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Gliomagenesis: genetic alterations and mouse models

Key Points

  • Gliomas are primary tumours that arise from glial cells in the brain and spinal cord. The most malignant gliomas — glioblastoma multiforme (GBM) — are nearly always fatal. Treatment strategies for this disease have remained unchanged for many years and most are based on a limited understanding of the biology of the disease.

  • Chromosomal instability and the deletion and amplification of certain genes are a hallmark of the more severe clinical grades of human glioma.

  • The cells of malignant gliomas share certain characteristics with undifferentiated glial progenitor cells. Mutations found in GBMs frequently activate the signalling pathways that control the differentiation and proliferation of these progenitors or disrupt cell-cycle arrest pathways.

  • Recapitulating the genetic alterations found in human gliomas in mouse models gives rise to tumours that histologically resemble human gliomas. These mouse models have given clues as to the molecular origins of gliomas, and should contribute to the design and testing of new rational therapies.

Abstract

Glioblastoma multiforme is the most malignant of the primary brain tumours and is almost always fatal. The treatment strategies for this disease have not changed appreciably for many years and most are based on a limited understanding of the biology of the disease. However, in the past decade, characteristic genetic alterations have been identified in gliomas that might underlie the initiation or progression of the disease. Recent modelling experiments in mice are helping to delineate the molecular aetiology of this disease and are providing systems to identify and test novel and rational therapeutic strategies.

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Figure 1: Cellular differentiation in the central nervous system.
Figure 2: Signalling pathways altered by mutations in human gliomas.
Figure 3: INK4A-initiated cell-cycle arrest pathways.
Figure 4: Pathways to gliomagenesis.
Figure 5: Mouse glioma histology.

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Acknowledgements

I would like to thank Greg Fuller and Joseph Celestino for help with the pathology, Chengkai Dai for help with the cell-lineage discussion, and V. K. Rajasekhar for help with the signal-transduction discussion.

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DATABASE LINKS

GFAP

PDGF

FGF2

EGF

CNTF

EGFR

ERK

JNK

p38

NF1

PI(3)K

PTEN

AKT1

GSK3

mTOR

FHKR

RB

INK4A

p53

CDK4

CDK6

cyclin D1

MDM2

MYC

Myc

Akt

Nf1

Pdgfb

Ink4a

p53

Rb

Egfr

Cdk4

Gfap

PDGFR

VEGFR

FURTHER INFORMATION

Massachusetts General Hospital Brain Tumour Center

Clinical trials information for brain tumours

ENCYCLOPEDIA OF LIFE SCIENCES

Brain cancers

Brain imaging

Glossary

GLIA

The specialized connective tissue of the central nervous system. It is made up of glial cells such as astrocytes, oligodendrocytes and ependymal cells.

ASTROCYTE

One of the three main cell types in the brain, the others being neurons and oligodendrocytes. Astrocytes act as the scaffold that maintains the brain structure and that supports the functions of both neurons and oligodendrocytes.

OLIGODENDROCYTES

One of the three main cell types that make up the brain parenchyma, the other two being neurons and astrocytes. Oligodendrocytes produce myelin, which insulates axons to alter the conduction properties of neurons.

HYPERTROPHY

A pathological increase in the size of cells or the structure that they form.

BRAIN PARENCHYMA

The inner substance of the brain that is composed primarily of neurons, oligodendrocytes, astrocytes and blood vessels.

SUBPIA

The region directly below the pia, the membrane that forms the limiting edge of the brain. Invading glioma cells tend to accumulate in this region to generate one of the classic secondary structures of human gliomas.

ANAPLASTIC

When cells or tissues revert to a more embryonic or undifferentiated form and have an increased capacity to multiply.

GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP).

An intermediate filament protein. The expression of its gene is limited to astrocytes.

PLATELET-DERIVED GROWTH FACTOR (PDGF).

A growth factor that exists as a homodimer or heterodimer of PDGFA and PDGFB chains. This growth factor binds to and activates the PDGF receptor PDGFRA or PDGFRB.

FIBROBLAST GROWTH FACTOR 2 (FGF2).

This ligand binds to the FGF2 receptor, promotes the proliferation of undifferentiated cells and stimulates angiogenesis.

CILLIARY NEUROTROPHIC FACTOR (CNTF).

This ligand binds to the CNTF receptor and promotes oligodendrocyte and astrocyte differentiation.

EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)

This receptor is bound by epidermal growth factor and the transforming growth factor-α.

GLYCOGEN SYNTHASE KINASE 3 (GSK3).

A kinase involved in several biological processes, including glucose metabolism and signalling through the Wnt pathway. GSK3 also functions downstream of AKT.

MAMMALIAN TARGET OF RAPAMYCIN (mTOR).

A protein that is activated by AKT and which activates ribosomal protein S6 kinase. S6 kinase alters the ability of the ribosome to translate specific mRNAs.

BAD

BAD promotes apoptosis by dimerizing with and inhibiting BCL-2.

BCL-2

BCL-2 inhibits apoptosis by inhibiting caspase activation.

CASPASE

One of a family of proteases that are activated specifically in apoptotic cells.

FORKHEAD TRANSCRIPTION FACTOR (FKHR).

This protein activates cell death. It is inactivated by AKT-dependent phosphorylation, which relocalizes it from the nucleus to the cytoplasm.

PSEUDODIPLOID

DNA content similar to that of a diploid cell.

E2F1

A transcription factor that is bound to RB during G1 cell-cycle arrest and is released after phosphorylation of RB by CDK2 or CDK4. Free E2F1 then alters gene expression to lead to cell-cycle progression.

XENOGRAFT

Cells derived from one species that are implanted into a host of another species; for example, human tumour cells implanted into a mouse.

ALLOGRAFT

Cells implanted into a host that are derived from another individual of the same species.

POLYOMA VIRUS MIDDLE T ANTIGEN

Viral gene product that activates many signalling pathways that are activated by the PDGF receptors.

H-RAS

Harvey Ras. Activated Ras allele initially isolated from Moloney mouse leukaemia virus.

V-SRC

A virally encoded oncogene originally isolated from the Rous sarcoma virus. This gene encodes a deleted and activated version of the cellular Src gene. Expression of this gene activates multiple signalling pathways.

V-ERBB

A virally encoded oncogene originally isolated from the chicken erythroblastosis virus. This gene encodes an activated variant of the EGFR.

V-SIS

A virally encoded oncogene originally isolated from the simian sarcoma virus. This gene encodes the complete sequence of the PDGFB chain. Overexpression results in autocrine stimulation of the PDGF receptor.

K-RAS

Kirsten Ras. Activated Ras allele initially isolated from Kirsten mouse leukaemia virus.

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Holland, E. Gliomagenesis: genetic alterations and mouse models. Nat Rev Genet 2, 120–129 (2001). https://doi.org/10.1038/35052535

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