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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1999.)
© 2009 American Heart Association, Inc.

Brief Reviews

Tissue Factor and PAR2 Signaling in the Tumor Microenvironment

Florence Schaffner; Wolfram Ruf

From the Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, Calif.

Correspondence to Wolfram Ruf, Department of Immunology and Microbial Science, SP258, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail ruf{at}scripps.edu

Series Editor: Nigel Mackman Mark B. Taubman
ATVB In Focus

Tissue Factor: Past, Present, and Future

Diverse oncogenic transformations result in the constitutive expression of tissue factor (TF) in cancer cells. The local and systemic activation of the coagulation cascade has long been a recognized hallmark for aggressive cancer, but genetic mouse models and new experimental therapeutics have only recently demonstrated crucial roles for TF initiated cell signaling in the pathogenesis of cancer. On tumor cells, the TF-VIIa binary complex mediates activation of protease activated receptor (PAR) 2 and thereby shapes the tumor microenvironment by inducing an array of proangiogenic and immune modulating cytokines, chemokines, and growth factors. PAR2 also uniquely triggers tumor cell migration by G protein–independent pathways through β-arrestin scaffolding. Metastatic tumor cells use additional signaling networks of the coagulation cascade by activating PAR1 through thrombin or the ternary TF-VIIa-Xa signaling complex in the vascular and potentially lymphatic system. Selective antagonists of TF-VIIa-PAR2 signaling may be used as antiangiogenic therapy without increasing the risk of bleeding, whereas coagulation and associated signaling pathways on platelets and other host cells may be targeted for therapeutic benefit in advanced cancer and metastatic disease.

Tumor cell TF-VIIa-PAR2 signaling shapes the tumor microenvironment by inducing proangiogenic and immune modulating cytokines, chemokines, and growth factors. Selective inhibition of TF-PAR2 signaling is sufficient to reduce tumor angiogenesis and primary breast cancer growth, demonstrating that coagulation signaling can be targeted for therapeutic benefit.

Key Words: thrombosis • cancer • G protein-coupled receptor • coagulation signaling

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