FGF5 as an oncogenic factor in human glioblastoma multiforme: autocrine and paracrine activities.
Fibroblast growth factor 5 (FGF5) is widely expressed in embryonic but scarcely in adult tissues. Here we report simultaneous overexpression of FGF5 and its predominant high-affinity receptor (FGFR1 IIIc) in astrocytic brain tumour specimens (N=49) and cell cultures (N=49). The levels of both ligand and receptor increased with enhanced malignancy in vivo and in vitro. Furthermore, secreted FGF5 protein was generally present in the supernatants of glioblastoma (GBM) cells. siRNA-mediated FGF5 downmodulation reduced moderately but significantly GBM cell proliferation while recombinant FGF5 (rFGF5) increased this parameter preferentially in cell lines with low endogenous expression levels. Apoptosis induction by prolonged serum starvation was significantly prevented by rFGF5. Moreover, tumour cell migration was distinctly stimulated by rFGF5 but attenuated by FGF5 siRNA. Blockade of FGFR1-mediated signals by pharmacological FGFR inhibitors or a dominant-negative FGFR1 IIIc protein inhibited GBM cell proliferation and/or induced apoptotic cell death. Moreover, rFGF5 and supernatants of highly FGF5-positive GBM cell lines specifically stimulated proliferation, migration and tube formation of human umbilical vein endothelial cells. In summary, we demonstrate for the first time that FGF5 contributes to the malignant progression of human astrocytic brain tumours by both autocrine and paracrine effects.
Allerstorfer
S
S
Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
Sonvilla
G
G
Fischer
H
H
Spiegl-Kreinecker
S
S
Gauglhofer
C
C
Setinek
U
U
Czech
T
T
Marosi
C
C
Buchroithner
J
J
Pichler
J
J
Silye
R
R
Mohr
T
T
Holzmann
K
K
Grasl-Kraupp
B
B
Marian
B
B
Grusch
M
M
Fischer
J
J
Micksche
M
M
Berger
W
W
D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D001932:Brain Neoplasms / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018450:Disease Progression; D051521:Fibroblast Growth Factor 5 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005799:Genes, Dominant / Q000502:physiology; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics; D009857:Oncogenes / Q000502:physiology; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; C496449:FGF5 protein, human; D050505:Mutant Proteins; D011994:Recombinant Proteins; D051521:Fibroblast Growth Factor 5