Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice.
A prominent phenotype of plasmin deficiency in mice is reduced metastasis in the MMTV-PymT transgenic breast cancer model. Proteolytically active plasmin is generated from inactive plasminogen by one of 2 activators, uPA or tPA. We now find that uPA deficiency alone significantly reduces metastasis >7-fold in the MMTV-PymT model. We studied a cohort of 55 MMTV-PymT transgenic mice, either uPA-deficient or wild-type controls. Tumor incidence, latency, growth rate and final primary tumor burden were not significantly affected by uPA deficiency. In contrast, average lung metastasis volume was reduced from 1.58 mm(3) in wild-type controls to 0.21 mm(3) in uPA-deficient mice (p = 0.023). Tumor cell dissemination to brachial lymph nodes was also reduced from 53% (28/53) in wild-type controls to 31% (17/54) in uPA-deficient mice (p = 0.032). Mice without plasminogen display a severe pleiotropic phenotype. By comparison, spontaneous phenotypes are modest in uPA-deficient mice, probably because they still have active tPA. We show that metastasis is strongly and selectively decreased in uPA-deficient mice, suggesting that uPA-directed antimetastatic therapy would be efficacious and have limited side effects.
Almholt
Kasper
K
Finsen Laboratory, Rigshospitalet 8621, Strand-boulevarden 49, DK-2100 Copenhagen, Denmark. kasper@finsenlab.uk
Lund
Leif R
LR
Rygaard
Jørgen
J
Nielsen
Boye S
BS
Danø
Keld
K
Rømer
John
J
Johnsen
Morten
M
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D015994:Incidence; D008175:Lung Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary*; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010960:Plasminogen Activators / Q000172:deficiency*; D015996:Survival Rate; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency*
D000952:Antigens, Polyomavirus Transforming; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator