Function of aberrant EGFR in malignant gliomas

Abstract

The most common alteration of the epidermal growth factor receptor (EGFR) gene in human malignant gliomas is an in-frame deletion of exon 2-7 from the extra-cellular domain. To study the relationship between the expression of this aberrant EGFR and cell proliferation, as well as apoptosis in malignant gliomas, we have developed U-87MG cell transfectants that express the aberrant (mutant-type) or normal (wild-type) EGFR. We analyzed cell number, tumor volume, and MIB-1 positive rate as proliferation markers, and found that in tissue culture, tumors derived from U-87 MG cells (mutant-type) have the same proliferative activity as those derived from U-87 MG cells (wild-type). However, when cells expressing mutant EGFR were implanted into nude mice subcutaneously, the tumorigenic capacity was much enhanced. We also found that the apototic index of tumors derived from U-87 MG cells (mutant-type) was less than 0.1%, whereas that of wild-type tumor was 1%. These results suggest that aberrant EGFR affects the malignancy of glioma by stimulating proliferation and inhibiting apoptosis.

Epidermal growth factor receptor mutation type iii transfected into a small cell lung cancer cell line is predominantly localized at the cell surface and enhances the malignant phenotype

“…In all cases the cell lines exhibiting the EGFRvIII had an increased growth potential or ability to form tumors in the nude mouse model. 22,25,27,30,44 The in vitro invasion assay can mimic some of the events leading to the formation of metastasis, that is, attachment to the basement membrane, local proteolysis and migration. Various growth factors have been implied to play a significant role in the processes leading up to the formation of metastasis.…”

Epidermal Growth Factor Receptor Expression Identifies Functionally and Molecularly Distinct Tumor-Initiating Cells in Human Glioblastoma Multiforme and Is Required for Gliomagenesis

“…Likewise, EGFR gene amplification is positively correlated with molecularly defined GBM subclasses, characterized by active proliferation and poor prognosis (21). Valuable preclinical information has also been obtained by modulating EGFR expression in standard serum-cultured glioma cell lines (22)(23)(24)(25) and by using these in vitro cultures for testing different therapeutic approaches (26).…”

Analysis of the epidermal growth factor receptor specific transcriptome: Effect of receptor expression level and an activating mutation

“…These include: autocrine growth factor loops, overexpression, and deletions or mutations, which render the receptor independent of ligand and constitutively active [Wong et al, 1992;Damstrup et al, 1999;Peghini et al, 2002]. Recent evidence suggests that genetic alterations in the EGFR gene may be as important as overexpression with respect to the oncogenic potential and to correlate with poor prognosis [Schwechheimer et al, 1995;Sugawa et al, 1998;Ge et al, 2002;Pandita et al, 2004].…”