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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. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-101048v1 111/1/190    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Versteeg, H. H Articles by Ruf, W. Search for Related Content PubMed PubMed Citation Articles by Versteeg, H. H Articles by Ruf, W. Social Bookmarking                   What's this?  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Milsom, N. Magnus, B. Meehan, K. Al-Nedawi, D. Garnier, and J. Rak Tissue Factor and Cancer Stem Cells: Is There a Linkage? Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2005 - 2014. [Abstract] [Full Text] [PDF] F. Schaffner and W. Ruf Tissue Factor and PAR2 Signaling in the Tumor Microenvironment Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 1999 - 2004. [Abstract] [Full Text] [PDF] Y. W. van den Berg, L. G. van den Hengel, H. R. Myers, O. Ayachi, E. Jordanova, W. Ruf, C. A. Spek, P. H. Reitsma, V. Y. Bogdanov, and H. H. Versteeg Alternatively spliced tissue factor induces angiogenesis through integrin ligation PNAS, November 17, 2009; 106(46): 19497 - 19502. [Abstract] [Full Text] [PDF] A. P. B. Batschauer, C. P. Figueiredo, E. C. Bueno, M. A. Ribeiro, L. M. S. Dusse, A. P. Fernandes, K. B. Gomes, and M. G. Carvalho D-dimer as a possible prognostic marker of operable hormone receptor-negative breast cancer Ann. Onc., October 30, 2009; (2009) mdp474v1. [Abstract] [Full Text] [PDF] V. O. Melnikova, K. Balasubramanian, G. J. Villares, A. S. Dobroff, M. Zigler, H. Wang, F. Petersson, J. E. Price, A. Schroit, V. G. Prieto, et al. Crosstalk between Protease-activated Receptor 1 and Platelet-activating Factor Receptor Regulates Melanoma Cell Adhesion Molecule (MCAM/MUC18) Expression and Melanoma Metastasis J. Biol. Chem., October 16, 2009; 284(42): 28845 - 28855. [Abstract] [Full Text] [PDF] R. S. Kasthuri, M. B. Taubman, and N. Mackman Role of Tissue Factor in Cancer J. Clin. 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[Abstract] [Full Text] [PDF] E. M. Conn, M. A. Madsen, B. F. Cravatt, W. Ruf, E. I. Deryugina, and J. P. Quigley Cell Surface Proteomics Identifies Molecules Functionally Linked to Tumor Cell Intravasation J. Biol. Chem., September 26, 2008; 283(39): 26518 - 26527. [Abstract] [Full Text] [PDF] H. H. Versteeg, F. Schaffner, M. Kerver, L. G. Ellies, P. Andrade-Gordon, B. M. Mueller, and W. Ruf Protease-Activated Receptor (PAR) 2, but not PAR1, Signaling Promotes the Development of Mammary Adenocarcinoma in Polyoma Middle T Mice Cancer Res., September 1, 2008; 68(17): 7219 - 7227. [Abstract] [Full Text] [PDF]

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