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In glioblastoma multiforme, local invasive behavior by malignant cells into the surrounding normal brain confounds clinical management and contributes to poor outcome. Although neurosurgery and radiochemotherapy treatments target the tumor mass, repopulation by infiltrating tumor cells often results in tumor re-growth. Studies of the molecular mechanism underlying the invasiveness of malignant glioma cells reveal 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 on invasive glioma cells are being sought; the successful identification of these targets would be anticipated to catalyze development of novel directed therapies. The patterns of expressed genes in migrating and migration-restricted glioma cells were compared using Agilent Oligonucleotide MicroArrays. Genes potentially involved in cell migration and/or invasion, as well as anti-apoptotic related functions, have emerged as accentuated transcripts accompanying this malignant behavior. A strategy for narrowing the lists of differentially-expressed genes was adopted that focused on genes coding for transmembrane receptors over-expressed in the tumor and for which ligand expression is reported in normal brain. We identified several intriguing therapeutic candidates which function as transmembrane receptor including FRZ2, INHBA, INHBB, IL6ST, and LIF; each of which was over-expressed in the actively migrating glioma cells. In addition, anti-apoptotic candidates (BIRC3 and Fn14) and soluble growth factors (TGFβ2 and VEGFC) were upregulated in the migrating glioma population. QRT-PCR of mRNA isolated from a panel of human clinical specimens portrayed increased expression of these invasion-related genes that escalated with increasing tumor grade. Immunohistochemical evaluation of these candidates was performed on sections from an invasive glioma tissue microarray block containing 12 to 15 different surgical glioma cases representing matched tissue core and adjacent invasive rim from each specimen. Protein expression of these candidates corroborates the mRNA expression data and portrayed more intense staining in invasive cells than the tumor core. Targeted therapy against these candidates, or their signaling pathways, as an adjuvant to surgical extirpation may specifically treat invasive glioma cells and improve the outcome of this devastating cancer. Supported by NS042262 and NS043446.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]