title: Inhibition of tissue factor signaling suppresses tumor growth.
abstract: 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 beta1 integrins is regulated by TF extracellular ligand binding and independent of PAR2 signaling or proteolytic activity of VIIa. In contrast, alpha3beta1 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.
authors: Department of Immunology, SP258, Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Henri H
authors: HH
authors: Versteeg
authors: Florence
authors: F
authors: Schaffner
authors: Marjolein
authors: M
authors: Kerver
authors: Helle H
authors: HH
authors: Petersen
authors: Jasimuddin
authors: J
authors: Ahamed
authors: Brunhilde
authors: B
authors: Felding-Habermann
authors: Yoshikazu
authors: Y
authors: Takada
authors: Barbara M
authors: BM
authors: Mueller
authors: Wolfram
authors: W
authors: Ruf
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000556:secondary*; D002455:Cell Division; D002461:Cell Line, Transformed; D004730:Endothelium, Vascular / Q000166:cytology; D015942:Factor VIIa / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D013925:Thromboplastin / Q000276:immunology / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D000911:Antibodies, Monoclonal; D019012:Integrin beta1; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D013925:Thromboplastin; D015942:Factor VIIa