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

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Abstract
Pancreatic tumors overexpress FGF‐2 and t‐PA, but the implication of the growth factor in t‐PA synthesis and t‐PA‐dependent tumor invasion remains unknown. FGF‐2 is present in different isoforms: The 18 kDa FGF‐2 is secreted, while the 22.5 kDa one is nuclearized and exerts intracrine regulations bypassing cell‐surface FGF receptors. Rat pancreatic carcinoma AR4–2J cells producing 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 synthesis 2‐fold. Addition of recombinant 18 kDa FGF‐2 (rFGF‐2) to cell cultures resulted in increased t‐PA and decreased PAI‐1 expression. By contrast, rFGF‐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 the 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. The 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 the potential to reduce spreading of pancreatic cancer cells. Int. J. Cancer 85:555–562, 2000.

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