Editors' ChoiceBRAIN METASTASIS

The Serpin Shield

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Science Translational Medicine  12 Mar 2014:
Vol. 6, Issue 227, pp. 227ec43
DOI: 10.1126/scitranslmed.3008860

Even after successful treatment of primary cancers, 35% of lung and 25% of breast cancers will metastasize to the brain. It takes only a few cancer cells to travel through the bloodstream or the lymphatic system and lodge in the brain, forming remote tumors. How do metastatic lung and breast cancer cells survive and grow in the hostile brain environment—an environment that typically kills cancer cells?

By comparing the transcriptomic signatures of human brain metastatic subpopulations, Valiente and colleagues associated genes encoding for serpins—a family of potent inhibitors of plasminogen activator—with the brain metastatic phenotype. Analysis of mRNA, protein levels, and conditioned media in human cancer cell lines and metastasis tissue revealed a significant up-regulation of neuroserpin and serpins B2, E1, and E2 only in brain metastatic cells and tissue, but not in other cancer cells or in metastases present in other organs. The authors then introduced lung and breast cancer cell lines (H2030 and MDA231) and their metastatic counterparts (H2039-BrM3 and MDA231-BrM2) into the bloodstream of nude mice, to see whether they would lodge in the brain. Interestingly, only the metastatic cells were able to cross the capillary wall, wrap around brain capillaries, and survive. Metastatic cells were immune to plasmin and a plasmin downstream product, the proapoptotic cytokine FasL, which killed more than 90% of primary cancer cells.

This study presents a mechanism for serpin-mediated inhibition of plasminogen activator that enables both lung and breast metastatic cancer cells to colonialize the brain and shields them from apoptosis. Valiente et al. found that serpin knockdown in metastatic cell lines removed the serpin protection mechanism in mice brain slice assays. The new biology coupled with a potential therapeutic option suggests that targeting serpin could be an effective way to treat metastatic breast and lung cancers.

M. Valiente et al., Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014). [Abstract]

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