Post-natal expression of mutant epidermal growth factor receptor (EGFRvIII), potentiates astrocytoma development in GFAP-V12Ha-Ras transgenics

1117

Introduction: Mutation, amplification and overexpression of EGFR, such as EGFRvIII with a constitutively activating truncation in the extracellular domain, is common in malignant but not low-grade astrocytomas. Embryonic transgenesis of GFAP regulated EGFRvIII by itself does not result in gliomas, however, potentiates gliomagenesis in our GFAP-V12Ha-Ras astrocytoma model, with a switch towards mainly a oligodendroglioma lineage. Since gliomas usually occur in adults, we investigated the effects of post-natal expression of EGFRvIII in normal and GFAP-V12Ha-Ras astrocytoma susceptible mice. Methods: One-month old GFAP-V12Ha-Ras transgenics and normal littermates were injected with AdEGFRvIII or control AdGFP virus into the frontal lobe. The mice were observed for neurological symptoms, with brains analyzed for gliomas, as per animal committee guidelines. Results: AdEGFRvIII or AdGFP injection into normal mice did not result in gliomas, while 50% of GFAP-V12Ha-Ras,Ad:EGFRvIII injected mice developed large confluent high-grade gliomas, compared to 20% of GFAP-V12Ha-Ras mice. GFAP-V12Ha-Ras,Ad:EGFRvIII gliomas were mainly astrocytic, compared to oligodendrogliomas with embryonic expression of EGFRvIII. EGFRvIII expression was only detected in high-grade and not the lower-grade gliomas, in the GFAP-V12Ha-Ras,Ad:EGFRvIII injected mice, which were also detectable by MRI imaging. Conclusions: Like human tumors, embryonic or post-natal expression of EGFRvIII did not by itself induce gliomas in mice. However, in keeping with being a progression factor, EGFRvIII did potentiate glioma formation in genetically susceptible mice. Specifically in adults, it induced high-grade astrocytomas, in contrast to mainly oligodendrogliomas with embryonic expression. This data is another illustration that glioma and other tumor lineages is a function of the genetic alterations and also where they occur in developmental context. Ongoing experiments are directed towards understanding the role of EGFRvIII in gliomagenesis in the background of other relevant glioma associated genetic alterations.