Immunohistochemical analysis of the mutant epidermal growth factor, deltaEGFR, in glioblastoma

Abstract

The naturally occurring mutated form of the epidermal growth factor receptor, deltaEGFR (also named EGFRvIII and de2-7EGFR), greatly enhances glioblastoma (GBM) cell growth in vivo through several activities, such as down-regulating p27 and up-regulating BclX(L) while increasing signaling through the RAS-MAPK and PI3-K cascades. More than half of GBMs, especially of the de novo type, overexpress EGFR, and 50%-70% of these express deltaEGFR. However, little is known about the distribution of deltaEGFR-expressing tumor cells within surgical specimens. In order to address this clinically important issue, we performed immunohistochemical analyses of 53 GBMs obtained during surgery using the anti- deltaEGFR monoclonal antibody, DH8.3. We also simultaneously analyzed wild-type EGFR expression in these tissues using the anti-EGFR monoclonal antibody, EGFR.113. deltaEGFR and wild-type EGFR expression were observed in 20/53 (38%) and 29/53 (55%), respectively. Nineteen (95%) of the deltaEGFR-positive tumors also expressed wild-type EGFR; one case was deltaEGFR-positive but wild-type EGFR-negative. In 13/20 (65%) of the deltaEGFR-positive tumors, tumor cells were scattered diffusely within the tumors, 6/20 showed geographical distribution of deltaEGFR-positive tumor cells, and one case showed homogeneous staining. In the wild-type EGFR-positive cases, almost all tumor cells expressed EGFR. The differential distribution of cells expressing the two receptors observed here may suggest either that deltaEGFR arises at a low frequency from wild-type EGFR-expressing cells, perhaps during the process of gene amplification, or that there is a paracrine-type of interaction between them.