Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, biologically unique by virtue of the proclivity for local invasion into the adjacent normal brain tissue and the rarity of systemic metastasis. Genes over-expressed in migrating glioma cells have been identified using DNA MicroArray analysis 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. Among the migration-associated candidate genes is the transmembrane receptor fibroblast growth factor-inducible 14 (Fn14), whose level of expression correlates with glioma migration. The ligand for Fn14 is “TNF-like weak inducer of apoptosis” (TWEAK). Fn14 is a growth-factor-inducible immediate-early-response gene encoding a 102-amino-acid type I transmembrane protein. Fn14 is over-expressed in migrating astrocytoma cells in vitro and in invasive high-grade astrocytoma clinical specimens (Tran et al. Am J. Path. 162 2003). To elaborate the role of Fn14 in glioma pathobiology, we examined the downstream signaling pathway of Fn14 that fosters glioma cell migration. Over-expression of Fn14 or activation of Fn14 by addition of TWEAK, results in a 3-4 fold induction of astrocytoma cell motility. Over-expression of Fn14 in GBM cells induces the formation of filopodia, lamallepodia and microspikes. Fn14 colocalizes and activates Rac1, a member of the Rho family of GTPases. Furthermore, immunoprecipitation studies show that Fn14 physically associates with Rac1 GTPase and enhances Rac1 activation. In addition, glioma cells over-expressing Fn14 exhibit more rapid invasive dispersion in an ex vivo rat brain slice. Depletion of Fn14 or Rac1 expression using small interfering RNA oligonucleotides antagonized Fn14 mediated glioma cell migration and invasion. Thus, Fn14 overexpression triggers signaling pathways that dramatically influence tumor cell behavior, including activated motility functions and disengaged apoptotic activation. We hypothesize that the Fn14 protein functions, in part, to stimulate glioblastoma cell invasion into the normal brain parenchyma. Therapy designed to interfere with the function of Fn14 is likely to specifically target invasive glioblastoma cells and impact the ability of the tumor to recur. Supported by NS042262 and NS043446.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]