Research Papers:

Heparanase 2 expression inversely correlates with bladder carcinoma grade and stage

Miriam Gross-Cohen _, Sari Feld, Inna Naroditsky, Ofer Nativ, Neta Ilan and Israel Vlodavsky

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Oncotarget. 2016; 7:22556-22565. https://doi.org/10.18632/oncotarget.8003

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Miriam Gross-Cohen1, Sari Feld1, Inna Naroditsky2, Ofer Nativ3, Neta Ilan1, Israel Vlodavsky1

1Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel

2Department of Pathology, Rambam Health Care Campus, Haifa, Israel

3Department of Urology, Bnai-Zion Medical Center, Haifa, Israel

Correspondence to:

Israel Vlodavsky, e-mail: [email protected]

Keywords: Heparanase 2, bladder cancer, LOX, tumor growth, tumor grade

Received: February 16, 2016    Accepted: February 23, 2016    Published: March 9, 2016


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.

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