Functional Cooperation of Tissue Factor and Integrins

描述（由申请人提供）：要求继续支持直接组织因子（TF）信号促进肿瘤生长的机制研究。在之前的资助期内，我们发现TF胞质结构域信号调节3(1)介导的细胞迁移，配体VIIa的结合独立于蛋白水解事件，诱导TF与整合素的关联，并且癌细胞的特征是TF与整合素的组成性关联。通过一种独特的抗体，阻断TF-整合素结合并阻断所有直接TF信号而不抑制凝血，我们发现抑制肿瘤细胞的直接TF信号足以减弱肿瘤的生长。乳腺癌发展的遗传小鼠模型进一步支持了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。这项工作将利用人类和遗传小鼠的侵袭性乳腺癌模型来进一步确定TF-VIIa-PAR2信号通路失调控促进体内肿瘤进展的机制。Aim 1通过关注旁分泌对肿瘤微环境的影响以及肿瘤细胞运动中的TF-PAR2信号串扰来表征小鼠自发性肿瘤发展中的TF-PAR2信号通路。目的2是表征异位合成的VIIa在体内促进构成性tf整合素结合和促肿瘤PAR2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已被流行病学和临床试验充分证明。该应用程序解决了凝血信号促进肿瘤进展的新途径。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，因此提出的基本机制研究有助于将这一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.