Hemostasis System in Tumor Growth and Metastasis

先前的研究已经确定了止血与肿瘤生长和转移之间的关系。临床上，这些蛋白的血浆水平升高被认为是复发和生存率降低的预后标志。虽然存在这些相关因素，但该系统对疾病病理的具体体内机制仍然很大程度上未知。一些临床研究已经确定了止血系统的组成部分在调节一些癌症的病理。虽然许多基因与结肠癌的不同阶段有关，但在腺瘤形成的早期阶段发现了大肠腺瘤性息肉病（APC）基因的突变，并且认为该基因参与了肿瘤的发生和进展。这种基因的突变会导致家族性疾病

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.