Properties and function of heparanase in cancer metastasis and angiogenesis.

Cleavage of heparan sulfate proteoglycans affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Heparanase, degrading heparan sulfate (HS) at specific intrachain sites, is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase enzyme is preferentially expressed in human tumors and its overexpression in low-metastatic tumor cells confers a highly invasive phenotype in experimental animals. Heparanase also releases angiogenic factors and accessory fragments of HS from the tumor microenvironment and induces an angiogenic response in vivo. These effects were best demonstrated when the enzyme was secreted and/or expressed on the cell surface. Heparanase may thus facilitate tumor cell invasion, vascularization and survival, all critical events in cancer progression. These observations, the anti-cancerous effect of heparanase-inhibiting molecules, and the unexpected identification of a single predominant functional heparanase suggest that the enzyme is a promising target for drug development.