The analysis of the role and inhibition of heparanase in cancer metastasis and inflammation

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Heparanase (Hpa) is an endo-b-D-glucuronidase that specifically cleaves carbohydrate chains of heparan sulfate proteoglycans (HSPG) s. HSPGs are distributed ubiquitously and are common constituents of cell surfaces and the ECM, including basement membranes. HSPGs also bind and sequester a variety of bioactive proteins, including growth factors, chemokines, cytokines, and enzymes. After cleaving HSPGs by Hpa, HS-binding growth factors, such as bFGF, TGF-b, PDGF and VEGF, are released and activated. Hpa is involved in embryonic morphogenesis, wound healing, tissue repair and inflammation. The enzyme has been identified in a variety of normal and malignant cells and tissues, e.g., skin fibroblasts, cytotrophoblasts, hepatocytes, endothelial cells, platelets, mast cells, neutrophils, macrophages, T and B-lymphocytes, lymphoma, melanoma, and cancer cells. Previous studies demonstrated that the expression of Hpa gene and protein correlated with metastatic potential of several human and mouse … More cell lines such as breast, bladder, prostate, melanoma and T-lymphoma. We found that heparanase had an important role in gastric cancer invasion and metastasis and in other tumors. (Uno F, Naomoto Y et al; Antisense-mediated suppression of human heparanase gene expression inhibits pleural dissemination of human cancer cells. Cancer Res. 61(21):7855-60, 2001, Takaoka M, Naomoto Y et al; Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest. 83(5):613-22, 2003 )Heparanase has also important roles in inflammatory bowel disease and other diseases. Those results were submitted in the journals as follows ; (Nobuhisa T, Naomoto Y et al; Heparanase is a marker of poor prognosis and malignant potential of colon cancer. Submitted, in Clinical Cancer Research / Imada T, Naomoto Y et al; COX-2-induction by heparanase in the progession of breast cancer. Submitted in Cancer Research / Ohkawa T, Naomoto Y et al; Cytoplasmic, and nuclear localization of heparanase in esophageal cancer cells : Respective roles in prognosis and differentiation. Submitted in Cancer Research) Less