Advanced cancer frequently leads to Trousseau’s syndrome or thromboembolism that result from increased expression of Tissue Factor (TF) by cancer cells. TF function is also implicated in tumor progression. TF is the cellular receptor and cofactor for coagulation factor VIIa and thereby triggers coagulation. The TF-VIIa enzyme complex also mediates proteolytic cell signaling by cleaving the G-protein-coupled, protease activated receptor (PAR) 2. We have recently described a novel disulfide exchange mechanism that dynamically switches TF between coagulation and cell signaling and identified a monoclonal antibody that interrupts TF-VIIa cell signaling without inhibiting coagulation. Anti-TF antibodies that target the coagulant function of TF are also currently considered for cancer therapy. In this study we employed antibodies specific for human TF in the TF and PAR2 positive MDA-MB-231 breast cancer xenograft model. We tested the effect of prototypic inhibitors of TF-induced coagulation (mAb5G9) or TF-VIIa cell signaling (mAb10H10) on metastasis and tumor growth. Bioluminescence imaging was used to monitor metastatic tumor implantation, survival and subsequent expansion in the lungs. MDA-MB-231 cells tagged with luciferase were preincubated with antibody and injected into the tail vein of SCID mice that were subsequently imaged at 4h, 24h, 48h and 5 weeks. A significant 90% reduction of tumor cells in the lungs was apparent in mAb5G9 treated mice at 24 and 48 hours, but metastasis was similar in control and mAb10H10 treated animals until 48 hours. Metastatic burden remained low in mAb5G9-teated animals, demonstrating that initiation of coagulation by TF is critical for early survival of tumor cells. MAb10H10 treated mice showed a reduction in final metastatic load, indicating growth inhibition of metastases. In subcutaneous tumor growth experiments with highly aggressive MDA-MB-231mfp cells, mAb10H10 effectively suppressed tumor development, whereas coagulation blockade with mAb5G9 showed only marginal growth suppression. These data provide novel evidence that direct TF signaling pathways can be successfully targeted without coagulation inhibition which may increase bleeding risk in cancer patients.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA