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.

Synergistic Effects of Tamoxifen and Tranilast on VEGF and MMP-9 Regulation in Cultured Human Breast Cancer Cells

“…Garvin et al (2006) also demonstrated that similar events also occurred in ex vivo cultured normal human breast tissue (Garvin et al, 2006). In addition, MMP-9 are closely associated with tumor growth, invasion and metastasis (Versteeg et al, 2008) and estrogen has been shown to regulate the activity of MMP-2 and MMP-9 in breast cancer cells (Nilsson et al, 2007).…”

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

“…Evidence to this effect includes the role of clotting factors and platelets in such fundamental processes in cancer as cellular growth, angiogenesis, metastasis, inflammation, therapeutic responsiveness and vascular comorbidities, as extensively reviewed in the recent literature [6,7,20,21,25,[84][85][86][87][88][89][90][91]. Notably, pharmacological and genetic strategies targeting TF, FVIIa, thrombin, platelets and other coagulation mechanisms led to anti-tumor and anti-metastatic effects [61,[92][93][94][95][96], which are often comparable to other 'main stream' targeted agents [87,93].…”

The Endothelial Protein C Receptor Supports Tissue Factor Ternary Coagulation Initiation Complex Signaling through Protease-activated Receptors

“…signaling has been demonstrated in both murine and human cells (23,48,49), little is known about signaling of the ternary complex in primary cells isolated from mice. Because TF is not typically expressed by endothelial cells in the absence of proangiogenic or inflammatory stimuli, we focused on murine SMCs that constitutively express EPCR and TF (50,51).…”

“…TF with an unpaired Cys 186 can form a complex with PAR2, and in this non-coagulant TF-FVIIa binary complex, FVIIa cleaves PAR2 (22). In addition, the binary TF-FVIIa complex interacts with integrins that contribute to TF-FVIIa signaling activity in cancer cells (23). In contrast, signaling of the ternary TF-FVIIa-FXa product complex requires the allosteric Cys 186 -Cys 209 disulfide of TF and is mediated by FXa cleaving PAR1 or PAR2 (21,22).…”