Cell - Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis

Cell - Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis

Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis

Cell, Volume 156, Issue 5, 1002-1016, 27 February 2014
Copyright © 2014 Elsevier Inc. All rights reserved.
10.1016/j.cell.2014.01.040

Authors

Manuel Valiente,Anna C. Obenauf,Xin Jin,Qing Chen,Xiang H.-F. Zhang,Derek J. Lee,Jamie E. Chaft,Mark G. Kris,Jason T. Huse,Edi Brogi,Joan MassaguéSee Affiliations

• Highlights
• Metastatic cells in the brain survive and grow attached to capillaries
• Plasmin from the reactive stroma mobilizes FasL to repel brain-infiltrating cells
• Plasmin additionally prevents vascular cooption by cleaving cancer cell L1CAM
• Brain metastatic cells express Serpins to prevent Plasmin production

Summary

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.