The Role of Activated Protein C in Cancer

Abstract SCI-18

Activated protein C (APC) is a natural anticoagulant that blocks the amplification of the coagulation cascade via inactivation of factors Va and VIIIa. The APC/PC pathway is initiated by complex formation of thrombin, thrombomodulin (TM), and the endothelial protein C receptor (EPCR) allowing the conversion of zymogen protein C into its activated form. Based on the well-accepted view that coagulation contributes to cancer progression and that anticoagulant treatment may benefit some cancer patient groups, it has been hypothesized that the natural anticoagulant protein C pathway may also play a role in cancer progression. Interestingly, it has recently been shown that endogenous APC limits experimental metastasis of B16 melanoma cells in mouse lungs. Notably, an APC-blocking antibody dramatically increased the number of experimental lung metastasis although not due to diminished anticoagulant activity of APC but largely due to reduced APC-driven S1P1-mediated VE-cadherin-dependent vascular barrier enhancement. In line with these findings repeated administration of recombinant human APC as well as transgenic overexpression of EPCR also diminished experimental metastasis of B16 melanoma cells. It may thus be tempting to speculate that recombinant APC could be a novel treatment strategy to limit cancer progression. However, APC has however a short half-life, needs intravenous administration, and is associated with severe bleeding complications, complicating the potential clinical application of these findings. In contrast to APC, zymogen PC has a longer half-life and is associated with significantly less bleeding complications. To prove or refute the hypothesis that zymogen PC may be an attractive alternative treatment option for APC in cancer patients, we recently compared the effect of continuous overexpression of murine APC or zymogen PC in the liver by viral-mediated gene transfer in experimental metastasis. Interestingly, both APC and zymogen PC overexpression was highly effective in limiting experimental metastasis. An APC variant (APC-5A) with reduced anticoagulant but normal signaling properties did not limit experimental metastasis, whereas the protective effect of zymogen PC remained even in the absence of protease activated receptor-1 (PAR-1), which is the main mediator of APCs cytoprotective effect. Zymogen PC may thus be a novel therapeutic target to limit cancer progression. In conclusion, the natural anticoagulant APC pathway may play an important role in limiting cancer cell extravasation and interventions seeking to modulate the PC system may ultimately benefit the cancer patient. The challenge is however to confirm these findings in alternative preclinical cancer models and eventually to translate our findings into a clinical setting.