Functional Cooperation of Tissue Factor and Integrins

描述（由申请人提供）：需要持续支持以研究直接组织因子（TF）信号传导促进肿瘤生长的机制。在前一个资助期，我们发现TF胞质结构域信号调节β 1介导的细胞迁移，配体VIIa的结合，不依赖于蛋白水解事件，诱导TF与整联蛋白的结合，并且癌细胞的特征在于组成性TF-整联蛋白结合。利用中断TF-整联蛋白缔合并阻断所有直接TF信号传导而不抑制凝血的独特抗体，我们表明直接肿瘤细胞TF信号传导的抑制足以减弱肿瘤生长。TF主要通过直接细胞信号传导而不是凝血激活来支持癌症发展的新概念进一步得到了乳腺癌发展的遗传小鼠模型的支持。拟议的工作将使用人类以及侵袭性乳腺癌的遗传小鼠模型，以进一步确定TF-VIIa-PAR 2信号转导失调促进体内肿瘤进展的机制。目的1通过关注肿瘤微环境的旁分泌效应和癌细胞运动中的TF-PAR 2信号串扰来表征小鼠自发肿瘤发展中的TF-PAR 2信号通路。目的2是表征异位合成的VIIa在体内促进组成性TF-整合素缔合和促肿瘤发生PAR 2信号传导中的作用。目的3探讨EPCR作为TF复合物的潜在共信号受体在体内肿瘤生长中的作用。这些实验将为凝血蛋白酶信号如何促进肿瘤进展提供新的见解。公共卫生相关性：凝血激活和癌症进展的作用在流行病学和临床试验中得到了充分的证明。本申请提出了一种新的途径，凝血信号通过该途径促进肿瘤进展。由于该途径的原型抑制剂在临床前模型中有效地减弱肿瘤生长，因此所提出的基本机制研究促进了将该新概念合理地转化为临床。

DESCRIPTION (provided by applicant): Continuing support is requested to study mechanisms by which direct tissue factor (TF) signaling promotes tumor growth. In the previous funding period, we showed that TF cytoplasmic domain signaling regulates (3(1-mediated cell migration, that binding of ligand VIIa, independent of proteolytic events, induces association of TF with integrins, and that cancer cells are characterized by constitutive TF-integrin association. With a unique antibody that interrupts TF- integrin association and blocks all direct TF signaling without inhibiting coagulation, we showed that inhibition of direct tumor cell TF signaling is sufficient to attenuate tumor growth. The novel concept that TF supports cancer development predominantly through direct cell signaling and not coagulation activation is further supported by genetic mouse models of breast cancer development. The proposed work will use human as well as genetic mouse models of aggressive breast cancer to further define the mechanisms by which deregulated TF-VIIa-PAR2 signaling promotes tumor progression in vivo. Aim 1 characterizes the TF-PAR2 signaling pathway in spontaneous tumor development in the mouse by focusing on paracrine effects on the tumor microenvironment and the TF-PAR2 signaling crosstalk in cancer cell motility. Aim 2 is to characterize the role of ectopically synthesized VIIa in promoting constitutive TF-integrin association and pro-tumorigenic PAR2 signaling in vivo. Aim 3 addresses the role of EPCR as a potential co-signaling receptor for TF complexes in tumor growth in vivo. These experiments will provide new insight into how coagulation protease signaling promotes tumor progression. PUBLIC HEALTH RELEVANCE: The role of coagulation activation and cancer progression is well documented by epidemiology and clinical trials. This application addresses a novel pathway by which coagulation signaling promotes tumor progression. Because a prototypic inhibitor of this pathway is effective to attenuate tumor growth in preclinical models, the proposed basic mechanistic studies facilitate a rational translation of this novel concept into the clinic.