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Heparanase is an endoglycosidase involved in cleavage of heparan sulfate and hence in degradation and remodeling of the basement membrane and extracellular matrix (ECM). Heparanase activity facilitates cell invasion associated with cancer metastasis, angiogenesis, autoimmunity and inflammation. The enzyme is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype. Heparanase 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. Moreover, heparanase levels in the urine and plasma of cancer patients often correlate with the severity of the disease and response to anti-cancer treatments. These observations, the anti-cancerous effect of heparanase gene silencing and of heparanase-inhibiting molecules, as well as the unexpected identification of a single functional heparanase, suggest that the enzyme is a valid target for anti-cancer drug development and a promising tumor marker. Heparanase also exhibits non-enzymatic activities, stimulating, among other effects, cell adhesion, Akt signaling and PI3K-dependent endothelial cell migration and invasion. It also promotes VEGF expression via the Src pathway and hence may activate endothelial cells and elicit angiogenic and survival responses. Studies with heparanase over-expressing transgenic mice revealed that the enzyme functions in normal processes (i.e., wound healing) involving cell mobilization, HS turnover, tissue vascularization and remodeling. Inhibitors directed against domains critical for heparanase secretion and signaling, combined with inhibitors of heparanase enzymatic activity (i.e., nonanticoagulant glycol-split heparin) are being developed to halt tumor growth, angiogenesis and metastasis. In this review, we summarize the current status of heparanase' research, emphasizing molecular and cellular aspects of the enzyme, including its mode of processing and activation, control of heparanase gene expression, cytoplasmic vs. nuclear localization, enzymatic and non-enzymatic functions, causal involvement in cancer metastasis and angiogenesis, and strategies for the development of heparanase inhibitors. [ABSTRACT FROM AUTHOR]

A definition of the term "heparanase," is presented, which refers to a mammalian enzyme, that is endo-β-glucuronidase, degrading heparan sulfate, a ubiquitous strongly anionic linear polysaccharide associated with the cell surface and extracellular matrix of a wide range of cells of vertebrate and invertebrate tissues.