Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells.
Using both human and murine cell lines, we show that malignant cells are able to invade through basement membrane and also secrete elevated amounts of collagenase IV, an enzyme implicated in the degradation of basement membranes. Using serine proteinase inhibitors and antibodies to plasminogen activators as well as a newly described collagenase inhibitor we demonstrate that a protease cascade leads to the activation of an enzyme(s) that cleaves collagen IV. Inhibition at each step reduces the invasion of the tumor cells through reconstituted basement membrane in vitro. Treatment with a collagenase inhibitor reduced the incidence of lung lesions in mice given i.v. injections of malignant melanoma cells.
Reich
R
R
Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, Bethesda, Maryland 20892.
Thompson
E W
EW
Iwamoto
Y
Y
Martin
G R
GR
Deason
J R
JR
Fuller
G C
GC
Miskin
R
R
D000818:Animals; D001485:Basement Membrane / Q000473:pathology*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors* / Q000502:physiology; D009361:Neoplasm Invasiveness; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors* / Q000502:physiology; D015849:Plasminogen Inactivators; D012697:Serine Endopeptidases / Q000502:physiology; D015842:Serine Proteinase Inhibitors; D014407:Tumor Cells, Cultured
D015849:Plasminogen Inactivators; D015842:Serine Proteinase Inhibitors; D010960:Plasminogen Activators; D012697:Serine Endopeptidases; D003012:Microbial Collagenase