Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice
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 a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2021-11-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-021-00444-3 |
| _version_ | 1818988186855014400 |
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| author | Takamasa Kinoshita Hiroyuki Tomita Hideshi Okada Ayumi Niwa Fuminori Hyodo Tomohiro Kanayama Mikiko Matsuo Yuko Imaizumi Takahiro Kuroda Yuichiro Hatano Masafumi Miyai Yusuke Egashira Yukiko Enomoto Noriyuki Nakayama Shigeyuki Sugie Kazu Matsumoto Yu Yamaguchi Masayuki Matsuo Hideaki Hara Toru Iwama Akira Hara |
| author_facet | Takamasa Kinoshita Hiroyuki Tomita Hideshi Okada Ayumi Niwa Fuminori Hyodo Tomohiro Kanayama Mikiko Matsuo Yuko Imaizumi Takahiro Kuroda Yuichiro Hatano Masafumi Miyai Yusuke Egashira Yukiko Enomoto Noriyuki Nakayama Shigeyuki Sugie Kazu Matsumoto Yu Yamaguchi Masayuki Matsuo Hideaki Hara Toru Iwama Akira Hara |
| author_sort | Takamasa Kinoshita |
| collection | DOAJ |
| description | 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 (Ext1 CKO ) 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 Ext1 CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1 CKO 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 Ext1 CKO 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. |
| first_indexed | 2024-12-20T19:18:35Z |
| format | Article |
| id | doaj.art-b5d26bf40ce2496e8e351218cdfaeb3c |
| institution | Directory Open Access Journal |
| issn | 2730-6011 |
| language | English |
| last_indexed | 2024-12-20T19:18:35Z |
| publishDate | 2021-11-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj.art-b5d26bf40ce2496e8e351218cdfaeb3c2022-12-21T19:29:04ZengSpringerDiscover Oncology2730-60112021-11-0112111510.1007/s12672-021-00444-3Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in miceTakamasa Kinoshita0Hiroyuki Tomita1Hideshi Okada2Ayumi Niwa3Fuminori Hyodo4Tomohiro Kanayama5Mikiko Matsuo6Yuko Imaizumi7Takahiro Kuroda8Yuichiro Hatano9Masafumi Miyai10Yusuke Egashira11Yukiko Enomoto12Noriyuki Nakayama13Shigeyuki Sugie14Kazu Matsumoto15Yu Yamaguchi16Masayuki Matsuo17Hideaki Hara18Toru Iwama19Akira Hara20Department of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Emergency and Disaster Medicine, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Radiology, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineDepartment of Neurosurgery, Ogaki Tokusyukai HospitalDepartment of Neurosurgery, Gifu University Graduate School of MedicineDepartment of Neurosurgery, Gifu University Graduate School of MedicineDepartment of Neurosurgery, Gifu University Graduate School of MedicineDepartment of Pathology, Asahi University HospitalDepartment of Orthopaedic Surgery, Gifu University Graduate School of MedicineSanford Burnham Prebys Medical Discovery InstituteDepartment of Radiology, Gifu University Graduate School of MedicineMolecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical UniversityDepartment of Neurosurgery, Gifu University Graduate School of MedicineDepartment of Tumor Pathology, Gifu University Graduate School of MedicineAbstract 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 (Ext1 CKO ) 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 Ext1 CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1 CKO 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 Ext1 CKO 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.https://doi.org/10.1007/s12672-021-00444-3GlioblastomaAngiogenesisHeparan sulfateFibroblast growth factor 2 |
| spellingShingle | Takamasa Kinoshita Hiroyuki Tomita Hideshi Okada Ayumi Niwa Fuminori Hyodo Tomohiro Kanayama Mikiko Matsuo Yuko Imaizumi Takahiro Kuroda Yuichiro Hatano Masafumi Miyai Yusuke Egashira Yukiko Enomoto Noriyuki Nakayama Shigeyuki Sugie Kazu Matsumoto Yu Yamaguchi Masayuki Matsuo Hideaki Hara Toru Iwama Akira Hara Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice Discover Oncology Glioblastoma Angiogenesis Heparan sulfate Fibroblast growth factor 2 |
| title | Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice |
| title_full | Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice |
| title_fullStr | Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice |
| title_full_unstemmed | Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice |
| title_short | Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice |
| title_sort | endothelial cell specific reduction of heparan sulfate suppresses glioma growth in mice |
| topic | Glioblastoma Angiogenesis Heparan sulfate Fibroblast growth factor 2 |
| url | https://doi.org/10.1007/s12672-021-00444-3 |
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