Abstract
Heparanase, a β-D-endoglucuronidase abundant in platelets that was discovered 30 years ago, is an enzyme that cleaves heparan sulfate side chains on the cell surface and in the extracellular matrix. It was later recognized as being a pro-inflammatory and pro-metastatic protein. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. We had shown that heparanase up-regulated the expression of the blood coagulation initiator tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we have demonstrated that heparanase directly enhanced TF activity which led to increased factor Xa production and subsequent activation of the coagulation system. Recently, heparanase inhibitory peptides derived of TFPI-2 were demonstrated by us to inhibit heparanase procoagulant activity and attenuate sepsis in mouse models.
Highlights
Heparanase activity heparan sulfate (HS) side chains at a limited correlated with the metastatic potential of tumor number of sites, yielding HS fragments of still cells, attributed to enhanced cell dissemination as a Abbreviations: ECM, extracellular matrix; HS, heparan sulfate; LPS, lipopolysaccharide; OC, oral contraceptives; thrombinantithrombin complex (TAT), thrombin-antithrombin; TF, tissue factor; TFPI, tissue factor pathway inhibitor; VEGF, vascular endothelial growth factor
We have demonstrated that heparanase over-expression in human leukemia, glioma, and breast carcinoma cells results in a marked increase in TF levels verified by immunoblot and real-time PCR analyses.[13]
We demonstrated that exogenous addition or overexpression of heparanase by transfected cells resulted in release of TFPI from the cell surface and its accumulation in the cell culture medium.[27]
Summary
Consequence of HS cleavage and remodeling of the extracellular matrix (ECM) barrier.[3,4] heparanase activity was implicated in neovascularization, inflammation, and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system.[3,4,5] Up-regulated expression of heparanase was noted in essentially all human tumors examined, as well as in inflammation, wound healing, and diabetic nephropathy.[3,4,5] A single human heparanase cDNA sequence was independently reported by several research groups.[6,7,8,9] unlike the large number of proteases that can degrade polypeptides in the ECM, one major heparanase appears to be used by cells to degrade the HS side chains of HS proteoglycans. Expression of heparanase is restricted primarily to the placenta, platelets, and activated blood cells of the immune system, with little or no expression in connective tissue cells and most normal epithelia.[3,4] During embryogenesis, the enzyme is preferentially expressed in cells of the developing vascular and nervous systems.[10]
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