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19.04.2019 | Laboratory Investigation | Ausgabe 2/2019

Journal of Neuro-Oncology 2/2019

Isocitrate dehydrogenase1 mutation reduces the pericyte coverage of microvessels in astrocytic tumours

Zeitschrift:
Journal of Neuro-Oncology > Ausgabe 2/2019
Autoren:
Chao Sun, Yuanlin Zhao, Jiankuan Shi, Jin Zhang, Yuan Yuan, Yu Gu, Feng Zhang, Xing Gao, Chao Wang, Yingmei Wang, Zhe Wang, Peizhen Hu, Junhui Qin, Liming Xiao, Ting Chang, Liang Wang, Yibin Xi, Hong Yin, Huangtao Chen, Lijun Zhang, Guang Cheng, Jiaji Lin, MingMing Zhang, Zhuyi Li, Jing Ye
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s11060-019-03156-5) contains supplementary material, which is available to authorized users.
Chao Sun, Yuanlin Zhao, and Jiankuan Shi contributed equally as first authors.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

Introduction

Tumour-associated angiogenesis is associated with the malignancy and poor prognosis of glioma. Isocitrate dehydrogenase (IDH) mutations are present in the majority of lower-grade (WHO grade II and III) and secondary glioblastomas, but their roles in tumour angiogenesis remain unclear.

Methods

Using magnetic resonance imaging (MRI), the cerebral blood flow (CBF) of IDH-mutated glioma was measured and compared with the IDH-wildtype glioma. The densities of microvessels in IDH-mutated and wildtype astrocytoma and glioblastoma were assessed by immunohistochemical (IHC) staining with CD34, and the pericytes were labelled with α-smooth muscle antigen (α-SMA), neural-glial antigen 2 (NG2) and PDGF receptor-β (PDGFR-β), respectively. Furthermore, glia-specific mutant IDH1 knock-in mice were generated to evaluate the roles of mutant IDH1 on brain vascular architectures. The transcriptions of the angiogenesis-related genes were assessed in TCGA datasets, including ANGPT1, PDGFB and VEGFA. The expressions of these genes were further determined by western blot in U87-MG cells expressing a mutant IDH1 or treated with 2-HG.

Results

The MRI results indicated that CBF was reduced in the IDH-mutated gliomas. The IHC staining showed that the pericyte coverages of microvessels were significantly decreased, but the microvessel densities (MVDs) were only slightly decreased in IDH-mutated glioma. The mutant IDH1 knock-in also impeded the pericyte coverage of brain microvessels in mice. Moreover, the TCGA database showed the mRNA levels of angiogenesis factors, including ANGPT1, PDGFB and VEGFA, were downregulated, and their promoters were also highly hyper-methylated in IDH-mutated gliomas. In addition, both mutant IDH1 and D-2-HG could downregulate the expression of these genes in U87-MG cells.

Conclusions

Our results suggested that IDH mutations could reduce the pericyte coverage of microvessels in astrocytic tumours by inhibiting the expression of angiogenesis factors. As vascular pericytes play an essential role in maintaining functional blood vessels to support tumour growth, our findings imply a potential avenue of therapeutic strategy for IDH-mutated gliomas.

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