A Blazing Landscape: Neuroinflammation Shapes Brain Metastasis

Overview

Journal Cancer Res

Specialty Oncology

Date 2019 Jan 26

PMID 30679177

Citations 38

Authors

Hila Doron

Tobias Pukrop

Neta Erez

Affiliations

Soon will be listed here.

Abstract

Brain metastases are more common than primary CNS tumors and confer grave prognosis on patients, as existing treatments have very limited efficacy. The tumor microenvironment has a central role in facilitating tumorigenesis and metastasis. In recent years, there has been much progress in our understanding of the functional role of the brain metastatic microenvironment. In this review, we discuss the latest advances in brain metastasis research, with special emphasis on the role of the brain microenvironment and neuroinflammation, integrating insights from comparable findings in neuropathologies and primary CNS tumors. In addition, we overview findings on the formation of a hospitable metastatic niche and point out the major gaps in knowledge toward developing new therapeutics that will cotarget the stromal compartment in an effort to improve the treatment and prevention of brain metastases.

Citing Articles

Breaking boundaries: role of the brain barriers in metastatic process.

Izadi N, Solar P, Hasanova K, Zamani A, Akbar M, Mrazova K Fluids Barriers CNS. 2025; 22(1):3.

PMID: 39780275 PMC: 11708195. DOI: 10.1186/s12987-025-00618-z.

Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities.

Dotto G, Buckinx A, Ozdemir B, Simon C Nat Rev Cancer. 2024; 25(2):93-108.

PMID: 39587300 DOI: 10.1038/s41568-024-00772-w.

In Situ Detection of Neuroinflammation using Multi-cellular 3D Neurovascular Unit-on-a-Chip.

Choi J, Choi H, Lee K Adv Funct Mater. 2024; 33(46).

PMID: 39308874 PMC: 11412436. DOI: 10.1002/adfm.202304382.

Immunotherapy revolutionizing brain metastatic cancer treatment: personalized strategies for transformative outcomes.

Li T, Sun S, Li Y, Zhang Y, Wei L Front Immunol. 2024; 15:1418580.

PMID: 39136027 PMC: 11317269. DOI: 10.3389/fimmu.2024.1418580.

The interaction of lipocalin-2 and astrocytes in neuroinflammation: mechanisms and therapeutic application.

Tan Q, Zhang C, Rao X, Wan W, Lin W, Huang S Front Immunol. 2024; 15:1358719.

PMID: 38533497 PMC: 10963420. DOI: 10.3389/fimmu.2024.1358719.

References

Shechter R, London A, Schwartz M . Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol. 2013; 13(3):206-18. DOI: 10.1038/nri3391. View

Cagney D, Martin A, Catalano P, Redig A, Lin N, Lee E . Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017; 19(11):1511-1521. PMC: 5737512. DOI: 10.1093/neuonc/nox077. View

Sperduto P, Yang T, Beal K, Pan H, Brown P, Bangdiwala A . Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA). JAMA Oncol. 2016; 3(6):827-831. PMC: 5824323. DOI: 10.1001/jamaoncol.2016.3834. View

Takei H, Rouah E, Ishida Y . Brain metastasis: clinical characteristics, pathological findings and molecular subtyping for therapeutic implications. Brain Tumor Pathol. 2015; 33(1):1-12. DOI: 10.1007/s10014-015-0235-3. View

Lin Q, Balasubramanian K, Fan D, Kim S, Guo L, Wang H . Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia. 2010; 12(9):748-54. PMC: 2933695. DOI: 10.1593/neo.10602. View

Moshe A, Izraely S, Sagi-Assif O, Prakash R, Telerman A, Meshel T . Cystatin C takes part in melanoma-microglia cross-talk: possible implications for brain metastasis. Clin Exp Metastasis. 2018; 35(5-6):369-378. PMC: 6208992. DOI: 10.1007/s10585-018-9891-0. View

Cox G, Kithcart A, Pitt D, Guan Z, Alexander J, Williams J . Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation. J Immunol. 2013; 191(3):1043-54. DOI: 10.4049/jimmunol.1200485. View

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

Oskarsson T, Batlle E, Massague J . Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014; 14(3):306-21. PMC: 3998185. DOI: 10.1016/j.stem.2014.02.002. View

10.

Kim S, Kim J, Park E, Lee J, Lin Q, Langley R . Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia. 2011; 13(3):286-98. PMC: 3050871. DOI: 10.1593/neo.11112. View

11.

Melero-Jerez C, Ortega M, Moline-Velazquez V, Clemente D . Myeloid derived suppressor cells in inflammatory conditions of the central nervous system. Biochim Biophys Acta. 2015; 1862(3):368-80. DOI: 10.1016/j.bbadis.2015.10.015. View

12.

Zubrilov I, Sagi-Assif O, Izraely S, Meshel T, Ben-Menahem S, Ginat R . Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells. Cancer Lett. 2015; 361(1):86-96. DOI: 10.1016/j.canlet.2015.02.041. View

13.

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

14.

Kisler K, Nelson A, Montagne A, Zlokovic B . Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci. 2017; 18(7):419-434. PMC: 5759779. DOI: 10.1038/nrn.2017.48. View

15.

Kim S, Lee H, Kim M, Choi H, He J, Wu Q . Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice. Clin Cancer Res. 2015; 21(20):4630-41. PMC: 4780217. DOI: 10.1158/1078-0432.CCR-14-3195. View

16.

Brastianos P, Carter S, Santagata S, Cahill D, Taylor-Weiner A, Jones R . Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015; 5(11):1164-1177. PMC: 4916970. DOI: 10.1158/2159-8290.CD-15-0369. View

17.

Pedemonte E, Mancardi G, Giunti D, Corcione A, Benvenuto F, Pistoia V . Mechanisms of the adaptive immune response inside the central nervous system during inflammatory and autoimmune diseases. Pharmacol Ther. 2006; 111(3):555-66. DOI: 10.1016/j.pharmthera.2005.11.007. View

18.

Zeng Y, Liao H, Qin T, Zhang L, Wei W, Liang J . Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. Oncotarget. 2015; 6(10):8366-76. PMC: 4480758. DOI: 10.18632/oncotarget.3187. View

19.

Hanisch U, Kettenmann H . Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007; 10(11):1387-94. DOI: 10.1038/nn1997. View

20.

Pulaski B, Ostrand-Rosenberg S . Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res. 1998; 58(7):1486-93. View