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Acta Neuropathologica

, Volume 123, Issue 2, pp 205–222 | Cite as

Brain metastases: pathobiology and emerging targeted therapies

  • Matthias PreusserEmail author
  • David Capper
  • Aysegül Ilhan-Mutlu
  • Anna Sophie Berghoff
  • Peter Birner
  • Rupert Bartsch
  • Christine Marosi
  • Christoph Zielinski
  • Minesh P. Mehta
  • Frank Winkler
  • Wolfgang Wick
  • Andreas von Deimling
Review

Abstract

Brain metastases (BM) are common in cancer patients and are associated with high morbidity and poor prognosis, even after intensive multimodal therapy including resection, radiotherapy (stereotactic radiosurgery or whole brain radiotherapy) and chemotherapy. However, advances in the understanding of the pathobiology of BM and the development of molecular targeted agents hold promise for improved prophylaxis and therapy of BM. Here we provide a comprehensive review of the current concepts on mechanisms of the brain-metastatic cascade involving hematogenous dissemination of tumor cells, attachment to microvessel endothelial cells, extravasation into the brain, interaction with the local microenvironment, angiogenesis and intraparenchymal proliferation. Transendothelial migration depends on adhesion molecules such as integrins, selectins and chemokines. Tumor cells invade the brain by degrading extracellular matrix components using heparanase and matrix metalloproteinases. Astrocytes and microglial cells exert not only anti-, but also pro-neoplastic effects on brain-invading tumor cells. Some tumor types (e.g. melanoma) show prominent cooption of preexisting vasculature, while other tumor types (e.g. lung cancer) tend to show early angiogenesis after brain invasion. In this article we also critically summarize the data on currently studied targeted therapeutics in BM especially in the context of recent preclinical data. The most promising agents for BM patients include anti-angiogenic drugs, inhibitors of v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) for BRAF V600E mutated melanoma and inhibitors of epithelial growth factor receptor for non-small cell lung cancer. Molecular analysis of the BRAF V600E status of melanoma BM using DNA-based methods or immunohistochemistry may soon enter the routine neuropathological practice.

Keywords

Brain metastases Cancer Pathobiology Molecular targets Therapy 

Notes

Acknowledgments

Dr. Preusser acknowledges support by a European Association of Neurooncology (EANO) Fellowship Grant. We thank Mr. Engin Mutlu (DH & Partners Media Group) for help with the preparation of Figures.

Conflict of interest

Andreas von Deimling and David Capper declare shared inventorship of anti- BRAF V600E antibody clone VE1. A patent for diagnostic application of VE1 has been applied for. All terms are being managed by the German Cancer Research Center in accordance with its conflict of interest policies. Minesh Mehta has or has had the following roles in the last 2 years (2010–2011): Consultant: Adnexus, Bayer, Bristol-Meyers-Squibb, Elekta (non-reimbursed), Merck, Novartis, Quark, Tomotherapy; Stock Options: Accuray, Colby, Pharmacyclics, Procertus, Stemina; Data Safety Monitoring Boards: Apogenix; Board of Directors: Pharmacyclics; Medical Advisory Boards: Colby, Stemina, Procertus; Speaker: GRACE Foundation, MCM, Merck, Prime Oncology, Strategic Edge, WebMD; Patents: WARF/Procertus; Royalties: DEMOS Publishers. All other authors do not report potential conflicts of interests.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Matthias Preusser
    • 1
    Email author
  • David Capper
    • 2
  • Aysegül Ilhan-Mutlu
    • 1
  • Anna Sophie Berghoff
    • 3
  • Peter Birner
    • 4
  • Rupert Bartsch
    • 1
  • Christine Marosi
    • 1
  • Christoph Zielinski
    • 1
  • Minesh P. Mehta
    • 5
  • Frank Winkler
    • 6
  • Wolfgang Wick
    • 6
  • Andreas von Deimling
    • 2
  1. 1.Department of Medicine I, Comprehensive Cancer Center, CNS Tumours Unit (CCC-CNS)Medical University of ViennaViennaAustria
  2. 2.Department of Neuropathology, Institute of PathologyRuprecht-Karls-University Heidelberg, Clinical Cooperation Unit Neuropathology, German Cancer Research CenterHeidelbergGermany
  3. 3.Institute of Neurology, Comprehensive Cancer Center, CNS Tumours Unit (CCC-CNS)Medical University of ViennaViennaAustria
  4. 4.Department of Clinical Pathology and Comprehensive Cancer Center, CNS Tumours Unit (CCC-CNS)Medical University of ViennaViennaAustria
  5. 5.Northwestern UniversityChicagoUSA
  6. 6.Neurology Clinic and National Center for Tumor DiseaseUniversity of HeidelbergHeidelbergGermany

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