Plasminogen-Activator Inhibitor Type 1 is a Potent Natural Inhibitor of Extracellular Matrix Degradation by Fibrosarcoma and Colon Carcinoma Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 87; no. 18; pp. 6939 - 6943
• Main Authors: Cajot, J. F., Bamat, J., Bergonzelli, G. E., Kruithof, E. K. O., Medcalf, R. L.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.09.1990; National Acad Sciences
• Subjects: Animals; Antibodies; Biological and medical sciences; Carcinoma; Carcinoma, Hepatocellular; Cell Line; Cell lines; Cell membranes; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells; Coculture techniques; Colonic Neoplasms - metabolism; Complementary DNA; Endothelial cells; extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - ultrastructure; Fibrosarcoma - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Kinetics; L cells; L Cells (Cell Line) - metabolism; Liver Neoplasms; Mice; Molecular and cellular biology; Plasminogen Activators - isolation & purification; Plasminogen Activators - metabolism; Plasminogen Inactivators - isolation & purification; Plasminogen Inactivators - metabolism; Transfection; Tumors; Human; Radiolabelling; Immunocytochemistry; Enzyme inhibitor; Plasminogen activator; Tumorigenicity; Regulation(control); Cell line; Transfection; Microscopy; Correlation analysis; Enzymatic digestion; Extracellular matrix; Tumor; Localization
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.18.6939

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 β 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 LPAIcells prevented matrix degradation by Lu-PAcells (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.