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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.
 Previous Article | Next Article 
Submitted July 12, 2007
Accepted September 24, 2007
Inhibition of tissue factor signaling suppresses tumor growth
Henri H Versteeg, Florence Schaffner, Marjolein Kerver, Helle H. Petersen, Jasimuddin Ahamed, Brunhilde Felding-Habermann, Yoshikazu Takada, Barbara M. Mueller, and Wolfram Ruf*
Department of Immunology, The Scripps Research Institute, La Jolla, CA, United States
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States
Department of Dermatology, University of California Davis, Sacramento, CA, United States
Sidney Kimmel Cancer Center, San Diego, CA, United States
* Corresponding author; email: ruf{at}scripps.edu.
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 employing a unique pair of isotype-matched antibodies that inhibit either coagulation (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  1 integrins is regulated by TF extracellular ligand binding and independent of PAR2 signaling or proteolytic activity of VIIa. In contrast,  31 integrin association of TF is constitutive in breast cancer cells and blocked by Mab-10H10 but not by Mab-5G9. Mab-5G9 has anti-tumor activity in vivo, but we show here that Mab-10H10 is at least as effective in suppressing human xenograft tumors in two 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.
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