Mechanisms Linking Metastasis to Tumor Procoagulant and Innate Immunity

描述（由申请人提供）：大量研究已经建立了关键止血系统成分与肿瘤进展之间的明确联系。最近的研究揭示了这种关系的机制，表明血小板活化和纤维蛋白原通过阻碍自然杀伤（NK）细胞对新形成的微转移瘤的清除来促进转移。然而，肿瘤细胞参与宿主止血系统的机制以及血小板和纤维蛋白原与自然杀伤细胞功能减弱的联系机制仍不清楚。肿瘤细胞参与止血的一个可能途径是组织因子（TF）的表达，它是细胞相关的凝血启动因子。尽管有大量证据表明肿瘤细胞的TF表达与转移有关，但仍不清楚TF是否通过其凝血功能或与止血无关的TF介导过程相关的机制支持肿瘤扩散。计划中的实验将使用肿瘤进展的体内模型和转基因小鼠来探索肿瘤相关TF、循环止血系统成分和先天免疫监视机制之间相互作用的重要性，以确定转移潜力。拟议的研究将验证以下假设：1)肿瘤细胞相关的TF通过与凝血酶生成、局部血小板-纤维蛋白血栓形成和随后抑制NK细胞介导的微转移清除相关的机制增强转移潜力，2)NK细胞参与活化血小板和/或纤维蛋白原或暴露于血小板衍生的可溶性因子导致NK细胞功能下调。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的重要串扰机制。所获得的知识可能指向新的治疗靶点，以治疗或预防转移性疾病。与公共卫生的相关性：癌症向远处器官扩散（即转移）是癌症死亡的一个主要原因。癌细胞可以通过破坏宿主的凝血系统来促进这一过程，而宿主的凝血系统可以保护癌细胞免受能够识别和杀死肿瘤细胞的免疫细胞的攻击。对凝血因子如何促进癌症扩散的更深入了解可能会导致设计治疗或预防转移的新疗法。

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.