Review Article | Published:

Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma

Nature Reviews Cancer volume 10, pages 319331 (2010) | Download Citation

Abstract

Malignant brain tumours continue to be the cause of a disproportionate level of morbidity and mortality across a wide range of individuals. The most common variants in the adult and paediatric populations — malignant glioma and medulloblastoma, respectively — have been the subject of increasingly intensive research over the past two decades that has led to considerable advances in the understanding of their basic biology and pathogenesis. This Review summarizes these developments in the context of the evolving notion of molecular pathology and discusses the implications that this work has on the design of new treatment regimens.

Key points

  • Malignant gliomas and medulloblastomas — the most common brain tumours affecting adults and children, respectively — remain responsible for a disproportionate level of morbidity and mortality among cancer patients.

  • The morphological histopathology traditionally used for the subclassification of these brain tumour variants is gradually giving way to more molecularly grounded criteria that better reflect the underlying biology.

  • Recent integrated genomics has further implicated specific molecular networks in the pathogenesis of gliomas and medulloblastomas. These most prominently include receptor tyrosine kinase (RTK) signalling through the Ras–MAPK and PI3K–AKT–mTOR pathways, Wnt signalling and sonic hedgehog (SHH) signalling, along with the cell cycle-regulating RB and p53 pathways.

  • Expression analysis has recently defined transcriptional subclasses for both malignant gliomas and medulloblastomas that seem to be driven by distinct abnormalities in core signalling pathways. Such findings suggest that tumours in a particular molecular subgroup would preferentially respond to different targeted therapies.

  • Malignant gliomas and medulloblastomas also exhibit heterogeneity at the cellular level, with subpopulations of tumour cells harbouring stem-like properties rendering them more resistant to therapy. Such stem-like pools seem to reside in specialized microenvironments that actively maintain their biological characteristics.

  • Treatment challenges posed by malignant gliomas and medulloblastomas remain considerable, and many derive from the molecular and cellular heterogeneity inherent to these tumour variants. They include innate and acquired resistance and the obstacle to effective drug delivery posed by the blood–brain barrier.

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Acknowledgements

The authors would like to thank M. Rosenblum for providing representative tumour micrographs.

Author information

Affiliations

  1. Departments of Pathology, 408 East 69th Street (Z1304), New York, NY 10065, USA.

    • Jason T. Huse
  2. Departments of Surgery, 408 East 69th Street (Z1304), New York, NY 10065, USA.

    • Eric C. Holland
  3. Departments of Neurosurgery, 408 East 69th Street (Z1304), New York, NY 10065, USA.

    • Eric C. Holland
  4. Departments of Cancer Biology and Genetics, 408 East 69th Street (Z1304), New York, NY 10065, USA.

    • Eric C. Holland
  5. Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, 408 East 69th Street (Z1304), New York, NY 10065, USA.

    • Jason T. Huse
    •  & Eric C. Holland

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric C. Holland.

Glossary

Malignant glioma

Diffuse glioma of astrocytic, oligodendroglial or mixed lineage with a World Health Organization grade of either III or IV.

Glial

Pertaining to glia, the non-neuronal support cells in the nervous system.

Neuronal

Pertaining to neurons, the primary functional unit of the nervous system.

Histogenesis

The origin of a tissue or tumour especially with regard to its development and formation.

Variant III deletion

Pathogenic deletion mutant of EGFR involving exons 2–7 that leads to a constitutively active truncated protein.

Neurofibromatosis type 1

Hereditary cancer-predisposing syndrome caused by mutations in NF1 and characterized most commonly by neurofibromas, optic gliomas and malignant peripheral nerve sheath tumours.

Turcot's syndrome

Hereditary cancer-predisposing syndrome caused by mutations in APC and most commonly characterized by adenomatous polyposis of the colon and an increased incidence of neuroepithelial tumours.

Supratentorial PNET

A class of PNET arising in the forebrain that is distinct from medulloblastoma.

Atypical teratoid/rhabdoid tumour

An aggressive brain tumour variant that occurs in young children and is characterized by loss of the transcription factor integrase interactor 1 (INI1).

Perivascular niche

A specialized microenvironment intimately associated with the microvasculature where the plurality of brain tumour stem-like cells seem to reside.

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DOI

https://doi.org/10.1038/nrc2818

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