title: Heparanase 2 Attenuates Head and Neck Tumor Vascularity and Growth.
abstract: The endoglycosidase heparanase specifically cleaves the heparan sulfate (HS) side chains on proteoglycans, an activity that has been implicated strongly in tumor metastasis and angiogenesis. Heparanase-2 (Hpa2) is a close homolog of heparanase that lacks intrinsic HS-degrading activity but retains the capacity to bind HS with high affinity. In head and neck cancer patients, Hpa2 expression was markedly elevated, correlating with prolonged time to disease recurrence and inversely correlating with tumor cell dissemination to regional lymph nodes, suggesting that Hpa2 functions as a tumor suppressor. The molecular mechanism associated with favorable prognosis following Hpa2 induction is unclear. Here we provide evidence that Hpa2 overexpression in head and neck cancer cells markedly reduces tumor growth. Restrained tumor growth was associated with a prominent decrease in tumor vascularity (blood and lymph vessels), likely due to reduced Id1 expression, a transcription factor highly implicated in VEGF-A and VEGF-C gene regulation. We also noted that tumors produced by Hpa2-overexpressing cells are abundantly decorated with stromal cells and collagen deposition, correlating with a marked increase in lysyl oxidase expression. Notably, heparanase enzymatic activity was unimpaired in cells overexpressing Hpa2, suggesting that reduced tumor growth is not caused by heparanase regulation. Moreover, growth of tumor xenografts by Hpa2-overexpressing cells was unaffected by administration of a mAb that targets the heparin-binding domain of Hpa2, implying that Hpa2 function does not rely on heparanase or heparan sulfate. Cancer Res; 76(9); 2791-801. ©2016 AACR.
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gross-Cohen
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Sari
authors.initials: S
authors.lastname: Feld
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Carmel Medical Center, Haifa, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Doweck
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.affiliation: Department of Anatomy and Cell Biology, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Peleg
authors.initials: P
authors.lastname: Hasson
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Arvatz
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Barash
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Naroditsky
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. vlodavsk@mail.huji.ac.il.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005966:Glucuronidase / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase