Molecular properties and involvement of heparanase in cancer progression and normal development

Heparan sulfate proteoglycans (HSPGs) play a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellula r matrices. Hence, cleavage of heparan sulfate (HS) affects the integrity a nd functional state of tissues and thereby fundamental normal and pathologi cal phenomena involving cell migration and response to changes in the extra cellular microenvironment. Here, we describe the molecular properties, expr ession and function of a human heparanase, degrading HS at specific intrach ain sites. The enzyme is synthesized as a latent similar to 65 kDa protein that is processed at the N-terminus into a highly active similar to 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metas tatic cell lines and human tumor tissues. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The hep aranase enzyme also releases ECM-resident angiogenic factors in vitro and i ts overexpression induces an angiogenic response in vivo. Heparanase may th us facilitate both tumor cell invasion and neovascularization, both critica l steps in cancer progression. The enzyme is also involved in cell migratio n associated with inflammation and autoimmunity. The unexpected identificat ion of a single predominant functional heparanase suggests that the enzyme is a promising target for drug development. In fact, treatment with heparan ase inhibitors markedly reduces tumor growth, metastasis and autoimmune dis orders in animal models. Studies are underway to elucidate the involvement of heparanase in normal processes such as implantation, embryonic developme nt, morphogenesis, tissue repair, inflammation and HSPG turnover. Heparanas e is the first functional mammalian HS-degrading enzyme that has been clone d, expressed and characterized. This may lead to identification and cloning of other glycosaminoglycan degrading enzymes, toward a better understandin g of their involvement and significance in normal and pathological processe s. (C) 2001 Societe francaise de biochimie et biologie moleculaire/Editions scientifiques et medicales Elsevier SAS. All rights reserved.