Antibodies to PAI-1 alter the invasive and migratory properties of human tumour cells in vitro

Recent reports suggest that elevated levels of plasminogen activator inhibi tor-1 (PAI-1) may contribute to tumour progression. The studies reported he re were designed to help elucidate PAI-1's contribution to the invasive and migratory phenotype. Antibodies to PAI-1 dose-dependently, and significant ly, inhibited the invasive and migratory potential of human HT1080 fibrosar coma cells, as did an antibody to uPA and the plasmin inhibitor aprotinin. Invasion of the human melanoma cell line, BLM, was also attenuated by the a nti-PAI-1 monoclonal antibody MAI-12. The non-invasive human melanoma cell line, IF6, which does not express uPA, provided further confirmation of PAI -1 and uPA's role as, upon transfection with uPA, this cell line attained a n invasive phenotype, which was again attenuated by MAI- 12. Although antib odies to PAI-1 did not affect the adhesion of HT1080 cells to vitronectin, the antibody to uPA reduced their attachment. Addition of exogenous PAI-1, however, prevented HT1080 cell adhesion (IC50 180nM) and promoted cell deta chment from vitronectin. Furthermore melanoma cells transfected with a uPA variant, which had an impaired interaction with PAI-1, were not invasive an d had impaired binding to vitronectin. These data highlight the importance of a balanced proteolysis and suggest an additional role for PAI-1 distinct from its role in proteolysis. These data also suggest that uPA and PAI-1 m ay co-operate in the migratory process by respectively facilitating the att achment to, and subsequent detachment from, vitronectin in the extracellula r matrix. These results support the clinical findings and indicate that mod ulation of PAI-1 activity may be of therapeutic benefit for the treatment o f cancer.