Brain Metastasis

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2019 Nov 30

PMID 31780784

Citations 176

Authors

Adrienne Boire

Priscilla K Brastianos

Livia Garzia

Manuel Valiente

Affiliations

Soon will be listed here.

Abstract

Brain metastasis, which commonly arises in patients with lung cancer, breast cancer and melanoma, is associated with poor survival outcomes and poses distinct clinical challenges. The brain microenvironment, with its unique cell types, anatomical structures, metabolic constraints and immune environment, differs drastically from microenvironments of extracranial lesions, imposing a distinct and profound selective pressure on tumour cells that, in turn, shapes the metastatic process and therapeutic responses. Accordingly, the study of brain metastasis could uncover new therapeutic targets and identify novel treatment approaches to address the unmet clinical need. Moreover, such efforts could provide insight into the biology of primary brain tumours, which face similar challenges to brain metastases of extracranial origin, and vice versa. However, the paucity of robust preclinical models of brain metastasis has severely limited such investigations, underscoring the importance of developing improved experimental models that holistically encompass the metastatic cascade and/or brain microenvironment. In this Viewpoint, we asked four leading experts to provide their opinions on these important aspects of brain metastasis biology and management.

Citing Articles

Confocal Laser Endomicroscopy: Enhancing Intraoperative Decision Making in Neurosurgery.

Carbone F, Fochi N, Di Perna G, Wagner A, Schlegel J, Ranieri E Diagnostics (Basel). 2025; 15(4).

PMID: 40002650 PMC: 11854171. DOI: 10.3390/diagnostics15040499.

The bacterial microbiome modulates the initiation of brain metastasis by impacting the gut-to-brain axis.

Massara M, Ballabio M, Dolfi B, Morad G, Wischnewski V, Lamprou E iScience. 2025; 28(2):111874.

PMID: 39995854 PMC: 11848439. DOI: 10.1016/j.isci.2025.111874.

Research trends on stereotactic radiosurgery in brain metastases: a bibliometric analysis from 2013 to 2023.

Zhong Y, Wang Y, Zhang L, Wen Z, Bao S, Chen S Quant Imaging Med Surg. 2025; 15(2):1297-1311.

PMID: 39995737 PMC: 11847207. DOI: 10.21037/qims-24-1403.

Invasion and metastasis in cancer: molecular insights and therapeutic targets.

Li Y, Liu F, Cai Q, Deng L, OuYang Q, Zhang X Signal Transduct Target Ther. 2025; 10(1):57.

PMID: 39979279 PMC: 11842613. DOI: 10.1038/s41392-025-02148-4.

Clinical characteristics and outcomes of surgical resection for brain metastases from lung adenocarcinoma.

Li M, Li Z, Zhang H, Wakimoto H, Sun L, Wang T Front Oncol. 2025; 14:1453177.

PMID: 39906663 PMC: 11790614. DOI: 10.3389/fonc.2024.1453177.

References

Valiente M, Ahluwalia M, Boire A, Brastianos P, Goldberg S, Lee E . The Evolving Landscape of Brain Metastasis. Trends Cancer. 2018; 4(3):176-196. PMC: 6602095. DOI: 10.1016/j.trecan.2018.01.003. View

Boire A, Zou Y, Shieh J, Macalinao D, Pentsova E, Massague J . Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis. Cell. 2017; 168(6):1101-1113.e13. PMC: 5405733. DOI: 10.1016/j.cell.2017.02.025. View

Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik C . Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc Natl Acad Sci U S A. 2014; 111(3):984-9. PMC: 3903266. DOI: 10.1073/pnas.1322098111. View

Berghoff A, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T . Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. 2016; 5(1):e1057388. PMC: 4760339. DOI: 10.1080/2162402X.2015.1057388. View

Sevenich L, Bowman R, Mason S, Quail D, Rapaport F, Elie B . Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol. 2014; 16(9):876-88. PMC: 4249762. DOI: 10.1038/ncb3011. View

Tawbi H, Forsyth P, Algazi A, Hamid O, Hodi F, Moschos S . Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med. 2018; 379(8):722-730. PMC: 8011001. DOI: 10.1056/NEJMoa1805453. View

Long G, Atkinson V, Lo S, Sandhu S, Guminski A, Brown M . Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018; 19(5):672-681. DOI: 10.1016/S1470-2045(18)30139-6. View

Lun M, Monuki E, Lehtinen M . Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015; 16(8):445-57. PMC: 4629451. DOI: 10.1038/nrn3921. View

Banks W . From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discov. 2016; 15(4):275-92. DOI: 10.1038/nrd.2015.21. View

10.

Follain G, Osmani N, Azevedo A, Allio G, Mercier L, Karreman M . Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells. Dev Cell. 2018; 45(1):33-52.e12. DOI: 10.1016/j.devcel.2018.02.015. View

11.

Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert W, Goldbrunner R, Herms J . Real-time imaging reveals the single steps of brain metastasis formation. Nat Med. 2009; 16(1):116-22. DOI: 10.1038/nm.2072. View

12.

Lorger M, Felding-Habermann B . Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol. 2010; 176(6):2958-71. PMC: 2877856. DOI: 10.2353/ajpath.2010.090838. View

13.

Valiente M, Obenauf A, Jin X, Chen Q, Zhang X, Lee D . Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014; 156(5):1002-16. PMC: 3988473. DOI: 10.1016/j.cell.2014.01.040. View

14.

Zhang L, Zhang S, Yao J, Lowery F, Zhang Q, Huang W . Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015; 527(7576):100-104. PMC: 4819404. DOI: 10.1038/nature15376. View

15.

Priego N, Zhu L, Monteiro C, Mulders M, Wasilewski D, Bindeman W . Author Correction: STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat Med. 2018; 24(9):1481. DOI: 10.1038/s41591-018-0108-5. View

16.

da Fonseca A, Matias D, Garcia C, Amaral R, Geraldo L, Freitas C . The impact of microglial activation on blood-brain barrier in brain diseases. Front Cell Neurosci. 2014; 8:362. PMC: 4217497. DOI: 10.3389/fncel.2014.00362. View

17.

Seano G, Nia H, Emblem K, Datta M, Ren J, Krishnan S . Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium. Nat Biomed Eng. 2019; 3(3):230-245. PMC: 6452896. DOI: 10.1038/s41551-018-0334-7. View

18.

Venkatesh H, Johung T, Caretti V, Noll A, Tang Y, Nagaraja S . Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion. Cell. 2015; 161(4):803-16. PMC: 4447122. DOI: 10.1016/j.cell.2015.04.012. View

19.

Venkatesh H, Morishita W, Geraghty A, Silverbush D, Gillespie S, Arzt M . Electrical and synaptic integration of glioma into neural circuits. Nature. 2019; 573(7775):539-545. PMC: 7038898. DOI: 10.1038/s41586-019-1563-y. View

20.

Zeng Q, Michael I, Zhang P, Saghafinia S, Knott G, Jiao W . Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019; 573(7775):526-531. PMC: 6837873. DOI: 10.1038/s41586-019-1576-6. View