FGF7/KGF triggers cell transformation and invasion on immortalised human prostatic epithelial PNT1A cells.
Fibroblast growth factor 7 (FGF7/KGF) is synthesized exclusively by fibroblasts in normal tissues; it acts as a potent mitogen on epithelial cells, through interaction with the FGF7-specific receptor FGFR2/IIIb. To examine the importance of this growth factor both to prostate physiology and to prostate-cancer progression, we have tested the exogenous effect of FGF7. Thus, by mimicking the paracrine pathway (on proliferation, growth in soft agar and invasion) on the human prostatic epithelial cell line PNT1A positively checked for FGFR2/IIIb expression, FGF7 significantly enhanced cell proliferation at an optimal concentration of 7.5 x 10(-11) M, but no significant invasion or growth in soft agar were observed. To confirm FGF7 properties on human prostatic epithelial cells, we constitutively expressed FGF7 by transfecting PNT1A cells with FGF7-cDNA. The FGF7-transfected clones, PNT1A/ FGF7-T5 and PNT1A/FGF7-T6, were stable and expressed FGF7. Analysis of the FGF7-autocrine loop on the non-tumorigenic epithelial cells PNT1A showed acquired invasive potential in in vitro extracellular-matrix migration assays, specifically inhibited by an FGF7-neutralizing antibody, and over-expressed factors implicated in the migration process: the metalloproteinase MMP-1 and the plasminogen activator uPA. Taken together, these results demonstrate a role for FGF7 in triggering invasion of human prostatic epithelial cells. Furthermore, these FGF7-transfected clones exhibited functional and physiological differences from the original PNT1A cell line: anchorage-independent growth, growth in serum-free media and increased proliferation. These data confirm the oncogenic function of FGF7 in prostate progression potentially acting through paracrine and/or autocrine regulatory pathways.
Ropiquet
F
F
Centre de Recherche pour les Pathologies Prostatiques, Département d'Urologie, Hôpital Saint Louis, Paris, France.
Huguenin
S
S
Villette
J M
JM
Ronflé
V
V
Le Brun
G
G
Maitland
N J
NJ
Cussenot
O
O
Fiet
J
J
Berthon
P
P
D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006133:Growth Substances / Q000633:toxicity*; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000032:analysis; D008934:Mitogens / Q000633:toxicity; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
D004273:DNA, Neoplasm; C496453:FGF7 protein, human; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D008934:Mitogens; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases