Exposure to asbestos fibers causes mesotheliomas, malignant tumors arising from the pleural or peritoneal lining, in humans and in experimental animals. A new model system was developed to induce mesotheliomas in mice after 30-50 weekly injections of 200 ug of crocidolite asbestos fibers. The proposed experiments will explore the mechanisms responsible for the development of these tumors. Two important steps in tumor development are loss of growth regulation and induction of angiogenesis. Specific poly- peptide mediators involved in these two critical steps will be identified in this model system. It is hypothesized that transforming growth factor (TGF-beta) is an inhibitor of mesothelial cell proliferation. The effects of exogenous TGF-beta on proliferation of reactive, preneoplastic. and neoplastic cell lines will be studied in intro and in vivo. regulation of mesothelial cell proliferation may occur by a paracrine or autocrine mechanism. Expression of TGF-beta mRNA by peritoneal macrophages and mesothelial cells will be determined by Northern blot analysis and in situ hybridization. TGF-beta is secreted as a latent, protein-bound complex. Activation of TGF- beta by macrophages or mesothelial cells exposed to asbestos will be tested using an in vitro bioassay. In order for neoplastic mesothelial cells to proliferate autonomously, it is hypothesized that they escape from inhibition by TGF-beta. The following escape mechanisms will be explored: physical migration away from peritoneal macrophages which secrete and activate TGF-beta, loss of ability to activate endogenous TGF-beta, or decreased response to active TGF-beta. Intraperitoneal injection of asbestos fibers induces angiogenesis in the mesothelial lining after 2 weeks. It is hypothesized that this early angiogenic response is mediated by angiogenic factors released from peritoneal macrophages. Expression of mRNA for angiogenic factors will be determined by Northern blot analysis and in situ hybridization. Induction of angiogenesis is also a property of malignant tumors. Release of angiogenic factors from neoplastic mesothelial cells will be determined using an in vivo angiogenesis assay. The role of these mediators in the growth of mesotheliomas in vivo will be tested using blocking antibodies and specific antagonists. These experiments may lead to a rational approach to delay or interrupt the sequence of events leading to the development of mesotheliomas in individuals exposed to asbestos.
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