Hemostasis System in Tumor Growth and Metastasis

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Previous studies have identified relationships between hemostasis and tumor growth and metastasis. Clinically, elevated plasma levels of these proteins have been suggested as prognostic markers for relapse and reduced survival. While these correlates exist, specific in vivo mechanisms by which this system contributes to the pathology of the disease remains largely unknown. Several clinical studies have identified components of the hemostasis system in regulating the pathology of a number of cancers. While a number of genes have been implicated in various stages of colon cancer, mutations in the adenomatous polyposis coli (APC) gene have been found during the early stages of adenoma formation, and it is believed that this gene is involved in tumor development and progression. Mutations of this gene result in familial adenomatous polyposis (FAP), which is characterized by the formation of multiple colonic adenomatous polyps. These adenomas predispose to the development of colon carcinoma. A mouse model (APC[Min+/o] )has been developed that mimics the clinical features of FAP. Therefore, studies to directly determine the role of hemostasis in this cancer can be effectively studied in APC[Min+/o] mice with additional alterations inexpression of hemostasis proteins. Specifically this study is focused on: 1) utilization of the spontaneous tumor model, APC[Min+/o], with additional alterations in expression of components of the hemostasis system and comparisons of tumor development and dissemination in these various genotypically-distinct groups. This will involve analyses of tumor growth rate, spatial and temporal involvement of proteins and other host cells, and extent of vascularization, associated with tumor progression; 2) identification and quantitation of the relative abundance of angiogenic factors in primary and metastatic tumors utilizing quantitative real-time RT-PCR (Q-RT-PCR) and determination of the spatial expression patterns by in situ hybridization. Since preliminary studies in our laboratory have demonstrated an attenuation of the pathology in APC[Min+/o]/UPA-/- mice relative to APC [Min+/o] or APC[Min+/o]/PG-/- mice 3) characterization of the mechanism associated with the uPA/uPAR system in the regulation of intestinal/colonic tumor formation will be assessed. This will include in vitro and in vivo analyses of effects on proteins associated with cell signaling pathways, and generation of mice with targeted mutations of uPA with specific alterations of domains associated with receptor interaction and proteolytic activity, in order to further elucidate functional domains of uPA involved in regulating tumor formation.