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.
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.
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