Inhibition of Tissue Factor—Factor VIIa Proteolytic Activity Blunts Hepatic Metastasis in Colorectal Cancer

Background

Expression of the principal initiator of coagulation, tissue factor (TF), by colorectal cancer (CRC) cells is involved in tumoral angiogenesis and metastasis progression, after binding of factor VIIa (FVIIa) to TF and generation of TF-FVIIa activity. We thus hypothesized that inhibition of the TF pathway by active site-blocked FVIIa (FFR-FVIIa) may prevent the development of hepatic metastasis in CRC.

Methods

Rat tumoral cells (DHDK12 proB cells) expressing high levels of TF were injected in the portal vein in syngenic BDIX rats. Rats received intraperitoneal injection of either FFR-FVIIa, from d 3 to d 7 (adjuvant treatment) (n = 19), or solvent buffer (n = 18) (control group). Additionally, cancer cells were infused subcutaneously in 20 other rats, which were assigned to FFR-FVIIa adjuvant treatment (n = 10), or buffer treatment (n = 10). Macroscopic and histological analysis was performed at d 14.

Results

In the control group, infusion of cancer cells resulted in development of macroscopic hepatic tumors in 17/18 rats. In the adjuvant FFR-FVIIa group, macroscopic hepatic tumors were visible on the liver surface in 3/19 rats (P = 0.002 versus control). All rats with subcutaneous injection of proB cells exhibited macroscopic tumors, with no significant difference between the control and the treated ones.

Conclusion

Inhibition of the proteolytic activity of TF-FVIIa complex blunted hematogenous hepatic metastasis, suggesting that TF-FVIIa is a relevant target for the prevention of hepatic metastasis in CRC. TF-blocking agents should be investigated as adjuvant treatment in this setting.

Key Words: colorectal cancer, tissue factor, hepatic metastasis, experimental model