Heparanase, heparin and the coagulation system in cancer progression

Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). The enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an accelerated growth and invasive phenotype in experimental animals. In contrast, heparanase gene silencing is associated with a marked inhibition of tumor progression. Heparanase upregulation correlates with increased tumor vascularity and poor postoperative survival of cancer patients. Studies on relationships between structure and the heparanase-inhibiting activity of nonanticogulant heparins systematically differing in their O-sulfation patterns, degrees of N-acetylation, and glycol-splitting of nonsulfated uronic acid residues, have permitted to select effective inhibitors of the enzymatic activity of heparanase. N-acetylated, glycol-split heparins emerged as highly effective and specific inhibitors of heparanase and tumor growth and metastasis. Several observations support the involvement of heparanase in haemostasis. A marked induction of tissue factor (TF) was noted in response to heparanase over-expression in tumor-derived cell lines and heparanase over-expressing transgenic mice. A direct correlation was also found between heparanase and TF expression levels in leukemia patients. TF induction was even more pronounced upon exogenous addition of heparanase to primary endothelial cells that do not normally express TF, and this induction was associated with enhanced coagulation. These and other results indicate that pro-heparanase is rapidly tethered on cell surfaces, partially depending on cell surface heparan sulfate, generating a local procoagulant effect. In addition, pro-heparanase can reverse the anti-coagulant effect of unfractionated heparin and the Factor Xa inhibitory activity of low molecular weight heparin (LMWH). These effects were also demonstrated in plasma derived from patients treated with LMWH. The pro-coagulant effects of pro-heparanase were also exerted by a peptide corresponding to its major functional heparin-binding domain. Heparanase pro-coagulant activities suggest its possible role as a natural regulator of heparinoid anti-coagulant activities, and point to a possible use of this molecule or its heparin binding domain as antidote for heparinoid therapies.