Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis.

Studies of the involvement of ECM molecules in cell attachment, growth, and differentiation have revealed a central role of heparan sulfate (HS) proteoglycans (HSPGs) in early embryogenesis, morphogenesis, angiogenesis, and epithelial-mesenchymal interactions (1–3). HS chains bind a multitude of proteins and ensure that a wide variety of bioactive molecules (e.g., heparin-binding growth factors, chemokines, lipoproteins, and enzymes) cling to the cell surface and ECM. HSPGs can thus influence a variety of normal and pathologic processes, among which are tissue repair, neurite outgrowth, inflammation and autoimmunity, tumor growth and metastasis, vasculogenesis and angiogenesis (1–4). Binding to HS can modulate a tethered molecule’s biological activity or protect it from proteolytic cleavage and inactivation. Transmembrane and phospholipid-anchored HSPGs (syndecans and glypicans, respectively) mediate cell interactions with components of the microenvironment that control cell shape, adhesion, proliferation, survival, and differentiation (2, 3). These species of HSPGs can also serve as coreceptors along with the other cell surface molecules to form functional receptor complexes that transduce signals from various ligands (2, 3). Because of the important and multifaceted roles of HSPGs in cell physiology, their cleavage is likely to alter the integrity and functional state of tissues and to provide a mechanism by which cells can respond rapidly to changes in the extracellular environment. Enzymatic degradation of HS is, therefore, likely to be involved in fundamental biological phenomena, ranging from pregnancy, morphogenesis, and development to inflammation, angiogenesis, and cancer metastasis. Contrary to some early claims, there is no good evidence for more than one endogenous mammalian HS-degrading endoglycosidases. The recent cloning of a single gene by several groups (5–10), together with biochemical studies (11), suggests that mammalian cells express primarily a single dominant heparanase enzyme (12). This Perspective focuses on the molecular properties, expression pattern, biological functions, and clinical significance of this heparanase in normal and pathological processes, with emphasis on tumor metastasis and angiogenesis.