Takamasa Kinoshita1,2, Hiroyuki Tomita3, Hideshi Okada4, Ayumi Niwa1, Fuminori Hyodo5, Tomohiro Kanayama1, Mikiko Matsuo1, Yuko Imaizumi1, Takahiro Kuroda1, Yuichiro Hatano1, Masafumi Miyai6, Yusuke Egashira2, Yukiko Enomoto2, Noriyuki Nakayama2, Shigeyuki Sugie7, Kazu Matsumoto8, Yu Yamaguchi9, Masayuki Matsuo5, Hideaki Hara10, Toru Iwama2, Akira Hara1. 1. Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan. 2. Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan. 3. Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan. h_tomita@gifu-u.ac.jp. 4. Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan. hideshi@gifu-u.ac.jp. 5. Department of Radiology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan. 6. Department of Neurosurgery, Ogaki Tokusyukai Hospital, Ogaki, Gifu, 503-0015, Japan. 7. Department of Pathology, Asahi University Hospital, Gifu, 500-8523, Japan. 8. Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan. 9. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, CA, USA. 10. Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, 501-1196, Japan.
Abstract
PURPOSE: Heparan sulfate (HS) is one of the factors that has been suggested to be associated with angiogenesis and invasion of glioblastoma (GBM), an aggressive and fast-growing brain tumor. However, it remains unclear how HS of endothelial cells is involved in angiogenesis in glioblastoma and its prognosis. Thus, we investigated the effect of endothelial cell HS on GBM development. METHODS: We generated endothelial cell-specific knockout of Ext1, a gene encoding a glycosyltransferase and essential for HS synthesis, and murine GL261 glioblastoma cells were orthotopically transplanted. Two weeks after transplantation, we examined the tumor progression and underlying mechanisms. RESULTS: The endothelial cell-specific Ext1 knockout (Ext1CKO) mice exhibited reduced HS expression specifically in the vascular endothelium of the brain capillaries compared with the control wild-type (WT) mice. GBM growth was significantly suppressed in Ext1CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1CKO mice than in WT mice. We investigated how the effect of fibroblast growth factor 2 (FGF2), which is known as an angiogenesis-promoting factor, differs between Ext1CKO and WT mice by using an in vivo Matrigel assay and demonstrated that endothelial cell-specific HS reduction attenuated the effect of FGF2 on angiogenesis. CONCLUSIONS: HS reduction in the vascular endothelium of the brain suppressed GBM growth and neovascularization in mice.
PURPOSE: Heparan sulfate (HS) is one of the factors that has been suggested to be associated with angiogenesis and invasion of glioblastoma (GBM), an aggressive and fast-growing brain tumor. However, it remains unclear how HS of endothelial cells is involved in angiogenesis in glioblastoma and its prognosis. Thus, we investigated the effect of endothelial cell HS on GBM development. METHODS: We generated endothelial cell-specific knockout of Ext1, a gene encoding a glycosyltransferase and essential for HS synthesis, and murine GL261 glioblastoma cells were orthotopically transplanted. Two weeks after transplantation, we examined the tumor progression and underlying mechanisms. RESULTS: The endothelial cell-specific Ext1 knockout (Ext1CKO) mice exhibited reduced HS expression specifically in the vascular endothelium of the brain capillaries compared with the control wild-type (WT) mice. GBM growth was significantly suppressed in Ext1CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1CKO mice than in WT mice. We investigated how the effect of fibroblast growth factor 2 (FGF2), which is known as an angiogenesis-promoting factor, differs between Ext1CKO and WT mice by using an in vivo Matrigel assay and demonstrated that endothelial cell-specific HS reduction attenuated the effect of FGF2 on angiogenesis. CONCLUSIONS: HS reduction in the vascular endothelium of the brain suppressed GBM growth and neovascularization in mice.
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