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Glioblastoma cell growth is suppressed by disruption of Fibroblast Growth Factor pathway signaling
Watcharin Loilome1, Avadhut D Joshi, Colette M J ap Rhys
1Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
Abstract:
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.
Insights
Fibroblast Growth Factor (FGF) signaling promotes glioblastoma (GBM) growth. Inhibiting FGF signaling slows GBM cell proliferation but does not completely arrest it, suggesting combination therapies may be needed.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- The Fibroblast Growth Factor (FGF) signaling pathway is implicated in promoting glioblastoma (GBM) tumor progression.
- Understanding the role of FGF signaling in GBM is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the effect of FGF2 ligand and inhibition of the FGF signaling pathway on glioblastoma cell growth.
- To evaluate the efficacy of small molecule inhibitors targeting FGF receptors (FGFRs) in GBM.
Main Methods:
- Assessed the impact of FGF2 addition on GBM cell lines cultured in standard and stem-cell media.
- Utilized a neutralizing FGF2 monoclonal antibody and RNA interference for FGFR1 suppression.
- Administered a small molecule inhibitor (PD173074) with FGFR/VEGFR activity.
- Monitored downstream signaling pathways including MAPK and AKT, and cell cycle regulators (cyclin D1, cyclin D2, CDK4).
Main Results:
- FGF2 ligand significantly stimulated growth in 8 out of 10 GBM cell lines.
- FGF signaling disruption partially inhibited cell proliferation, correlating with reduced MAPK signaling.
- PD173074 demonstrated reproducible growth inhibition, associated with decreased AKT and MAPK phosphorylation.
- Inhibition led to subsequent downregulation of cyclin D1, cyclin D2, and CDK4.
Conclusions:
- FGF signaling pathway inhibition can slow glioblastoma cell growth.
- Monotherapy targeting the FGF pathway is insufficient to completely halt GBM proliferation.
- Further research into combination therapies involving FGF pathway inhibitors is warranted.
