title: Heparanase 2 expression inversely correlates with bladder carcinoma grade and stage.
abstract: While the pro-tumorigenic function of heparanase is well taken, the role of its close homolog, heparanase 2 (Hpa2) in cancer is by far less investigated. Utilizing immunohistochemical analysis we found that Hpa2 is expressed by normal bladder transitional epithelium and its levels are decreased substantially in bladder cancer. Notably, tumors that retain high levels of Hpa2 were diagnosed as low grade (p=0.001) and low stage (p=0.002), suggesting that Hpa2 is required to preserve cell differentiation and halt cell motility. Indeed, migration of 5637 bladder carcinoma cells was attenuated significantly by exogenous addition of purified Hpa2, and over expression of Hpa2 in 5637 cells resulted in smaller tumors that were diagnosed as low grade. We also noted that tumors produced by Hpa2 over expressing cells are abundantly decorated with stromal cells and collagen deposition evident by Masson's/Trichrome staining, correlating with a marked increase in lysyl oxidase (LOX) staining. The association between Hpa2 and LOX was further confirmed clinically, because of the 16 cases that exhibited strong staining of Hpa2, 14 (87.5%) were also stained strongly for LOX (p=0.05). Collectively, our results suggest that Hpa2 functions as a tumor suppressor in bladder cancer, maintaining cellular differentiation and decreasing cell motility in a manner that appears to be independent of regulating heparanase activity.
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gross-Cohen
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Sari
authors.initials: S
authors.lastname: Feld
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Naroditsky
authors.affiliation: Department of Urology, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Nativ
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005966:Glucuronidase / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012189:Retrospective Studies; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology*; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase
keywords: Heparanase 2; LOX; bladder cancer; tumor grade; tumor growth