rNAPc2 Inhibits Colorectal Cancer in Mice through Tissue Factor

Abstract

Purpose: Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel antithrombotic activity. TF is highly expressed in human colorectal tumors, and levels are positively correlated with disease progression. Experimental Design: To explore the therapeutic potential and mechanism of action of rNAPc2 during tumor growth and metastasis, we tested rNAPc2 in several experimental colorectal cancer models in mice. Results: Administration of rNAPc2 inhibited pulmonary metastasis in mice systemically disseminated with CT26 murine colon carcinoma cells in a dose-dependent fashion. Combining rNAPc2 with the cytotoxic agent 5-fluorouracil or bevacizumab (humanized anti-vascular endothelial growth factor monoclonal antibody) resulted in additive growth inhibition and simultaneous reduction of microvessel density in HCT116 human colorectal tumor xenografts in nude mice. Furthermore, rNAPc2 potentiated CPT-11 in inhibiting hepatic metastasis in nude mice with portal vein injection of HCT116 tumor cells. Long-term administration of rNAPc2 significantly suppressed spontaneous formation of intestinal tumors in Apc Min/+ mice. Using a RNA interference approach, we showed thatTF expression is necessary for rNAPc2-mediated inhibition of HCT116 human colorectal tumor xenograft growth in nude mice, indicating that the antitumor effect of rNAPc2 may be transduced throughTF that is expressed on tumor cells. Conclusions: rNAPc2 is a potent anticancer agent when used in combination with chemotherapy or antiangiogenic therapy in mouse models of colorectal cancer, and TF positivity appears to be required for its activity.

Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development

“…These data are in excellent agreement with results demonstrating that pharmacological inhibition of direct TF signaling reduced angiogenesis in several tumor models 16,44 and markedly suppressed colon cancer progression in the mouse. 45 Our data also indicate that interruption of TF signaling perturbs angiogenesis and immune cells in the host tumor microenvironment. While species-selective antibodies had provided clear evidence for an important role of tumor cell BLOOD, 23 DECEMBER 2010 ⅐ VOLUME 116, NUMBER 26 For personal use only.…”

Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations

“…Thus, in several experimental studies TF obliteration was shown to impede tumor growth (49)(50)(51)(52), but other studies have shown that TF-negative cells may readily form aggressive tumors in mice (53)(54)(55)(56). Similar differences could be expected also among patients with brain tumors.…”

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

“…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].…”