The objective of this research program is to define the mechanisms by which hemostatic factors promote colorectal cancer (CRC) pathogenesis. Growing evidence suggests that CRC pathobiology is uniquely dependent on the central hemostatic protease, thrombin. The unique importance of thrombin in CRC pathogenesis is evinced by recently published studies from the PIs laboratory revealing that thrombin and fibrinogen drive tumorigenesis in colitis-associated colon cancer. These studies represent the only definitive example of a context where the thrombin/fibrinogen axis plays a major role in tumorigenesis and tumor growth. The proposed studies build on these results, as well as powerful preliminary data revealing that thrombin-mediated proteolysis in the premalignant and malignant tumor microenvironments is a broadly important determinant of CRC pathogenesis, not just settings associated with inflammatory colitis. Thrombin appears to promote CRC tumorigenesis and tumor growth through unique mechanisms coupled to fibrinogen and the thrombin-activatable receptor, protease activated receptor-1 (PAR-1). The proposed studies will directly define the mechanisms coupling thrombin to CRC pathogenesis, and explore, for the first time, the therapeutic potential of recently approved and next-generation pharmacological agents targeting pro/thrombin to impede the development and progression of CRC. The studies in this proposal will use novel gene-targeted mouse lines developed specifically for this proposal, cutting-edge pharmacological agents, and innovative complementary in vitro analyses to test the following specific hypotheses: 1) the thrombin/fibrinogen axis is broadly important in shifting the local immunological microenvironment towards a pathogenic, inflammatory state capable of supporting intestinal tumorigenesis, 2) extravascular fibrin deposition, and specifically fibrin-mediated engagement of the integrin ?M?2, drives intestinal tumorigenesis b pushing intestinal monocytes toward a pro-tumorigenic phenotype, 3) fibrin-mediated binding of macrophage-associated ?M?2 triggers NF-?B-dependent production of pro-tumorigenic cytokines, chemokines, and growth factors, thereby supporting the proliferation/survival of transformed intestinal epithelial cells, 4) thrombin is also coupled to the development and progression of CRC through activation of distinct, tissue-specific PAR-1 signaling mechanisms involving macrophages in the premalignant and tumor microenvironments, as well as transformed intestinal epithelial cells, and 5) CRC pathogenesis can be limited in mice by multiple distinct pharmacological approaches at the level of prothrombin expression or thrombin generation. The proposed studies will provide much needed insights into the precise contribution of hemostatic factors in CRC pathobiology, will illuminate key mechanistic pathways coupling thrombin-mediated proteolysis to CRC progression, and will provide essential proof-of-principle data in experimental animals regarding the translatability of advanced anticoagulants as adjuvant therapy for the prevention or treatment of CRC.
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, highlighting the critical need to better understand this malignancy and develop innovative treatments. Multiple lines of evidence suggest that CRC progression is uniquely dependent on the local action of clotting system proteins. This proposal builds on published and strong preliminary data suggesting that clotting proteins are fundamental drivers of CRC development and progression. A deeper understanding of how clotting factors support CRC pathobiology could lead to novel therapies for preventing and/or treating this important malignancy.
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