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


Authors: Valiente, M.; Obenauf, A. C.; Jin, X.; Chen, Q.; Zhang, X. H. F.; Lee, D. J.; Chaft, J. E.; Kris, M. G.; Huse, J. T.; Brogi, E.; Massagué, J.
Article Title: Serpins promote cancer cell survival and vascular co-option in brain metastasis
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. © 2014 Elsevier Inc.
Keywords: controlled study; human tissue; unclassified drug; human cell; nonhuman; mouse; cell death; cell survival; breast cancer; gene expression; cell infiltration; fas ligand; cell line; animal experiment; lung cancer; vascularization; cancer inhibition; tumor suppressor gene; nerve fiber; cancer cell; serine proteinase inhibitor; brain metastasis; paracrine signaling; stroma; inflammatory infiltrate; cell adhesion molecule; circulating tumor cell; plasmin; plasminogen activator; brain tissue; tumor invasion; microvascular endothelial cell; human; priority journal; article; l1 cell adhesion molecule; neuroserpin; serine proteinase inhibitor b2; brain capillary endothelial cell; vascular cooption
Journal Title: Cell
Volume: 156
Issue: 5
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2014-02-27
Start Page: 1002
End Page: 1016
Language: English
DOI: 10.1016/j.cell.2014.01.040
PROVIDER: scopus
PMCID: PMC3988473
PUBMED: 24581498
DOI/URL:
Notes: Export Date: 2 April 2014 -- CODEN: CELLB -- Source: Scopus
Altmetric Score
MSK Authors
  1. Jamie Erin Chaft
    127 Chaft
  2. Qing Chen
    7 Chen
  3. Jason T Huse
    127 Huse
  4. Joan Massague
    287 Massague
  5. Edi Brogi
    306 Brogi
  6. Xiang Zhang
    16 Zhang
  7. Anna Obenauf
    11 Obenauf
  8. Mark Kris
    612 Kris
  9. Derek Justin Lee
    2 Lee
  10. Xin Jin
    5 Jin