Increased Fn14 Links to Glioma Cell Invastion and Poor Patient Outcome

Glial tumors progress to malignant grades by heightened proliferation and relentless dispersion into normal brain. Understanding genetic and biochemical processes that foster these behaviors is likely to reveal specific and effective targets for therapeutic intervention. Our current report shows that the fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Forced Fn14 overexpression stimulates glioma cell migration and invasion, and depletion of the small GTP-binding protein, Rac1, by siRNA inhibits this cellular response. Activation of Fn14 signaling by its ligand, TNF-like weak inducer of apoptosis (TWEAK), stimulates migration and also upregulates expression of Fn14; this TWEAK effect requires Rac1 and nuclear factor kB (NF-kB) activity. The Fn14 promoter region contains NF-kB binding sites, which mediate positive feedback causing sustained overexpression of Fn14 and enduring glioma cell invasion. Furthermore, Fn14 gene expression levels increase with glioma grade; within GBM specimens, levels of Fn14 expression inversely correlate with patient survival. These results demonstrate that the Fn14 cascade operates as a positive feedback mechanism for elevated and sustained Fn14 expression. Currently, we are testing the applicability of the inhibition of the Fn14 pathway by functional blocking monoclonal antibodies against Fn14 as a means to selectively target invasive glioma cells. Analysis of Fn14 protein expression on glioma xenograft tissue microarrays revealed two xenografts with high Fn14 expression. Orthotopic xenograft studies using these two human glioblastomas are in progress to assess the effects of biological inhibitors to the Fn14 pathway on the induction of cell death by a cytotoxic agent, temozolomide (Temodar) as well as the effects on the extent of tumor invasion. Histological assessment of tumor size, invasion pattern, and cell death will be employed to measure the effectiveness of the biological inhibitors to Fn14. These studies are currently under investigation to assess the suitability of Fn14 as a targeted therapy against invasive human glioma cells.