Phenotypical Flexibility of the EGFRvIII-Positive Glioblastoma Cell Line and the Multidirectional Influence of TGFβ and EGF on These Cells-EGFRvIII Appears as a Weak Oncogene

Background: The biological role of EGFRvIII (epidermal growth factor receptor variant three) remains unclear. Methods: Three glioblastoma DK-MG sublines were tested with EGF (epidermal growth factor) and TGF beta (transforming growth factor beta). Sublines were characterized by an increased percentage of EGFRvIII-positive cells and doubling time (DK-MG(low) to DK-MG(extra-high)), number of amplicons, and EGFRvIII mRNA expression. The influence of the growth factors on primary EGFRvIII positive glioblastomas was assessed. Results: The overexpression of exoEGFRvIII in DK-MG(high) did not convert them into DK-MG(extra-high), and this overexpression did not change DK-MG(low) to DK-MG(high); however, the overexpression of RAS(G12V) increased the proliferation of DK-MG(low). Moreover, the highest EGFRvIII phosphorylation in DK-MG(extra-high) did not cause relevant AKT (known as protein kinase B) and ERK (extracellular signal-regulated kinase) activation. Further analyses indicate that TGF beta is able to induce apoptosis of DK-MG(high) cells. This subline was able to convert to DK-MG(extra-high), which appeared resistant to this proapoptotic effect. EGF acted as a pro-survival factor and stimulated proliferation; however, simultaneous senescence induction in DK-MG(extra-high) cells was ambiguous. Primary EGFRvIII positive (and SOX2 (SRY-Box Transcription Factor 2) positive or SOX2 negative) glioblastoma cells differentially responded to EGF and TGF beta. Conclusions: The roles of TGF beta and EGF in the EGFRvIII context remain unclear. EGFRvIII appears as a weak oncogene and not a marker of GSC (glioma stem cells). Hence, it may not be a proper target for CAR-T (chimeric antigen receptor T cells).

Automated summary

This study investigates the biological role of EGFRvIII in glioblastoma. The results suggest that EGFRvIII is not a marker of glioma stem cells and may not be a suitable target for CAR-T therapy. The effects of TGF beta and EGF in the context of EGFRvIII remain unclear.