Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice.
To investigate the role of plasmin(ogen) in mammary tumor development and progression, plasminogen-deficient mice were crossed with transgenic mice expressing Polyoma middle T antigen under the control of the mouse mammary tumor virus long terminal repeat. Virgin females carrying the Polyoma middle T antigen uniformly developed multiple, bilateral mammary tumors, regardless of the presence or absence of circulating plasminogen. Both the age at which these tumors became palpable and subsequent tumor growth were indistinguishable between plasminogen-deficient mice and plasminogen-expressing littermates. However, plasminogen was found to greatly modify the metastatic potential in this model system; lung metastasis in plasminogen-deficient mice was significantly reduced as compared to littermate controls with respect to frequency of occurrence, total number of metastases, and total metastatic tumor burden. Plasminogen activators, as well as other key factors that govern the conversion of plasminogen to plasmin, were expressed within the mammary tumors, suggesting that the plasminogen/plasmin system may promote metastasis by contributing to tumor-associated extracellular proteolysis. The data provide direct evidence that plasmin(ogen) is a tumor progression factor in PymT-induced mammary cancer, and support the hypothesis that hemostatic factors play an important role in tumor biology.
Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
T H
TH
Bugge
L R
LR
Lund
K K
KK
Kombrinck
B S
BS
Nielsen
K
K
Holmbäck
A F
AF
Drew
M J
MJ
Flick
D P
DP
Witte
K
K
Danø
J L
JL
Degen
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D001483:Base Sequence; D015152:Blotting, Northern; D017931:DNA Primers; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000473:pathology* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D010958:Plasminogen / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D000952:Antigens, Polyomavirus Transforming; D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator