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Cell. 2014 Feb 27;156(5):1002-16. doi: 10.1016/j.cell.2014.01.040.

Serpins promote cancer cell survival and vascular co-option in brain metastasis.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Metastasis Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 21205, USA. Electronic address: j-massague@ski.mskcc.org.

Abstract

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

PMID:
24581498
PMCID:
PMC3988473
DOI:
10.1016/j.cell.2014.01.040
[Indexed for MEDLINE]
Free PMC Article
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