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Blood, 1 January 2008, Vol. 111, No. 1, pp. 190-199. Prepublished online as a Blood First Edition Paper on September 27, 2007; DOI 10.1182/blood-2007-07-101048.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Inhibition of tissue factor signaling suppresses tumor growth1 Department of Immunology and 2 Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA; 3 University of California Davis, Sacramento; and 4 Sidney Kimmel Cancer Center, San Diego, CA
Coagulation activation by tissue factor (TF) is implicated in cancer progression, cancer-associated thrombosis and metastasis. The role of direct TF signaling pathways in cancer, however, remains incompletely understood. Here we address how TF contributes to primary tumor growth by using a unique pair of isotype-matched antibodies that inhibit either coagulation (monoclonal antibody [Mab]-5G9) or direct signaling (Mab-10H10). We demonstrate that the inhibitory antibody of direct TF-VIIa signaling not only blocks TF-VIIa mediated activation of PAR2, but also disrupts the interaction of TF with integrins. In epithelial and TF-expressing endothelial cells, association of TF with β1 integrins is regulated by TF extracellular ligand binding and independent of PAR2 signaling or proteolytic activity of VIIa. In contrast,
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
3β1 integrin association of TF is constitutive in breast cancer cells and blocked by Mab-10H10 but not by Mab-5G9. Mab-5G9 has antitumor activity in vivo, but we show here that Mab-10H10 is at least as effective in suppressing human xenograft tumors in 2 different models. Breast tumor growth was also attenuated by blocking PAR2 signaling. These results show that tumor cell TF-PAR2 signaling is crucial for tumor growth and suggest that anti-TF strategies can be applied in cancer therapy with minor impairment of TF-dependent hemostatic pathways. 
