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 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.
Escaffit
F
F
Laboratoire de Biologie et Pathologie Digestive, INSERM U151, ILB, Toulouse, France.
Estival
A
A
Bertrand
C
C
Vaysse
N
N
Hollande
E
E
Clemente
F
F
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D004318:Doxycycline / Q000633:toxicity; D004338:Drug Combinations; D005109:Extracellular Matrix; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007700:Kinetics; D007797:Laminin; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D017354:Point Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011509:Proteoglycans; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D004338:Drug Combinations; D007797:Laminin; D017395:Plasminogen Activator Inhibitor 1; D020033:Protein Isoforms; D011509:Proteoglycans; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D004318:Doxycycline