FGF-2 isoforms of 18 and 22.5 kDa differentially modulate T-PA and PAI-1 expressions on the pancreatic carcinoma cells AR4-2J: Consequences on cell spreading and invasion

Pancreatic tumors overexpress FGF-2 and t-PA, but the implication of the gr owth factor in t-PA synthesis and t-PA-dependent tumor invasion remains unk nown. FGF-2 is present in different isoforms: The is kDa FGF-2 is secreted, while the 22.5 kDa one is nuclearized and exerts intracrine regulations by passing cell-surface FGF receptors. Rat pancreatic carcinoma AR4-2J cells p roducing either the 18 or the 22.5 kDa FGF-2 after transfection with FGF-2 cDNAs have been used to analyze the role of FGF-2 in t-PA expression and t- PA-related cell spreading. The 22.5 kDa FGF-2 reduced t-PA and PAI-1 synthe sis 2-fold. Addition of recombinant is kDa FGF-2 (rFGF-2) to cell cultures resulted in increased t-PA and decreased PAI-1 expression. By contrast, rFG F-2 did not significantly modify t-PA synthesis in cells producing the 22.5 kDa FGF-2. Cell spreading was t-PA-dependent. Furthermore, cells producing the 22.5 kDa FGF-2 migrated less than control cells and cells producing th e 18 kDa FGF-2, Overall, our data show that secretory FGF-2 is involved in t-PA synthesis by pancreatic cancer cells and facilitates cell spreading. T he 22.5 kDa FGF-2 exerts opposite effects by decreasing t-PA expression in basal conditions and during rFGF-2 stimulation. Since the expression of the 22.5 kDa FGF-2 is under specific controls, its up-regulation might have th e potential to reduce spreading of pancreatic cancer cells. Int. J. Cancer 85:555-562, 2000. (C) 2000 Wiley-Liss, Inc.