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: 7136035
• 负责人: JOSEPH S. PALUMBO
• 金额: $ 37.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7136035
• 关键词: blood coagulation; cell cell interaction; cell migration; circulating neoplastic cell; cytotoxicity; fibrinogen; genetically modified animals; hemostasis; host neoplasm interaction; immunity; laboratory mouse; leukocyte activation /transformation; lung neoplasms; melanoma; metastasis; natural killer cells; neoplasm /cancer immunology; neoplastic cell; platelet activation; prothrombin; thrombin; thromboplastin; tissue /cell culture

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：许多研究已经在关键的止血系统成分与肿瘤进展之间建立了明确的联系。 最近的研究表明，通过阻碍天然杀伤（NK）细胞的新形成的微分光聚糖酶的清除，血小板激活和纤维蛋白原促进转移，从而促进了这种关系的基础机制。 然而，肿瘤细胞用来接合宿主止血系统的机械以及将血小板和纤维蛋白原与自然杀伤细胞功能降低的机制保持不确定。 肿瘤细胞可用于引起止血的一种可能手段是组织因子（TF）的表达，这是与细胞相关的凝结剂。 尽管有大量证据将肿瘤细胞与转移的TF表达联系起来，但尚不清楚TF是否通过与其在凝血或与止血偶联的TF介导的过程中的功能相关的机制来支持肿瘤扩散。 计划的实验将在肿瘤进展和转基因小鼠的体内模型中探索相关TF之间相互作用的重要性，循环止血系统成分以及先天的免疫监测机制在确定转移性潜能中的重要性。 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. 这些研究将加深我们对转移过程的理解，并阐明止血和先天免疫系统之间重要的串扰机制。 获得的知识可能指出了治疗或预防转移性疾病的新型治疗靶标。 与公共卫生有关：癌症传播到遥远的器官（即转移）是癌症死亡的主要原因。 癌细胞可以通过颠覆宿主凝血系统来促进这一过程，该系统可以保护它们免受能够识别和杀死肿瘤细胞的免疫细胞。 对凝血因子如何导致癌症扩散的更深入的了解可能导致旨在治疗或预防转移的新型疗法。