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.