Mechanisms Linking Metastasis to Tumor Procoagulant and Innate Immunity

许多研究已经在关键止血系统成分和肿瘤之间建立了明确的联系 进展最近的研究表明，这种关系背后的机制是， 血小板活化和纤维蛋白原通过阻碍新生血管的清除而促进转移。 自然杀伤（NK）细胞的微转移。然而，肿瘤细胞用来与宿主结合的机制 止血系统以及血小板和纤维蛋白原与自然杀伤细胞减少的联系机制 函数未定义。肿瘤细胞参与止血的可能手段是表达 组织因子（TF），细胞相关的凝血起始物。尽管有大量证据表明 肿瘤细胞表达TF与转移有关，TF是否通过机制支持肿瘤扩散仍不清楚 与其在凝血或TF介导的过程中的功能有关，与止血无关。计划 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之间的相互作用 监测机制，以确定转移潜力。拟议的研究将测试以下内容 假设：1）肿瘤细胞相关TF通过与凝血酶相关的机制增强转移潜能 产生，局部血小板-纤维蛋白血栓形成和随后的NK细胞介导的抑制 清除微转移，2）NK细胞与活化血小板和/或纤维蛋白原的接合或暴露于 血小板衍生的可溶性因子导致NK细胞功能的下调。这些研究将加深我们的 的转移过程的理解，并阐明了重要的串扰机制之间的 止血和先天免疫系统。所获得的知识可以指向新的治疗靶点， 治疗或预防转移性疾病。 与公共卫生的相关性：癌症向远处器官的扩散（即转移）是导致癌症复发的主要原因。 癌症死亡癌细胞可以通过破坏宿主凝血系统来促进这一过程， 用于保护它们免受能够识别和杀死肿瘤细胞的免疫细胞的侵害。更深 了解凝血因子如何促进癌症扩散可能会导致新的治疗方法， 治疗或预防转移。

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.