Heparanase coagulation and cancer progression

Abstract

Heparanase is an endo-beta-D-glucuronidase capable of cleaving heparan sulphate (HS) side chains of heparan sulphate proteoglycans on cell surfaces and the extracellular matrix; activity that is strongly implicated in tumour metastasis and angiogenesis. It has been shown that heparanase overexpression in human leukaemia, glioma and breast carcinoma cells results in a marked increase in tissue factor (TF) levels. In addition, TF was induced by exogenous addition of recombinant heparanase to tumour cells and primary endothelial cells; induction that was mediated by p38 phosphorylation and correlated with enhanced procoagulant activity. TF induction was further confirmed in transgenic mice overexpressing heparanase, and correlated with heparanase expression levels in leukaemia patients. Heparanase was also found to be involved in the regulation of tissue factor pathway inhibitor (TFPI). It has been shown that heparanase overexpression or exogenous addition induces a two- to three-fold increase in TFPI expression. Similarly, heparanase stimulated accumulation of TFPI in the cell culture medium. However, extracellular accumulation exceeded the observed increase in TFPI at the protein level, and appeared to be independent of HS and heparanase enzymatic activity. Instead, a physical interaction between heparanase and TFPI was demonstrated, suggesting a mechanism by which secreted heparanase interacts with TFPI on the cell surface, leading to dissociation of TFPI from the cell membrane and increased coagulation activity, thus further supporting the local prothrombotic function of heparanase. As heparins are strong inhibitors of heparanase, in view of the effect of heparanase on the TF/TFPI pathway, the role of anticoagulant activity of heparin may potentially be expanded. Taking into account the prometastatic and pro-angiogenic functions of heparanase, its overexpression in human malignancies and abundance in platelets, its involvement in the coagulation machinery is an intriguing novel arena for further research.