Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells.
ABSTRACT Overexpressed epidermal growth receptor factor receptors (EGFRs) are thought to contribute to the malignant phenotype of human glioblastomas (GBMs), but the mechanism is not well understood. We found that SKMG-3 cells, a rare GBM cell line that maintains EGFR gene amplification in vitro, produced high levels of EGFR protein. The cells also expressed the related receptors HER2/neu and HER4, but not HER3. Immunoblots and tryptic phosphopeptide maps showed that the SKMG-3 EGFRs were intact and functional and that a subset of these receptors were spontaneously autophosphorylated. EGF treatment stimulated phosphorylation of the EGFRs as well as the downstream effectors Erk, AKT1, stat3 and c-Cbl. Under minimal growth conditions, the unstimulated SKMG-3 cells contained constitutively phosphorylated Erk and AKTI but no detectable stat3 DNA-binding complexes. The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1. In contrast, inhibition of phosphatidylinositol-3-kinase (PI3K) blocked the constitutive phosphorylation of Erk and AKT-1 but not the EGFR. We conclude that the SKMG-3 cells represent the subset of GBMs with amplified EGFR genes that overexpress intact receptors. The results also suggest that in some GBMs, signals from overexpressed EGFRs contribute to the constitutive phosphorylation of Erk, but these signals may not required for the constitutive activation of PI3K or AKT1.
Article: Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma.[show abstract] [hide abstract]
ABSTRACT: Anti-Human Epithelial Receptor Type 2 (HER2) antibodies have the ability to induce in vitro apoptosis of glioblastoma (GBM) cells. This study was designed to evaluate the variability of HER2 expression in GBM and its role as a possible prognosis factor. Data of 57 patients with GBM and 16 patients with grade III gliomas were retrospectively analyzed. The expression of HER2 was determined by immunohistochemistry and intensity was noted from 0+ to 3+. We compared the HER2 expression in de novo GBM and in GBM resulting from anaplastic transformation of low-grade glioma ("secondary GBM"). Statistical analysis was performed using univariate analysis and the Kaplan-Meier method. All GBM expressing highly HER2 (2+ and 3+) were de novo GBM. All secondary GBM expressed HER2 with low intensity (0+ and 1+). Survival time was significantly longer when HER2 expression was low (Log Rank test P = 0.04). The patterns of HER2 expression were similar between grade III gliomas and secondary GBM. To our best knowledge, our study showed for the first time a significant association between HER2 expression and the type of GBM, with subsequent influence on survival rate. GBM with low-HER2 expression are more likely to be secondary GBM, carrying a better prognosis than de novo GBM.Journal of Neuro-Oncology 01/2008; 85(3):281-7. · 3.21 Impact Factor