Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependentand -independent mechanisms

We undertook a series of systematic studies to address the role of fibrobla st growth factor/fibroblast growth factor receptor (FGF/FGFR) activity in t umor growth and angiogenesis, We expressed dominant-negative FGFR2 (FGFR2-D N) or FGFR1 (FGFR1-DN) in glioma C6 cells by using constitutive or tetracyc line-regulated expression systems. Anchorage-dependent or independent growt h was inhibited in FGFR-DN-expressing cells. Tumor development after xenogr afting FGFR-DN-expressing cells in immunodeficient mice or after transplant ation in rat brain was strongly inhibited. Quantification of microvessels d emonstrated a significant decrease in vessel density in tumors derived from FGFR-DNexpressing cells, Furthermore, in a rabbit corneal assay, the angio genic response after implantation of FGFR-DN-expressing cells was decreased . In tumors expressing FGFR-DN, vascular endothelial growth factor expressi on was strongly inhibited as compared with control tumor. These results ind icate that inhibition of FGF activity may constitute a dominant therapeutic strategy in the treatment of FGF-producing cerebral malignancies and may d isrupt both angiogenesis-dependent and -independent signals required for gl ioma growth and invasion.