Editors' ChoiceCancer

Astrocytes promote brain metastasis

Sci. Signal.  10 Nov 2015:
Vol. 8, Issue 402, pp. ec332
DOI: 10.1126/scisignal.aad8224

Metastatic seeding and proliferation at the new site requires cancer cells to adapt to a new environment, and different cancers typically have preferred metastatic target tissues. The brain is a preferred metastatic target for breast cancer cells. Zhang et al. found that cells in the brain enable the proliferation of breast cancer cells by transferring a microRNA (miRNA) that silences the tumor suppressor and lipid phosphatase PTEN. Gene expression analysis of primary tumors and metastases either from mice injected with various cancer cells or in patient cohorts revealed that PTEN expression was markedly decreased in brain metastases compared with primary tumors or other sites of metastases. The incidence of brain metastases did not correlate with PTEN abundance in the matched primary tumor in mice or in patients. PTEN abundance in cells isolated from brain metastases in mice increased with time in culture. Coculturing breast tumor cells with primary glia (of which most cells were astrocytes), but not with cancer-associated fibroblasts, decreased the abundance of PTEN in the tumor cells without affecting methylation of the PTEN promoter, indicating that glial cells promote a reversible loss of PTEN abundance in metastatic cells mediated through a nongenetic and nonepigenetic mechanism. Experiments using coculture paradigms or in vivo metastasis models in mice revealed that astrocytes released exosomes containing miR-19a, which were taken up by the tumor cells and reduced PTEN abundance. Blocking the release of exosomes in the brain or in cultured astrocytes prevented the reduction in PTEN in breast or melanoma tumor cells in culture or in metastatic lesions and suppressed metastatic growth. Analysis of patient tumor tissue indicated that the reduction in PTEN in breast tumor cells upon metastasis to the brain enabled increased activity of the transcription factor NF-κB and subsequently increased abundance of the inflammatory cytokine CCL2, which recruits myeloid cells. Thus, astrocytes promote survival and proliferation of metastatic tumors in the brain. Blocking exosome release might suppress the growth of metastatic brain lesions.

L. Zhang, S. Zhang, J. Yao, F. J. Lowery, Q. Zhang, W.-C. Huang, P. Li, M. Li, X. Wang, C. Zhang, H. Wang, K. Ellis, M. Cheerathodi, J. H. McCarty, D. Palmieri, J. Saunus, S. Lakhani, S. Huang, A. A. Sahin, K. D. Aldape, P. S. Steeg, D. Yu, Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015). [PubMed]

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