Heparanase procoagulant activity in cancer progression

Abstract

Heparanase is an endo-β-D-glucuronidase that is capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans on cell surfaces and the extracellular matrix. This activity is strongly implicated in tumor metastasis and angiogenesis. We have earlier demonstrated that apart of its well characterized enzymatic activity, heparanase may also affect the hemostatic system in a non-enzymatic manner. We showed that heparanase up-regulated the expression of the blood coagulation initiator-tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we demonstrated that heparanase directly enhanced TF activity, which led to increased factor Xa production and subsequent activation of the coagulation system. In patients with cancer, increased heparanase procoagulant activity appeared to be a potential predictor of survival. We have also shown that JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor, a finding that may point to a new mechanism of thrombosis in JAK-2 positive patents with essential thrombocytosis. Recently, we found that the solvent accessible surface of TFPI-2 first Kunitz domain had a role in TF/heparanase complex inhibition. Peptides derived from TFPI-2 inhibitory site were shown to reduce coagulation activation induced by heparanase and to attenuate sepsis severity and tumor growth in a mouse model, without predisposing to significant bleeding tendency. These data imply that inhibition of heparanase procoagulant domain is potentially a good target for sepsis and cancer therapy.