Particularly salient are the following: (1) gene amplification is related to increasing grade of human glioma malignancy and occurs in approximately 40% of the most common and most malignant variety of glioma, glioblastoma multiforme (GBM), (2) by far the most commonly amplified gene in glioblastomas is the epidermal growth factor receptor (EGFR) gene, which is amplified in about one third of GBMs, (3) a small percentage of GBMs amplify N-myc or the novel sequence gli, (4) the EGFR gene is rearranged in at least half of gliomas in which it is amplified, and (5) EGFR gene rearrangement results in external domain deletions that yield truncated EGF receptors.
Two transplantable cell lines of human glioblastoma multiforme GL-3 and GL-5 carried an amplification and overexpression of structurally altered epidermal growth factor (EGF) receptor gene: the 140 kilodalton EGF receptors in these cases exhibited a constitutively expressed tyrosine kinase activity without the ligand.
In view of the similarity to the activated viral and cellular erbB genes in the avian system, these mutated and overexpressed EGF receptors might play a role in the onset or development of human glioblastoma cells.
Our data from immunohistochemistry indicate that ERBB2 expression in GBM is closely correlated with EGF receptor levels and is therefore not useful as an independent prognostic parameter.
These data indicate that overexpression of the EGF receptor and mutations of the p53 tumor suppressor gene are mutually exclusive events defining two different genetic pathways in the evolution of glioblastoma as the common phenotypic endpoint.
Furthermore, astrocytoma cells expressing a constitutively phosphorylated and truncated EGF-R common in GBMs (EGFRvIII or p140(EGF-R)) demonstrate further elevations in Ras activation, resulting in a further increase in VEGF secretion.
Here we report the development and selection for a rearranged amplified EGF receptor, which lacks cytoplasmic amino acid sequences in a human glioblastoma xenograft.
Kinase-deficient erbB proteins reduced epidermal growth factor (EGF)-induced tyrosine phosphorylation of endogenous Shc proteins and also reduced immediate and sustained EGF-induced ERK MAPK activities in human glioblastoma cells, although basal ERK MAPK activities were unaffected.
The atypical protein kinase C inhibitor induced rapid apoptosis in glioblastoma cells expressing EGFRvIII and killed these cells with an IC50 of 16 microM.
Diphtheria toxin-epidermal growth factor fusion protein and Pseudomonas exotoxin-interleukin 13 fusion protein exert synergistic toxicity against human glioblastoma multiforme cells.
A functional polymorphism in the EGF gene is found with increased frequency in glioblastoma multiforme patients and is associated with more aggressive disease.