ReviewMechanisms of heparanase inhibitors in cancer therapy

•The role of heparanase and heparanase inhibitors in cancer biology and therapy is reviewed.•Heparanase promotes invasion, angiogenesis, and tumor metastasis in preclinical models.•Inhibition of heparanase results in decreased tumor growth and metastasis in vivo.•Several classes of heparanase inhibitors are presently being investigated.

Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains contributing to breakdown of the extracellular matrix. Increased expression of heparanase has been observed in numerous malignancies and is associated with a poor prognosis. It has generated significant interest as a potential antineoplastic target because of the multiple roles it plays in tumor growth and metastasis. The protumorigenic effects of heparanase are enhanced by the release of heparan sulfate side chains, with subsequent increase in bioactive fragments and cytokine levels that promote tumor invasion, angiogenesis, and metastasis. Preclinical experiments have found heparanase inhibitors to substantially reduce tumor growth and metastasis, leading to clinical trials with heparan sulfate mimetics. In this review, we examine the role of heparanase in tumor biology and its interaction with heparan surface proteoglycans, specifically syndecan-1, as well as the mechanism of action for heparanase inhibitors developed as antineoplastic therapeutics.