Plasminogen-activator inhibitor type 1 is a potent natural inhibitor of extracellular matrix degradation by fibrosarcoma and colon carcinoma cells.
We have analyzed the role of plasminogen-activator inhibitor type 1 (PAI-1) in the regulation of tumor cell-mediated extracellular matrix degradation. Immunocytochemical analysis revealed PAI-1 associated with microgranular and fibrillar material of the extracellular matrix and demonstrated the presence of PAI-1 as a cell surface-associated antigen. Transforming growth factor beta significantly reduced matrix degradation mediated by HT-1080 human fibrosarcoma cells. This inhibition was correlated with an increase in PAI-1 antigen expression, whereas urinary-type plasminogen activator (u-PA) secretion was unaffected. In this experimental system, PAI-1 regulated extracellular matrix breakdown, as added PAI-1 inhibited matrix solubilization, whereas monoclonal antibodies to PAI-1 increased it. A cell line (LPAI) producing high levels of biologically active PAI-1 was established by transfection of a human PAI-1 cDNA clone into mouse L cells. Coculture experiments demonstrated that LPAI cells prevented matrix degradation by Lu-PA cells (L cells expressing high levels of u-PA) or Co-115 human colon carcinoma cells (expressing tissue-type plasminogen activator). These results indicate that PAI-1 may play a critical role in the regulation of extracellular matrix degradation during tumor cell invasion.
Cajot
J F
JF
Swiss Institute for Experimental Cancer Research, Epalinges.
Bamat
J
J
Bergonzelli
G E
GE
Kruithof
E K
EK
Medcalf
R L
RL
Testuz
J
J
Sordat
B
B
D000818:Animals; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D003110:Colonic Neoplasms / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005354:Fibrosarcoma / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D007739:L Cells / Q000378:metabolism; D008113:Liver Neoplasms; D051379:Mice; D010960:Plasminogen Activators / Q000302:isolation & purification / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000302:isolation & purification / Q000378:metabolism*; D014162:Transfection
D015849:Plasminogen Inactivators; D010960:Plasminogen Activators