Heparanase is an
endoglycosidase which cleaves
heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM).
Heparanase is preferentially expressed in human
tumors and its over-expression in
tumor cells confers an invasive phenotype in experimental animals. The
enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo.
Heparanase upregulation correlates with increased
tumor vascularity and poor postoperative survival of
cancer patients.
Heparanase is synthesized as a 65 kDa inactive precursor that undergoes proteolytic cleavage, yielding 8 kDa and 50 kDa
protein subunits that heterodimerize to form an active
enzyme.
Heparanase exhibits also non-enzymatic activities, independent of its involvement in ECM degradation. Among these, are the enhancement of Akt signaling, stimulation of PI3K- and p38-dependent endothelial cell migration, and up regulation of
VEGF, all contributing to its potent pro-angiogenic activity. Studies on relationships between structure and
heparanase inhibition activity of nonanticogulant heparins systematically differing in their O-sulfation patterns, degrees of N-acetylation, and glycol-splitting of both pre-existing nonsulfated
uronic acid residues (prevalently D-glucuronic) and/or those (L-
iduronic acid/L-
galacturonic acid) generated by graded 2-O-desulfation, have permitted to select effective inhibitors of the enzymatic activity of
heparanase. N-acetylated, glycol-split heparins emerged as especially strong inhibitors of
heparanase, exerting little or no release of
growth factors from ECM. N-acetylated glycol-split species of
heparin, as well as
heparanase gene silencing inhibit
tumor metastasis, angiogenesis and
inflammation in experimental animal models. These observations and the unexpected identification of a single functional
heparanase, suggest that the
enzyme is a promising target for anti-
cancer and anti-inflammatory drug development.