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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / secondary
  • Animals
  • Astrocytes / metabolism
  • Brain / metabolism*
  • Brain / pathology
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma / secondary
  • Cell Line, Tumor
  • Cell Survival
  • Disease Models, Animal
  • Fas Ligand Protein / metabolism
  • Female
  • Fibrinolysin / metabolism*
  • Humans
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Neural Cell Adhesion Molecule L1 / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Plasminogen Activator Inhibitor 2 / genetics
  • Plasminogen Activator Inhibitor 2 / metabolism*
  • Plasminogen Activators / metabolism
  • Serpins / genetics
  • Serpins / metabolism*

Substances

  • Fas Ligand Protein
  • Neural Cell Adhesion Molecule L1
  • Neuropeptides
  • Plasminogen Activator Inhibitor 2
  • Serpins
  • neuroserpin
  • Plasminogen Activators
  • Fibrinolysin