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  • Review Article
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The biology of brain metastases—translation to new therapies

Nature Reviews Clinical Oncology volume 8, pages 344–356 (2011)Cite this article

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Abstract

Brain metastases are a serious obstacle in the treatment of patients with solid tumors and contribute to the morbidity and mortality of these cancers. It is speculated that the frequency of brain metastasis is increasing for several reasons, including improved systemic therapy and survival, and detection of metastases in asymptomatic patients. The lack of preclinical models that recapitulate the clinical setting and the exclusion of patients with brain metastases from most clinical trials have slowed progress. Molecular factors contributing to brain metastases are being elucidated, such as genes involved in cell adhesion, extravasation, metabolism, and cellular signaling. Furthermore, the role of the unique brain microenvironment is beginning to be explored. Although the presence and function of the blood–brain barrier in metastatic tumors is still poorly understood, it is likely that some tumor cells are protected from therapeutics by the blood–tumor barrier, creating a sanctuary site. This Review discusses what is known about the biology of brain metastases, what preclinical models are available to study the disease, and which novel therapeutic strategies are being studied in patients.

Key Points

  • Longer survival of patients and more-sensitive detection of metastatic disease by improved imaging modalities might contribute to the increased incidence of detected brain metastases

  • Novel preclinical models that more accurately represent clinical brain metastases and imaging techniques that allow study of the formation of brain metastases and their response to treatments are emerging

  • Brain metastases grow by co-opting existing blood vessels and/or by forming new blood vessels; the brain microenvironment promotes tumor cell survival, tumor growth and resistance to therapy

  • Although a lesser problem in large metastases, the blood–brain barrier (BBB) could prevent therapeutic access to micrometastases; strategies to enhance drug delivery across the BBB are under investigation

  • Differential expression of genes involved in intravasation and extravasation, metabolism, cell adhesion, and cellular signaling in brain-specific metastatic clones have been identified

  • Targeted therapies, including inhibitors of EGFR, HER2, PI3K and BRAF, have shown promise in the treatment of brain metastases, but require testing in randomized trials

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Figure 1: Steps in the formation of hematogenous metastasis to the brain.
Figure 2: Imaging brain metastases in preclinical models and patients.
Figure 3: Approaches to enhance drug delivery to the brain.

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Acknowledgements

We thank J. Engelman, S. Goel, L. Xu, I. J. Fidler, R. S. Kerbel, W. Cruz-Munoz and S. Mohla for their helpful comments on the manuscript. This work was supported by the National Institutes of Health grants P01-CA080124 (R. K. Jain and D. Fukumura), R01-CA085140, R01-CA115767 and R01-CA126642 (R. K. Jain), R01-CA096915 (D. Fukumura), R21-CA135605 and U01-CA062490 (A. F. Eichler), a Federal Share Income Grant (R. K. Jain and D. Fukumura), T32-CA073479 (D. P. Kodak) and Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016 (R. K. Jain). E. Chung was supported by a Tosteson postdoctoral fellowship award from the Massachusetts Biomedical Research Corporation. E. Chung also acknowledges support from his current institute: Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.

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  1. Stephen E. and Catherine Pappas Center for Neuro-oncology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA

    April F. Eichler

  2. Deparment of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA

    Euiheon Chung, David P. Kodack, Jay S. Loeffler, Dai Fukumura & Rakesh K. Jain

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  1. April F. Eichler
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A. F. Eichler and R. K. Jain contributed equally to the preparation of this manuscript. All authors contributed to researching data for the article, discussions of content, writing of the manuscript, and to reviewing and editing of the article before submission.

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Correspondence to Rakesh K. Jain.

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R. K. Jain declares receiving consulting fees from Astellas, AstraZeneca, Dyax, Enlight Biosciences, Genzyme, Millenium, Noxxon and SynDevRx; lecture fees from MPM Capital; grant support from Dyax, AstraZeneca/MedImmune and Roche; and owning equity in Enlight Biosciences and SynDevRx. Other authors declare no competing interests.

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Eichler, A., Chung, E., Kodack, D. et al. The biology of brain metastases—translation to new therapies. Nat Rev Clin Oncol 8, 344–356 (2011). https://doi.org/10.1038/nrclinonc.2011.58

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