TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system

TCF-beta strongly promotes local tumor progression in advanced epithelial t umors, though the underlying mechanisms are poorly understood. In the prese nt study, we demonstrate the potential of TGF-beta to increase the invasive ness of the pancreatic cancer cell lines PANG-I and IMIM-PCI, TGF-beta -ind uced tumor cell invasion occurred in a time-dependent manner, started after 12 hr and continued to increase even 48 hr after a single application of t he growth factor. Blocking of secreted TGF-beta1 by application of neutrali zing antibodies 24 hr after TGF-beta treatment completely prevented the sus tained effects of TGF-beta on tumor cell invasion. Together with our previo us observation that TCF-beta1 up-regulates its own expression in both cell lines, our data suggest that TCF-beta1 acts in an autocrine manner to maint ain tumor cell invasion. As measured by Northern blot hybridization and zym ography, TGF-beta treatment of PANC-1 and IMIM-PC1 cells resulted in strong up-regulation of expression and activity of both matrix metalloproteinase- 2 (MMP-2) and the urokinase plasminogen activator (uPA) system. Treatment w ith MMP inhibitors or inhibitors of the uPA system caused significant reduc tion of TGF-beta -induced invasiveness in both cell lines. In contrast, exp ression and activity of MMP-2 and uPA as well as tumor cell invasiveness re mained unaffected in cell lines with defects of the TGF-beta type II recept or (MiaPaca2) or the Smad4 gene (IMIM-PC2 and CAPAN-1), In these cell lines , TGF-beta also failed to auto-induce its own expression. In conclusion, ou r results suggest that TGF-beta1 Is a strong promotor of pancreatic cancer progression. TGF-beta thereby acts in an autocrine manner to induce tumor c ell invasion, which is mediated by MMP-2 and the uPA system. (C) 2001 Wiley -Liss, Inc.