The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis.
BACKGROUND
Patients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model.


METHODS
Metastatic tumors to the brain were established by direct injection into the striatum or by intracarotid injection of B16F10 mouse melanoma cells in C57Bl mice. The role of plasminogen in the ability of human melanoma cells to cross a human blood-brain barrier model was studied on a transwell system.


RESULTS
Wild type mice treated with the plasmin inhibitor epsilon-aminocaproic acid (EACA) and plg-/- mice developed smaller tumors and survived longer than untreated wild type mice. Tumors metastasized to the brain of wild type mice treated with EACA and plg-/- less efficiently than in untreated wild type mice. No difference was observed in the tumor growth in any of the three groups of mice. Human melanoma cells were able to cross the human blood-brain barrier model in a plasmin dependent manner.


CONCLUSIONS
Plasmin facilitates the development of tumor metastasis to the brain. Inhibition of the fibrinolytic system could be considered as means to prevent tumor metastasis to the brain.
Perides
George
G
Department of Surgery, Division of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. gperides@tufts-nemc.org
Zhuge
Yuzheng
Y
Lin
Tina
T
Stins
Monique F
MF
Bronson
Roderick T
RT
Wu
Julian K
JK
D015119:Aminocaproic Acid / Q000494:pharmacology; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply / Q000166:cytology; D001932:Brain Neoplasms / Q000503:physiopathology / Q000556:secondary*; D002339:Carotid Arteries; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007267:Injections; D008546:Melanoma, Experimental / Q000473:pathology / Q000503:physiopathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D010958:Plasminogen / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology* / Q000503:physiopathology
D000933:Antifibrinolytic Agents; D010958:Plasminogen; D015119:Aminocaproic Acid