Thus, inhibition of heparanase enzymatic activity is expected to

Thus, inhibition of heparanase enzymatic activity is expected to suppress tumor progression. To examine this in myeloma, a chemically modified heparin, which is 100% N-acetylated and 25% glycol-split, was tested. This flexible molecule is a potent inhibitor of heparanase enzymatic activity, lacks anticoagulant activity typical of heparin, and does not displace ECM-bound FGF-2 or potentiate its mitogenic Inhibitors,research,lifescience,medical activity.48,85 The

modified heparin profoundly inhibits the progression of tumor xenografts produced by www.selleckchem.com/wee1-kinase.html myeloma58,83 and Ewing’s sarcoma95 cells. These studies support the notion that heparanase enzymatic activity not only facilitates tumor metastasis but also promotes the progression of primary tumors. CONCLUSIONS AND PERSPECTIVE

Although much has been learnt in the last decade, the repertoire of heparanase functions in health and disease is only starting to emerge. Clearly, from activity implicated mainly in cell invasion associated with tumor Inhibitors,research,lifescience,medical metastasis, Inhibitors,research,lifescience,medical heparanase has turned into a multi-faceted protein that appears to participate in essentially all major aspects of tumor progression. Heparanase expression is elevated already at the early stages of human neoplasia. In the colon, heparanase gene and protein are expressed already at the stage of adenoma,96 and during esophageal carcinogenesis heparanase expression is induced in Barrett’s epithelium, an early event that predisposes

Inhibitors,research,lifescience,medical patients to formation of dysplasia which may progress to adenocarcinoma.97 Heparanase expression at the early stages of tumor initiation and progression, and by Inhibitors,research,lifescience,medical the majority of tumor cells, can be utilized to turn the immune system against the very same cells. Accumulating evidence suggests that peptides derived from human heparanase can elicit a potent antitumor immune response, leading to lysis of heparanase-positive human gastric, colon, and breast carcinoma cells, as well as hepatoma and sarcoma cells.98,99 In contrast, no killing effect Phosphatidylinositol diacylglycerol-lyase was noted towards autologous lymphocytes.98,99 Notably, the development of tumor xenografts produced by B16 melanoma cells was markedly restrained in mice immunized with peptides derived from mouse heparanase (i.e. aa 398–405; 519–526) compared to a control peptide in both immunoprotection and immunotherapy approaches.99 T-regulatory cells are frequently present in colorectal cancer patients; interestingly, T-regulatory cells against heparanase could not be found.100 Antiheparanase immunotherapy is thus expected to be prolonged and more efficient due to the absence of T suppressor cells. A related treatment approach is being tested in advanced metastasized breast cancer patients.

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