Review Article | Published:

Multidimensional communication in the microenvirons of glioblastoma

Nature Reviews Neurology (2018) | Download Citation

Abstract

Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other cells in the brain environs, which supports tumour progression and resistance to therapy. Glioblastoma cells recruit innate immune cells and change their phenotype to support tumour growth. Tumour cells also suppress adaptive immune responses, and our increasing understanding of how T cells access the brain and how the tumour thwarts the immune response offers new strategies for mobilizing an antitumour response. Tumours also subvert normal brain cells — including endothelial cells, neurons and astrocytes — to create a microenviron that favours tumour success. Overall, after glioblastoma-induced phenotypic modifications, normal cells cooperate with tumour cells to promote tumour proliferation, invasion of the brain, immune suppression and angiogenesis. This glioblastoma takeover of the brain involves multiple modes of communication, including soluble factors such as chemokines and cytokines, direct cell–cell contact, extracellular vesicles (including exosomes and microvesicles) and connecting nanotubes and microtubes. Understanding these multidimensional communications between the tumour and the cells in its environs could open new avenues for therapy.

Key Points

  • Glioblastomas use numerous forms of communication to hijack many different cell types in the brain environs to support tumour progression.

  • Communication routes include secreted proteins and molecules, gap junctions between cells, extracellular vesicles, tunnelling nanotubes and microtubes.

  • Tumour cells co-opt microglia and infiltrating macrophages for their own benefit through the release of cytokines and extracellular vesicles.

  • Glioblastomas and pericytes generate a state of reduced T cell effector function that is commonly referred to as T cell exhaustion or dysfunction.

  • The interaction of tumour cells with normal brain cells, such as neurons, is not unidirectional, and neuronal activity is subverted to promote glioblastoma progression.

  • Comprehension and disruption of tumour directives in the glioblastoma microenvironment could improve therapeutic intervention for these lethal tumours.

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Acknowledgements

The authors thank S. McDavitt for her skilled editorial assistance. This work was supported by U19 CA179563 by the US NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director (X.O.B., A.M.K. and T.R.M.), and the US NIH National Cancer Institute (P01 CA069246 (X.O.B.), R01 AI123349 (T.R.M.) and R21 NS098051 (A.M.K.)).

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Nature Reviews Neurology thanks W. Wick and the other, anonymous reviewers for their contribution to the peer review of this work.

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Affiliations

  1. Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, USA

    • Marike L. Broekman
    • , Sybren L. N. Maas
    • , Erik R. Abels
    •  & Xandra O. Breakefield
  2. Department of Neurosurgery, Brain Center Rudolf Magnus, Institute of Neurosciences, University Medical Center, Heidelberglaan, Utrecht, Netherlands

    • Marike L. Broekman
    •  & Sybren L. N. Maas
  3. The Center for Immunology and Inflammatory Diseases and Department of Medicine, Massachusetts General Hospital, Charlestown, MA, USA

    • Thorsten R. Mempel
  4. Program in Immunology, Harvard Medical School, Boston, MA, USA

    • Thorsten R. Mempel
  5. Department of Neurology, Ann Romney Center for Neurologic Diseases, Initiative for RNA Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Anna M. Krichevsky

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All authors contributed to researching data, discussion of content, writing and review of the manuscript before submission.

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Correspondence to Marike L. Broekman or Xandra O. Breakefield.

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https://doi.org/10.1038/s41582-018-0025-8