In glioblastoma multiforme, local invasive behavior into surrounding normal brain underlies the difficult clinical management and poor outcome. Although neurosurgery and radiochemotherapy treatments distinctively target the tumor mass, repopulation by the infiltrating tumor cells often results in tumor re-growth that ultimately kills the patient. Studies of the molecular mechanism underlying the invasiveness of malignant glioma cells have revealed complex pathways involving altered cell-substrate attachment, cell-cell adhesion, secreted proteases and an increase in both cell motility and survival. Potential specific therapeutic targets for invasive glioma cells have yet to be identified; however, the successful identification of these targets would be anticipated to catalyze development of novel therapies.

Genes over-expressed in migrating glioma cells have been identified using DNA MicroArray analyses comparing migration-activated glioma cells to passive glioma cells. Several gene candidates potentially involved in cell migration or invasion, as well as anti-apoptotic related functions have emerged. Recently, Dr. Tran has described a candidate gene, the transmembrane receptor fibroblast growth factor-inducible 14 (Fn14), whose level of expression correlates with glioma migration(1). He has demonstrated that Fn14 expression is minimal-to-absent in normal brain tissue but increases with increasing tumor grade. Noteably, the exclusive ligand for Fn14, TWEAK, is downregulated in glioblastoma cells, yet highly expressed in the normal brain. Activation of Fn14 signaling by addition of recombinant TWEAK or over-expression of Fn14 enhances glioma cell motility and survival. Stimulation of Fn14 activates the PI 3K/Akt transduction pathway suggesting a role for Fn14 in promoting survival of invasive glioma cells. Minimal detection of Fn14 in normal brain in conjunction with the expression of Fn14 specifically in glioma cells lead us to hypothesize that the activity of Fn14 enhances malignant glioblastoma cell survival and invasion into the normal brain parenchyma. Interfering with the function of Fn14 is likely to specifically target invasive glioblastoma cells and impact the ability of the tumor to recur. Understanding Fn14 in the context of glioma migration and cell survival will provide mature insight into the molecular mechanisms of the invasive phenotype. We are currently profiling the suitability and applicability of Fn14 as a target for therapeutic intervention.

Dr. Tran obtained his undergraduate degree in microbiology from the University of Arizona, where he also completed his doctoral work in cancer biology.