Pre‐clinical and clinical significance of heparanase in Ewing’s sarcoma

• Published in: Journal of cellular and molecular medicine Vol. 15; no. 9; pp. 1857 - 1864
• Main Authors: Shafat, Itay, Ben‐Arush, Myriam Weyl, Issakov, Josephine, Meller, Isaac, Naroditsky, Inna, Tortoreto, Monica, Cassinelli, Giuliana, Lanzi, Cinzia, Pisano, Claudio, Ilan, Neta, Vlodavsky, Israel, Zunino, Franco
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011; John Wiley & Sons, Inc
• Subjects: Adult; age; Angiogenesis; Animals; Antibodies; Anticoagulants; Cancer therapies; Cell Line, Tumor; Cell migration; Cell Proliferation - drug effects; Clinical significance; Enzymatic activity; Enzyme Inhibitors - pharmacology; Enzymes; Ewing’s sarcoma; Female; Fibroblast Growth Factor 2 - pharmacology; Fibroblast Growth Factors - pharmacology; Glucuronidase - antagonists & inhibitors; Glucuronidase - metabolism; Heparan sulfate; heparanase; Heparin; Heparin - analogs & derivatives; Heparin - pharmacology; Humans; Immunohistochemistry; Localization; Male; Malignancy; Medical prognosis; Metastases; Metastasis; Mice; Mice, Nude; Neoplasm Invasiveness; Patients; Plasma; Proteoglycans; Remission (Medicine); Sarcoma; Sarcoma, Ewing - enzymology; Sarcoma, Ewing - pathology; SST0001; Statistical analysis; Subcellular Fractions - drug effects; Subcellular Fractions - enzymology; Treatment Outcome; Tumors; tumour size; Tel Aviv Israel; United States > US; Israel
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2010.01190.x

Heparanase is an endoglycosidase that specifically cleaves heparan sulphate side chains of heparan sulphate proteoglycans, activity that is strongly implicated in cell migration and invasion associated with tumour metastasis, angiogenesis and inflammation. Heparanase up‐regulation was documented in an increasing number of human carcinomas, correlating with reduced post‐operative survival rate and enhanced tumour angiogenesis. Expression and significance of heparanase in human sarcomas has not been so far reported. Here, we applied the Ewing’s sarcoma cell line TC71 and demonstrated a potent inhibition of cell invasion in vitro and tumour xenograft growth in vivo upon treatment with a specific inhibitor of heparanase enzymatic activity (compound SST0001, non‐anticoagulant N‐acetylated, glycol split heparin). Next, we examined heparanase expression and cellular localization by immunostaining of a cohort of 69 patients diagnosed with Ewing’s sarcoma. Heparanase staining was noted in all patients. Notably, heparanase staining intensity correlated with increased tumour size (P = 0.04) and with patients’ age (P = 0.03), two prognostic factors associated with a worse outcome. Our study indicates that heparanase expression is induced in Ewing’s sarcoma and associates with poor prognosis. Moreover, it encourages the inclusion of heparanase inhibitors (i.e. SST0001) in newly developed therapeutic modalities directed against Ewing’s sarcoma and likely other malignancies.