title: Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival.
abstract: Malignant glioma continues to be fatal, despite improved insight into its underlying molecular mechanisms. The most malignant form, glioblastoma (GBM), is characterized by aberrant activation of receptor tyrosine kinases (RTK) and infiltrative growth. Heparan sulfate proteoglycans (HSPG), integral components of the extracellular matrix of brain tumors, can regulate activation of many RTK pathways. This prompted us to investigate heparanase (HPSE), which cleaves HSPGs, for its role in glioma. This hypothesis was evaluated using tissue microarrays, GBM cells derived from patients, murine in vitro and in vivo models of glioma, and public databases. Downregulation of HPSE attenuated glioma cell proliferation, whereas addition of HPSE stimulated growth and activated ERK and AKT signaling. Using HPSE transgenic and knockout mice, it was demonstrated that tumor development in vivo was positively correlated to HPSE levels in the brain. HPSE also modified the tumor microenvironment, influencing reactive astrocytes, microglia/monocytes, and tumor angiogenesis. Furthermore, inhibition of HPSE reduces tumor cell numbers, both in vitro and in vivo HPSE was highly expressed in human glioma and GBM cell lines, compared with normal brain tissue. Indeed, a correlation was observed between high levels of HPSE and shorter survival of patients with high-grade glioma. In conclusion, these data provide proof-of-concept for anti-HPSE treatment of malignant glioma, as well as novel insights for the development of HPSE as a therapeutic target.
  
  
  
  This study aims to target both the malignant brain tumor cells per se and their microenvironment by changing the level of an enzyme, HPSE, that breaks down modified sugar chains on cell surfaces and in the extracellular space. Mol Cancer Res; 14(12); 1243-53. ©2016 AACR.
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Soumi
authors: S
authors: Kundu
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Anqi
authors: A
authors: Xiong
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Argyris
authors: A
authors: Spyrou
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Grzegorz
authors: G
authors: Wicher
authors: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Voichita D
authors: VD
authors: Marinescu
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Per-Henrik D
authors: PD
authors: Edqvist
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Lei
authors: L
authors: Zhang
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Magnus
authors: M
authors: Essand
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Anna
authors: A
authors: Dimberg
authors: Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
authors: Anja
authors: A
authors: Smits
authors: Cancer and Vascular Biology Research Center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Neta
authors: N
authors: Ilan
authors: Cancer and Vascular Biology Research Center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Israel
authors: I
authors: Vlodavsky
authors: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Jin-Ping
authors: JP
authors: Li
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. karin.nilsson@igp.uu.se.
authors: Karin
authors: K
authors: Forsberg-Nilsson
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D015854:Up-Regulation; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase