Coagulation factors as modifiers of the colon cancer microenvironment

凝血因子作为结肠癌微环境的调节剂

基本信息

批准号：
9080211
负责人：
JOSEPH S. PALUMBO
金额：
$ 35.69万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-05 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9080211
关键词：
Adjuvant Therapy Affect Alleles Animals Anticoagulants Antithrombin III Automobile Driving Binding Blood Coagulation Factor Cancer Etiology Cessation of life Clinical Research Clinical Trials Coagulation Process Colitis Colon Adenocarcinoma Colon Carcinoma Colonic Neoplasms Colorectal Cancer Coupled Coupling Data Deposition Development Disease Progression Drug Kinetics Epithelial Cells Epithelium FDA approved Factor XI Fibrin Fibrinogen GTP-Binding Proteins Gene Targeting Generations Growth Hemorrhage Hemostatic Agents Heparin In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Integrins Intestines Laboratories Lead Leukocytes Malignant - descriptor Malignant Neoplasms Mediating Mus Myeloid Cells PAR-1 Receptor Pathogenesis Pathology Pathway interactions Peptide Hydrolases Phenotype Play Premalignant Prevention Process Production Proteins Proteolysis Prothrombin Publishing Research Research Personnel Risk Role Signal Transduction Specificity Staging System Testing Therapeutic Thrombin Time Tissues Tumor Cell Biology United States Variant Warfarin base cancer cell cell type chemokine cytokine inhibitor/antagonist innovation insight macrophage monocyte mortality next generation novel novel strategies novel therapeutic intervention novel therapeutics polymerization pre-clinical prevent programs public health relevance receptor targeted agent tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): 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-κB-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.

描述（由适用提供）：该研究计划的目的是定义止血因素促进结直肠癌（CRC）发病机理的机制。越来越多的证据表明，CRC病理生物学独特地取决于中枢性止血蛋白，凝血酶。最近发表的PIS实验室的研究表明，凝血酶在CRC发病机理中的独特重要性表明，凝血酶和纤维蛋白原驱动结肠炎相关结肠癌的肿瘤发生。这些研究代表了凝血酶/纤维蛋白原轴在肿瘤发生和肿瘤生长中起主要作用的情况的唯一明确的例子。拟议的研究基于这些结果，以及强大的初步数据，表明凝血酶介导的蛋白水解在预呼应和恶性肿瘤微环境中是CRC发病机理的广义上的确定剂，而不仅仅是与炎性结肠炎相关的设置。凝血酶似乎通过与纤维蛋白原和可凝血酶激活受体蛋白酶激活受体1（PAR-1）结合的独特机制（PAR-1）促进CRC肿瘤发生和肿瘤生长。拟议的研究将直接定义将凝血酶耦合到CRC发病机理的机制，并首次探索靶向Pro/凝血酶的最近批准和下一代药物的治疗潜力，以阻止CRC的发育和进展。该提案中的研究将使用针对该建议，最先进的药物和创新的互补体外分析的新型基因靶向小鼠系来测试以下特定假设：1）凝血酶/纤维蛋白原轴对局部免疫学的侵蚀性，在转向局部免疫学的状态方面非常重要，对途径倾向，易生症状，以供体易生长，以供体易生长，以供体膨胀， extravascular fibrin deposition, and specifically fibrin-mediated engagement of the integrin M2, drives intestinal monocytes towards a pro-tumorigenic phenotype, 3) fibrin-mediated binding of macrophage-associated M2 triggers NF-κB-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 pharmaceutical approaches at the level凝血酶蛋白表达或凝血酶产生。拟议的研究将提供对CRC病理生物学中止血因素的确切贡献的急需见解，将阐明关键的机械途径将凝血酶介导的蛋白水解耦合到CRC进展，并将在经验性动物中提供有关先进抗凝剂的实验性动物的基本原则数据，以调整抗凝治疗疗法的治疗，以调整CRC的经验或治疗CRC的治疗。