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The neurobiology of gliomas: from cell biology to the development of therapeutic approaches

Key Points

  • Integrated genomic analyses with high-throughput technologies have pointed towards markers that allow for molecular classification of gliomas and for estimations of prognosis. Such markers may become part of the glioma classification and grading system and will also be used for the stratification of clinical trials.

  • The analysis of tumour initiating cells has pointed towards relationships with normal neuroglial stem cells or progenitors. Attempts to target these cells that are crucial for tumour recurrence must not affect normal cells, and the approach therefore requires that the subtle differences between these cells are defined.

  • Modelling glioma in animals with specific genetic backgrounds of conditional oncogene expressions has pointed towards pathways of glioma development. Convergence of such findings with findings relating to normal stem cell biology and signalling pathways during normal neural development, cell proliferation in the nervous system and neuroregeneration, will lead to a better understanding of the real paths that are involved in neuro-oncological progression.

  • The cellular complexity of high grade glial tumours is increasingly believed to be the result of the recruitment of non-glial cell types into the tumour, adding to the complexity of the oncological target structure.

  • The inaccesability of the infiltrative neoplastic cells beyond the bulk of the tumour and behind the blood–brain barrier calls for complex interstitial therapies, including the use of motile cellular therapies with tumour-specific homing capacities, some of which are derived from the characterization of human neuroglial stem cell properties.

Abstract

Gliomas are the most common type of primary brain tumour and are often fast growing with a poor prognosis for the patient. Their complex cellular composition, diffuse invasiveness and capacity to escape therapies has challenged researchers for decades and hampered progress towards an effective treatment. Recent molecular characterization of tumour cells combined with new insights into cellular diversification that occurs during development, and the modelling of these processes in transgenic animals have enabled a more detailed understanding of the events that underlie gliomagenesis. Combining this enhanced understanding of the relationship between neural stem cell biology and the cell lineage relationships of tumour cells with model systems offers new opportunities to develop specific and effective therapies.

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Figure 1: Stem cell differentiation and tumorigenesis.
Figure 2: Two illustrative cases of magnetic resonance images showing the invasive nature of gliomas.
Figure 3: Sequential events that cause glioma diversity and that are relevant to clinical tumour characteristics.

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Acknowledgements

The work of M.W. and K.L. in the Hans-Dietrich Herrmann Laboratory for Brain Tumor Biology in the department of Neurosurgery Eppendorf, Germany, has enjoyed the continuous support of the Deutsche Forschungsgemeinschaft (Grants We 928/2-1, 3-1 and 4-1; LA 1300/3-1 and 4-1), the Deutsche Krebshilfe, the Heinrich Bauer Stiftung, the Rickertsen Stiftung, the Monika Kutzner Stiftung, the Roggenbuck-Stiftung and the Bartling Stiftung.

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Glossary

Glioma

Intrinsic tumour of the brain, originating from any kind of glial cell.

Anaplasia

This describes structural and/or functional alterations in cancer cells in which they revert to an less differentiated state.

Glioma grading

A grading of oncological aggressiveness (anaplasia), from well differentiated to anaplastic.

Glioblastoma

According to the World Health Organization system of classification and grading, this is the most anaplastic tumour of astrocytic lineage — astrocytoma grade IV.

Glioma stem cell

Conceptually, a type of cell that represents the cell from which the tumour was generated, that has the capacity for self-renewal and after gross total surgical removal is responsible for repopulating a recurrent tumour.

Stem-like cells

As stem cells should only be referred to as such if they are omnipotent and have a defined role and specification, cells that have similar properties but that are obtained from a tumour are sometimes called stem-like.

Stemness

This describes the degree to which a cell posesses properties such as self renewal, clonogenicity and capacity for multilineage differentiation.

Orthotopic

This describes xenotransplanted tumours or tumour cells that are placed into the tissue environment — the origin of the implanted tumours. This is in contrast to tumour models that use subcutaneous tumour implantation.

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Westphal, M., Lamszus, K. The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat Rev Neurosci 12, 495–508 (2011). https://doi.org/10.1038/nrn3060

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