Mechanisms Linking Metastasis to Tumor Procoagulant and Innate Immunity

转移与肿瘤促凝血和先天免疫的联系机制

• 批准号: 7837534
• 负责人: JOSEPH S. PALUMBO
• 金额: $ 22.54万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837534
• 关键词: Applications Grants; Biological Response Modifiers; Blood Coagulation Factor; Blood Platelets; Cancer Etiology; Cell Communication; Cell physiology; Cells; Cessation of life; Coagulation Process; Coupled; Coupling; Defect; Development; Disease; Disseminated Malignant Neoplasm; Distant; Down-Regulation; Embolic Tumor Cells; Exposure to; Fibrin; Fibrinogen; Foundations; Generations; Goals; Hemostatic Agents; Hemostatic function; Immune; Immune system; Immunologic Surveillance; In Vitro; Kinetics; Knowledge; Laboratories; Lead; Lewis Lung Carcinoma; Light; Link; Malignant Neoplasms; Mediating; Micrometastasis; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Neoplasm Metastasis; Organ; Platelet Activation; Process; Prothrombin; Public Health; Research Personnel; Role; System; Testing; Therapeutic; Thrombin; Thromboplastin; Thrombus; Transgenic Mice; Tumor Cell Line; cancer cell; cell motility; cytotoxicity; in vivo; in vivo Model; killings; melanoma; metastatic process; neoplastic cell; new therapeutic target; novel; novel strategies; outcome forecast; prevent; programs; research study; success; therapy design; tumor; tumor growth; tumor progression

Numerous studies have established a clear link between key hemostatic system components and tumor progression. A mechanism underlying this relationship was recently illuminated by studies showing that platelet activation and fibrinogen facilitate metastasis by impeding the clearance of newly formed micrometastases by natural killer (NK) cells. However, the machinery used by tumor cells to engage the host hemostatic system and the mechanisms linking platelets and fibrinogen to diminished natural killer cell function remain undefined. A likely means available to tumor cells for engaging hemostasis is expression of tissue factor (TF), the cell-associated initiator of coagulation. Although there is substantial evidence linking TF expression by tumor cells to metastasis, it remains unclear if TF supports tumor spread by mechanisms linked to its function in coagulation or TF-mediated processes uncoupled from hemostasis. The planned experiments will use in vivo models of tumor progression and transgenic mice to explore the importance of interplay amongst tumor associated TF, circulating hemostatic system components, and innate immune surveillance mechanisms in determining metastatic potential. The proposed studies will test the following hypotheses: 1) Tumor cell associated TF enhances metastatic potential by a mechanism linked to thrombin generation, local platelet-fibrin thrombus formation and subsequent suppression of NK cell mediated clearance of micrometastases, 2) NK cell engagement of activated platelets and/or fibrinogen or exposure to platelet derived soluble factors results down-regulation of NK cell function. These studies will deepen our understanding of the metastatic process and shed light on important crosstalk mechanisms between the hemostatic and innate immune systems. The knowledge gained could point to novel therapeutic targets to treat or prevent metastatic disease. Relevance to public health: The spread of cancer to distant organs (i.e. metastasis) is a major cause of cancer deaths. Cancer cells can facilitate this process by subverting the host clotting system, which can serve to protect them from immune cells capable of recognizing and killing tumor cells. A deeper understanding of how clotting factors contribute to cancer spread could lead to novel therapies designed to treat or prevent metastases.

许多研究已经在关键止血系统和肿瘤之间建立了明确的联系 进展。最近的研究表明，这种关系的基础机制最近阐明了 血小板激活和纤维蛋白原通过阻碍新形成的清除来促进转移 天然杀伤（NK）细胞的微转移。但是，肿瘤细胞使用的机械吸引了宿主 止血系统以及将血小板和纤维蛋白原连接到减少天然杀手细胞的机制 功能仍然不确定。肿瘤细胞可用于引起止血的可能手段是表达 组织因子（TF），与细胞相关的凝结起始人。虽然有大量证据链接 肿瘤细胞对转移的TF表达，尚不清楚TF是否支持通过机制扩散的肿瘤 与其在与止血偶联的凝结或TF介导的过程中的功能有关。计划 实验将使用肿瘤进展和转基因小鼠的体内模型来探索的重要性 肿瘤相关的TF，循环止血系统成分和先天免疫之间的相互作用 确定转移潜力的监视机制。拟议的研究将测试以下 假设：1）与凝血酶相关的机制，肿瘤细胞相关TF可增强转移性电位 产生，局部血小板 - 纤维蛋白血栓形成以及随后抑制NK细胞介导的 微晶的清除率，2）活化血小板和/或纤维蛋白原或暴露于 血小板得出的可溶性因子导致NK细胞功能下调。这些研究将加深我们 了解转移过程，并阐明了重要的串扰机制 止血和先天免疫系统。获得的知识可能指向新颖的治疗靶点 治疗或预防转移性疾病。 与公共卫生有关：癌症传播到遥远的器官（即转移）是主要原因 癌症死亡。癌细胞可以通过颠覆宿主凝结系统来促进这一过程，这可以 用来保护它们免受能够识别和杀死肿瘤细胞的免疫细胞。更深 了解凝血因素如何导致癌症扩散可能导致新型疗法旨在 治疗或预防转移。