Inhibition of invasion of HT1080 sarcoma cells expressing recombinant plasminogen activator inhibitor 2.
Plasminogen activators (PA) elaborated by tumor cells play an important role in the complex process of tissue invasion and metastasis. In the present study the effect of the PA inhibitor type 2 (PAI-2) on tissue invasion in vitro and in vivo was investigated. Clones either expressing (B-) or not expressing the endogenous PAI-2 gene (C+) were isolated from the human HT1080 fibrosarcoma cell line and transfected with full-length PAI-2 cDNA. Recombinant PAI-2 (rPAI-2) expressed by these cells completely inhibited receptor-bound urokinase activity and partially neutralized secreted PA activity. Degradation of extracellular matrix proteins by these transfected cells was markedly decreased when compared to mock or untransfected control cells. The rPAI-2-expressing cells did not penetrate a multilayer of rat smooth muscle cells in vitro, which was readily invaded and destroyed by control cells. The PAI-2 transfectants remained tumorigenic in athymic/nude mice, but tumors originating from these cells showed the presence of a thick, collagenous capsule absent in tumors formed by control cells. Thus, expression of rPAI-2 in HT1080 cells resulted in neutralization of receptor-bound urokinase with subsequent inhibition of matrix protein degradation and invasion in vitro and induction of a thick, peritumoral capsule in vivo.
Laug
W E
WE
Department of Pediatrics, Childrens Hospital Los Angeles, CA 90027.
Cao
X R
XR
Yu
Y B
YB
Shimada
H
H
Kruithof
E K
EK
D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017396:Plasminogen Activator Inhibitor 2 / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D017396:Plasminogen Activator Inhibitor 2; D011994:Recombinant Proteins; D014568:Urokinase-Type Plasminogen Activator