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New aspects of glioblastoma multiforme revealed by similarities between neural and glioblastoma stem cells

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Abstract

Neural stem cells (NSCs) undergo self-renewal and generate neurons and glial cells under the influence of specific signals from surrounding environments. Glioblastoma multiforme (GBM) is a highly lethal brain tumor arising from NSCs or glial precursor cells owing to dysregulation of transcriptional and epigenetic networks that control self-renewal and differentiation of NSCs. Highly tumorigenic glioblastoma stem cells (GSCs) constitute a small subpopulation of GBM cells, which share several characteristic similarities with NSCs. GSCs exist atop a stem cell hierarchy and generate heterogeneous populations that participate in tumor propagation, drug resistance, and relapse. During multimodal treatment, GSCs de-differentiate and convert into cells with malignant characteristics, and thus play critical roles in tumor propagation. In contrast, differentiation therapy that induces GBM cells or GSCs to differentiate into a neuronal or glial lineage is expected to inhibit their proliferation. Since stem cell differentiation is specified by the cells’ epigenetic status, understanding their stemness and the epigenomic situation in the ancestor, NSCs, is important and expected to be helpful for developing treatment modalities for GBM. Here, we review the current findings regarding the epigenetic regulatory mechanisms of NSC fate in the developing brain, as well as those of GBM and GSCs. Furthermore, considering the similarities between NSCs and GSCs, we also discuss potential new strategies for GBM treatment.

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Abbreviations

2-HG:

2-hydroxyglutarate

5hmC:

5-hydroxymethyl cytosine

α-KG:

α-ketoglutaric acid

Ascl1:

Achaete scute homolog 1

ATRX:

Alpha-thalassemia/mental retardation syndrome X-linked

bFGF:

Basic fibroblast growth factor

BMPR1B:

bone morphogenetic protein receptor 1 B

CNTF:

Ciliary neurotrophic factor

DNMTs:

DNA methyltransferases

ES:

Embryonic stem cell

EZH2:

Enhancer of zeste homolog 2

G34R/V:

Substitution of glycine 34 with arginine or valine

GBM:

Glioblastoma multiforme

G-CIMP:

CpG island methylator phenotype of glioma

GSC:

Glioblastoma stem cell

H3K9:

Histone 3, lysine 9

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HOTAIR:

Hox transcript antisense intergenic RNA

IDH1:

Isocitrate dehydrogenase 1

iPS:

Induced pluripotent stem cell

KMT:

Lysine methyltransferase

K27 M:

Substitution of lysine 27 with methionine

LEF:

Lymphoid enhancer factor

lncRNA:

Long non-coding RNA

MGMT:

O6-methylguanine–DNA methyltransferase

miR:

MicroRNA

ncRNA:

Non-coding RNA

NeuroD:

Neurogenic differentiation

NICD:

Notch intracellular domain

Neurog1:

Neurogenin 1

NSC:

Neural stem cell

PRC1/2:

Polycomb repressor complex 1/2

REST1:

Repressor element 1 silencing transcription factor

RTK:

Receptor tyrosine kinase

SCP1:

Small C-terminal domain phosphatase 1

STAT:

Signal Transducer and Activator of Transcription

TCF:

T-cell factor

TCGA:

The Cancer Genome Atlas

TET:

Ten-eleven-translocation

TMZ:

Temozolomide

TSA:

Trichostatin A

VPA:

Valproic acid

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Acknowledgements

We apologize to colleagues whose work we may not have been able to be included in this review due to space constraints.We thank all of the members of the Laboratory of Molecular Neuroscience, Department of Stem Cell Biology and Medicine, Kyushu University, for their valuable comments, and Elizabeth Nakajima for critical reading of this manuscript. This work was supported by MEXT KAKENHI (16H06527) to K. N.

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  1. Division of Basic Stem Cell Biology, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Yoichiro Kawamura, Jun Takouda & Kinichi Nakashima

  2. Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yoichiro Kawamura & Koji Yoshimoto

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  1. Yoichiro Kawamura
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Correspondence to Kinichi Nakashima.

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Kawamura, Y., Takouda, J., Yoshimoto, K. et al. New aspects of glioblastoma multiforme revealed by similarities between neural and glioblastoma stem cells. Cell Biol Toxicol 34, 425–440 (2018). https://doi.org/10.1007/s10565-017-9420-y

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  • DOI: https://doi.org/10.1007/s10565-017-9420-y

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