10 Furthermore, these proteases can contribute to the sustained growth of established tumor foci by cleavage of the ectodomain of membrane-bound proforms of growth factors, releasing peptides that are mitogens for tumor cells and/or vascular endothelial cells.10 The other chief components of the ECM are glycosaminoglycan polysaccharides, of which heparan sulfate Inhibitors,research,lifescience,medical (HS) is the most abundant in

the subepithelial and subendothelial basement membranes. Heparan sulfate proteoglycans (HSPGs) are composed of a protein core covalently linked to heparan sulfate (HS) glycosaminoglycan chains that interact closely with other ECM components.11,12 These linear saccharide chains are selleck catalog cleaved by an endoglycosidase activity, heparanase, that degrades the HS side chains of HSPGs.13–15 Normally, the enzyme Inhibitors,research,lifescience,medical is found mainly in platelets, mast cells, placental trophoblasts, keratinocytes,

and leukocytes. Heparanase released from activated platelets and cells of the immune system facilitates extravasation of inflammatory cells. It also stimulates endothelial mitogenesis, primarily through release of HS-bound growth factors (i.e. fibroblast growth factor (FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)) Inhibitors,research,lifescience,medical residing in the ECM.16,17 Tumor cells appear to use the same molecular machinery during metastasis and neoangiogenesis (Figure 1). Thus, the normal physiological functions of proteases and heparanases in embryonic morphogenesis, wound-healing, tissue repair, and inflammation have been effectively “hijacked” Inhibitors,research,lifescience,medical by tumor cells. Figure 1 Heparanase-mediated extravasation of blood-borne cells. Heparanase expressed by tumor cells (left) and neutrophils (right) promotes cell invasion in between adjacent vascular endothelial cells (EC) and through their underlying basal lamina (BL) into the … Evidence indicates that heparanase not only assists in the break-down of ECM but also is involved in regulating the bioavailability and activity of growth factors Inhibitors,research,lifescience,medical and cytokines. Briefly, various heparin-binding growth factors are sequestered

by HS in the ECM, providing a localized, readily accessible depot, protected from proteolytic degradation,18,19 yet available to activate cells after being released by heparanase. It is conceivable that release of tissue-specific growth factors may be involved in the organ selectivity of metastasis. Although these well documented phenomena were investigated AV-951 by us and other groups, it has taken nearly 15 years to isolate and clone the heparanase gene, mainly because of instability of the enzyme(s) and the difficulty in designing specific, quantitative assays. The cDNA sequences of the first and apparently only mammalian heparanase, isolated from human placenta14 and platelets,15 have been reported in 1999, and putative precursor and active recombinant enzymes have been expressed.