Mammalian Heparanase: Molecular Properties, Inhibition and Involvement in Tumor Metastasis and Angiogenesis

Abstract

Tumor spread involves degradation of various components of the extracellular matrix (ECM) and blood vessel wall. Among these is heparan sulfate proteoglycan (HSPG) which plays a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. In view of this role, our research has been focusing on an enzyme (heparanase) which degrades heparan sulfate and hence facilitates tumor cell invasion and metastasis. We have demonstrated that expression of heparanase correlates with the metastatic potential of tumor cells and found that treatment with heparanase inhibitors markedly reduced the incidence of metastasis in experimental animals. We have also found that heparin-binding angiogenic promoting proteins are stored in a stable form in the microenvironment of tumors as a complex with heparan sulfate. These proteins are released and can induce new capillary growth when heparan sulfate is degraded by heparanase. This review describes the molecular cloning, expression and involvement in tumor progression of a human heparanase. The enzyme is synthesized as a latent ~65 kDa protein that is processed at the N-terminus into a highly active ~50 kDa form. The heparanase mRNA and protein are preferentially expressed in highly metastatic mouse and human cell lines and in biopsy specimens of human tumors.