TY - JOUR
T1 - Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling
AU - Loilome, Watcharin
AU - Joshi, Avadhut D.
AU - ap Rhys, Colette M.J.
AU - Piccirillo, Sara
AU - Angelo, Vescovi L.
AU - Gallia, Gary L.
AU - Riggins, Gregory J.
N1 - Funding Information:
Acknowledgements We thank Brenda Raymond for administrative support. This project was supported by NIH Grant R01 NS052507, the Johns Hopkins Department of Neurosurgery and the Virginia and the D. K. Ludwig Fund for Cancer Research. W. L. is supported by the Faculty of Medicine, Khon Kaen University, Thailand. A. J. is supported by an American Brain Tumor Association (ABTA) postdoctoral fellowship and G. J. R. is the Irving J. Sherman M.D. Neurosurgery Research Professor.
PY - 2009
Y1 - 2009
N2 - The Fibroblast Growth Factor (FGF) signaling pathway is reported to stimulate glioblastoma (GBM) growth. In this work we evaluated the effect of FGF2, FGF receptor (FGFR), and small molecule inhibition on GBM cells grown in traditional media, or cultured directly in stem-cell media. These lines each expressed the FGFR1, FGFR3 and FGFR4 receptors. Addition of FGF2 ligand showed significant growth stimulation in 8 of 10 cell lines. Disruption of FGF signaling by a neutralizing FGF2 monoclonal antibody and FGFR1 suppression by RNA interference both partially inhibited cell proliferation. Growth inhibition was temporally correlated with a reduction in MAPK signaling. A receptor tyrosine kinase inhibitor with known FGFR/VEGFR activity, PD173074, showed reproducible growth inhibition. Possible mechanisms of growth suppression by PD173074 were implicated by reduced phosphorylation of AKT and MAPK, known oncogenic signal transducers. Subsequent reduction in the cyclin D1, cyclin D2 and CDK4 cell cycle regulators was also observed. Our results indicate that FGF signaling pathway inhibition as a monotherapy will slow, but not arrest growth of glioblastoma cells.
AB - The Fibroblast Growth Factor (FGF) signaling pathway is reported to stimulate glioblastoma (GBM) growth. In this work we evaluated the effect of FGF2, FGF receptor (FGFR), and small molecule inhibition on GBM cells grown in traditional media, or cultured directly in stem-cell media. These lines each expressed the FGFR1, FGFR3 and FGFR4 receptors. Addition of FGF2 ligand showed significant growth stimulation in 8 of 10 cell lines. Disruption of FGF signaling by a neutralizing FGF2 monoclonal antibody and FGFR1 suppression by RNA interference both partially inhibited cell proliferation. Growth inhibition was temporally correlated with a reduction in MAPK signaling. A receptor tyrosine kinase inhibitor with known FGFR/VEGFR activity, PD173074, showed reproducible growth inhibition. Possible mechanisms of growth suppression by PD173074 were implicated by reduced phosphorylation of AKT and MAPK, known oncogenic signal transducers. Subsequent reduction in the cyclin D1, cyclin D2 and CDK4 cell cycle regulators was also observed. Our results indicate that FGF signaling pathway inhibition as a monotherapy will slow, but not arrest growth of glioblastoma cells.
KW - Fibroblast growth factor signaling pathway
KW - GBM stem-like cell
KW - Glioblastoma
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U2 - 10.1007/s11060-009-9885-5
DO - 10.1007/s11060-009-9885-5
M3 - Article
C2 - 19340397
AN - SCOPUS:69249234742
SN - 0167-594X
VL - 94
SP - 359
EP - 366
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 3
ER -