Exposure to asbestos fibers causes diffuse malignant mesothelioma arising from the pleural, pericardial, or peritoneal linings.The ultimate objective of this research is to identify the cellular and molecular events in the development and progression of malignant mesotheliomas induced by asbestos fibers. The proposed experiments will focus on the role of the TGF-beta growth stimulatory pathway and alterations in the p53 tumor suppressor gene during the preneoplastic and neoplastic stages in a murine model system of asbestos tumorigenesis. It is hypothesized that constitutive activation of the TGF- alpha growth stimulatory pathway is an early step in the development of malignant mesotheliomas, followed by alterations in the p53 tumor suppressor gene during progression from focal to invasive growth. The role of the TGF-alpha growth regulatory pathway in the development of malignant mesothelioma will be assessed in vivo and in vitro. MT42 transgenic mice will be used to test whether overexpression of TGF-alpha accelerates the development of malignant mesotheliomas induced by weekly intraperitoneal injections of asbestos fibers. The correlation between overexpression of TGF- alpha, its receptor (EGF-R), cell proliferation, and specific histopathologic stages in the development of malignant mesothelioma will be assessed. A critical evaluation of the role of TGF-alpha expression during the preneoplastic and neoplastic stages in the development of these tumors will be assessed directly by transfection of sense or antisense TGF-alpha vectors in vitro. The effects of increased or decreased TGF-alpha expression on growth of these transfected cell lines will be determined in vitro and in vivo. p53- deficient mice will be used to determine whether heterozygosity at this gene locus accelerates progression from focal to invasive malignant mesotheliomas. Man-made mineral fibers have been developed and used commercially as asbestos fiber substitutes. Few of these materials have been tested for carcinogenicity because lifetime rodent inhalation studies are technically difficult and expensive. These new transgenic mouse model systems may provide a more rapid, cost-effective screening assay for potentially carcinogenic man- made fibers.
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