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IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Shaanxi Normal Univ, Natl Engn Lab Resource Developing Endangered Chin, Coll Life Sci, Key Lab, Minist Educ Med Plant Resource & Nat Phar, Xian, Shaanxi, Peoples R China.
Tianjin Med Univ Gen Hosp, Key Lab Postneuroinjury Neurorepair & Regenerat C, Tianjin Neurol Inst, Dept Neurosurg, Minist Educ & Tianjin City, Tianjin, Peoples R China.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.ORCID iD: 0000-0003-2803-0343
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2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1505-1516Article in journal (Refereed) Published
Abstract [en]

Background: Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.

Methods: Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

Results: Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.

Conclusion: IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

Place, publisher, year, edition, pages
2018. Vol. 20, no 11, p. 1505-1516
Keywords [en]
angiogenesis, ANGPT2, glioma, IDH, tumor vessel
National Category
Basic Medicine Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-352016DOI: 10.1093/neuonc/noy088ISI: 000448665500010PubMedID: 29846705OAI: oai:DiVA.org:uu-352016DiVA, id: diva2:1211929
Funder
Swedish Cancer Society, CAN 2015/1216; CAN 2014/832; CAN 2017/502Swedish Childhood Cancer Foundation, PR2015-0133; NCP2015-0075Swedish Research Council, 2016-02495Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2019-01-08Bibliographically approved

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Zhang, LeiLugano, RobertaRoodakker, Kenney RoyBergqvist, MichaelSmits, AnjaDimberg, Anna

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Vascular BiologyScience for Life Laboratory, SciLifeLabNeurologyCentre for Research and Development, Gävleborg
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