The long-term objective of this research program is to define the mechanisms by which hemostatic system components contribute to prostate cancer pathogenesis. Prostate cancer is the second leading cause of cancer death in American men, accounting for approximately 30,000 deaths in the USA each year. There is a critical need to better understand the mechanisms underlying prostate cancer pathogenesis in order to develop new, effective therapies. Growing evidence suggests that prostate cancer pathogenesis is uniquely dependent on hemostatic factors, in that procoagulants not only drive metastatic potential, but also appear to strongly promote prostate tumorigenesis and tumor growth. Consistent with this view, multiple independent clinical studies have shown that reduced procoagulant function resulting from either hemophilia, or anticoagulation therapy to minimize thromboembolic risk results in a far lower incidence of prostate cancer. This proposal builds on strong preliminary studies in the PI's laboratory. Here, analyses of mice with either a gene-targeted mutation resulting in constitutively reduced prothrombin expression, or the use of novel antisense oligonucleotide (ASO) technology to pharmacologically lower prothrombin expression, both suggest that deficits at the level of prothrombin dramatically reduce prostate cancer growth in vivo and limit the formation of metastatic foci. The studies outlined in this proposal will buil on additional preliminary data suggesting that thrombin plays a multifaceted role in prostate cancer progression through distinct mechanisms involving thrombin signaling via PAR-1, as well as fibrin polymer formation. The proposed studies will use a combination of state-of-the-art gene-targeted mice and novel pharmacological tools to test the following hypotheses: (1) thrombin supports prostate cancer progression through multiple distinct mechanisms that support both early and late phases of disease progression, and therapeutic strategies directed at pro/thrombin constitute novel, safe, and effective means to impede prostate cancer growth and metastasis; (2) activation of PAR-1 expressed by both malignant prostate epithelial cells and carcinoma-associated fibroblasts promotes prostate cancer tumorigenesis and progression; (3) fibrin polymer, not soluble fibrinogen, is the form of the protein driving prostate cancer progression; (4) fibrin in the prostate tumor stroma promotes tumorigenesis and tumor growth by shaping the immunological tumor microenvironment through engagement of the leukocyte integrin ?M?2. The proposed studies will fill significant knowledge gaps in understanding the pathobiology of prostate cancer and the role of key coagulation factors in mediating tumorigenesis, tumor growth, and metastasis. Additionally, results generated through this proposal are likely to illuminate novel therapeutic targets and proof-of-principle strategies for limiting prostate cancer progression.
Prostate cancer is the second leading cause of cancer death in American men, underscoring the critical need to better understand this malignancy and develop new strategies to treat it. Multiple lines of evidence suggest that prostate cancer progression is uniquely dependent on clotting system proteins. This proposal builds on intriguing preliminary data suggesting that clotting proteins support prostate cancer development and progression, and may highlight novel therapeutic strategies for preventing and/or treating this important malignancy.
|Adams, G N; Sharma, B K; Rosenfeldt, L et al. (2018) Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice. J Thromb Haemost 16:2258-2269|
|Shaw, Maureen A; Kombrinck, Keith W; McElhinney, Kathryn E et al. (2016) Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice. Blood 128:721-31|