Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice.
The plasminogen activator inhibitor-1 (PAI-1) blocks the activation of plasmin(ogen), an extracellular protease vital to cancer invasion. PAI-1 is like the corresponding plasminogen activator uPA (urokinase-type plasminogen activator) consistently expressed in human breast cancer. Paradoxically, high levels of PAI-1 as well as uPA are equally associated with poor prognosis in cancer patients. PAI-1 is thought to play a vital role for the controlled extracellular proteolysis during tumor neovascularization. We have studied the effect of PAI-1 deficiency in a transgenic mouse model of metastasizing breast cancer. In these tumors, the expression pattern of uPA and PAI-1 resembles that of human ductal breast cancer and plasminogen is required for efficient metastasis. In a cohort of 63 transgenic mice that were either PAI-1-deficient or wild-type sibling controls, primary tumor growth and vascular density were unaffected by PAI-1 status. PAI-1 deficiency also did not significantly affect the lung metastatic burden. These results agree with the virtual lack of spontaneous phenotype in PAI-1-deficient mice and humans and may reflect that the plasminogen activation reaction is not rate limiting for tumor vascularization and metastasis, or that there is a functional redundancy between PAI-1 and other inhibitors of the uPA/plasmin system, masking the effect of PAI-1 deficiency.
Almholt
Kasper
K
The Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. kasper@finsenlab.dk
Nielsen
Boye S
BS
Frandsen
Thomas L
TL
Brünner
Nils
N
Danø
Keld
K
Johnsen
Morten
M
D000818:Animals; D005260:Female; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000517:prevention & control; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000502:physiology*; D017396:Plasminogen Activator Inhibitor 2 / Q000032:analysis; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D014568:Urokinase-Type Plasminogen Activator