Hemostatic Factors Drive Prostate Cancer Pathogenesis

 描述(由申请人提供)：本研究计划的长期目标是确定止血系统成分对前列腺癌发病机制的作用机制。前列腺癌是美国男性癌症死亡的第二大原因，美国每年约有30,000人死于前列腺癌。为了开发新的、有效的治疗方法，迫切需要更好地了解前列腺癌的发病机制。越来越多的证据表明，前列腺癌的发病机制唯一依赖于止血因素，因为促凝剂不仅驱动转移潜能，而且似乎强烈地促进前列腺癌的发生和肿瘤的生长。与这一观点一致的是，多项独立的临床研究表明，血友病或抗凝治疗导致的促凝血功能降低，将血栓栓塞的风险降至最低，前列腺癌的发病率要低得多。这项建议建立在PI实验室强有力的初步研究基础上。在这里，无论是通过基因靶向突变导致凝血酶原表达的结构性降低的小鼠，还是使用新型反义寡核苷酸(ASO)技术从药物上降低凝血酶原表达的小鼠的分析，都表明凝血酶原水平的缺陷极大地减少了体内前列腺癌的生长并限制了转移灶的形成。这项提案中概述的研究将建立在其他初步数据的基础上，这些数据表明，凝血酶通过不同的机制在前列腺癌的进展中发挥多方面的作用，这些机制涉及凝血酶通过PAR-1传递信号以及纤维蛋白聚合物的形成。建议的研究将使用最先进的基因靶向小鼠和新的药理学工具来检验以下假设：(1)凝血酶通过支持疾病进展的早期和晚期的多种不同机制来支持前列腺癌的进展，针对凝血酶原/凝血酶的治疗策略构成了阻止前列腺癌生长和转移的新的、安全和有效的手段；(2)由恶性前列腺上皮细胞和与癌症相关的成纤维细胞表达的PAR-1的激活促进了前列腺癌的发生和发展；(3)推动前列腺癌进展的蛋白质形式是纤维蛋白聚合物，而不是可溶性纤维蛋白原；(4)前列腺癌间质中的纤维蛋白通过与白细胞整合素αMβ2结合而形成免疫肿瘤微环境，从而促进肿瘤的发生和生长。这些研究将填补前列腺癌的病理生物学以及关键凝血因子在调节肿瘤发生、肿瘤生长和转移中的作用方面的重大知识空白。此外，通过这项提议产生的结果可能会阐明限制前列腺癌进展的新的治疗目标和原则证明策略。

 DESCRIPTION (provided by applicant): 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 αMβ2. 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.