradication of H. pylori on gastric cancer incidence will be evaluated. Intervention with H. pylori eradication therapy will be compared before and after the development of frequent intestinal metaplasia in this model. These studies will lead to improved understanding of the mechanisms of gastric carcinogenesis associated with H. pylori infection and will evaluate a novel mouse model of H. pylori-associated gastric carcinogenesis for preclinical testing. Because of the designation of H. pylori by the World Health Organization as a class I (definite) carcinogen in the etiology of the second most frequent cause of worldwide cancer mortality, this work has implications for a major global public health problem. Our overall long-term goal is to contribute to the development of new clinical strategies for the prevention, diagnosis and treatment of gastric cancer.Public Health Relevance Gastric (stomach) cancer is the second most common cause of cancer death in the world, usually arising as a consequence of chronic gastritis caused by infection with Helicobacter pylori bacteria. Research to investigate how H. pylori promotes gastric cancer and whether antibiotic therapy will prevent gastric cancer in humans, has been hampered by a lack of suitable animal models. We propose to evaluate a new mouse model of H. pylori-induced gastric cancer that we have developed, in order to address these important questions.
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