Differential Distribution of erbB Receptors in Human Glioblastoma Multiforme: Expression of erbB3 in CD133-Positive Putative Cancer Stem Cells

Glioblastomas are the most common primary central nervous system tumors in adults, and they remain resistant to current treatments. erbB1 signaling is frequently altered in glioblastomas, suggesting that erbB receptor family members may represent targets for molecular therapy. We performed a comprehensive analysis of erbB receptor and ligand expression profiles in a panel of 9 glioblastomas and compared them to nonneoplastic cerebral tissue containing neocortex and adjacent white matter. Quantitative reverse transcription-polymerase chain reaction and Western blot analysis showed that erbB1 signaling and erbB2 receptors exhibited highly variable deregulation profiles in the tumors, with patterns ranging from under-expression to overexpression; in contrast, erbB3 and erbB4 were downregulated. We next performed immunohistochemistry to determine the distribution patterns of erbB receptors among the main neural cell types in the tumors with special reference to the putative tumor stem cell population. Results revealed intertumoral and intratumoral heterogeneity in all 4 erbB expression profiles, but each receptor exhibited a distinct distribution pattern among glial fibrillary acidic protein-, Olig2-, NeuN-, and CD133-positive populations. Although erbB1 immunoreactivity was detected in only small subsets of CD133-positive putative tumor stem cells, erbB3 immunoreactivity was prominent in this population, suggesting that erbB3 may represent a new potential therapeutic target.