T-PA-DEPENDENT ACTIVATION OF C6 GLIOMA-BOUND PLASMINOGEN - A KINETIC-STUDY

Plasminogen-plasmin system activity has been correlated with glioblast oma growth and migration. Conversely to plasminogen activation in solu tion, plasminogen activation mainly by tissue-type plasminogen activat or (t-PA) is enhanced by cell-surface binding. We have recently shown that C6 cells, which are very typical of human glioma, produce t-PA. T his production is responsible for a fibrinolytic activity-induced intr a-tumoral haemorrhage. Here, we provide evidence that plasminogen bind s C6 cells and that C6 glioma cells enhance t-PA-induced cell-bound pl asminogen activation by inducing significant modifications in the kine tic parameters of the plasminogen-t-PA interaction. C6 cells are indee d responsible for a 42-fold increase in the catalytic efficiency of pl asmin generation by t-PA (k(cat)/K-m 0.126 mu M-1 s(-1)), mainly due t o a 20-fold decrease in the K-m of the reaction (0.49 +/- 0.02 mu M, v ersus 9.6 +/- 2.8 mu M in the fluid phase). This increase in the appar ent enzyme - substrate affinity for the activation reaction is particu larly favourable to cell-associated plasmin generation. This could exp lain the fibrinolytic activity and the haemorrhagic necrotic area desc ribed in such tumours.