Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice

TY - JOUR

T1 - Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice

AU - Almholt, Kasper

AU - Lund, L.R.

AU - Rygaard, Jørgen

AU - Nielsen, Boye Schnack

AU - Danø, Keld

AU - Nielsen, John Rømer

AU - Johnsen, Morten

N1 - Keywords urokinase-type plasminogen activator • plasminogen • proteolysis • mouse model • breast cancer

PY - 2005

Y1 - 2005

N2 - 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 mm3 in wild-type controls to 0.21 mm3 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. © 2004 Wiley-Liss, Inc.

AB - 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 mm3 in wild-type controls to 0.21 mm3 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. © 2004 Wiley-Liss, Inc.

U2 - 10.1002/ijc.20631

DO - 10.1002/ijc.20631

M3 - Journal article

C2 - 15472905

SN - 0020-7136

VL - 113

SP - 525

EP - 532

JO - Radiation Oncology Investigations

JF - Radiation Oncology Investigations

IS - 4

ER -