High-Grade Glioma Formation Results from Postnatal Pten Loss or Mutant Epidermal Growth Factor Receptor Expression in a Transgenic Mouse Glioma Model

Abstract

High-grade gliomas are devastating brain tumors associated with a mean survival of <50 weeks. Two of the most common genetic changes observed in these tumors are overexpression/ mutation of the epidermal growth factor receptor (EGFR) vIII and loss of PTEN/MMAC1 expression. To determine whether somatically acquired EGFRvIII expression or Pten loss accelerates high-grade glioma development, we used a previously characterized RasB8 glioma-prone mouse strain, in which these specific genetic changes were focally introduced at 4 weeks of age. We show that both postnatal EGFRvIII expression and Pten inactivation in RasB8 mice potentiate high-grade glioma development. Moreover, we observe a concordant loss of Pten and EGFR overexpression in nearly all high-grade gliomas induced by either EGFRvIII introduction or Pten inactivation. This novel preclinical model of highgrade glioma will be useful in evaluating brain tumor therapies targeted to the pathways specifically dysregulated by EGFR expression or Pten loss. (Cancer Res 2006; 66(15): 7429-37)

PTEN signaling in brain: neuropathology and tumorigenesis

“…Other mutations associated with human astrocytoma progression, such as Cdkn2a (Ink4a) loss or EGFR overexpression, were also seen (Shannon et al, 2005). The role of Pten, or activation of EGFR signaling, for increasing the severity of Ras-driven tumors was elegantly confirmed in vivo by targeted deletion of Pten using adenovirus expressing cre recombinase, or expression of a constitutively active EGFR (EGFRvIII) (Wei et al, 2006).…”

ConstitutiveEGFRSignaling in Oligodendrocyte Progenitors Leads to Diffuse Hyperplasia in Postnatal White Matter

“…The deregulation of EGFR signaling is often manifested in human gliomas (Collins, 1995;Rao and James, 2004), and previous animal studies have shown that the expression of mutant EGFR VIII can cooperate with other genetic lesions to facilitate the formation of gliomas (Holland et al, 1998;Wei et al, 2006). However, the functional role of EGFR signaling in glioma formation is not understood.…”

The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo

“…Mutation or deletion of PTEN, often by way of complete loss of its locus on chromosome 10q, is found in a large percentage of GBM (James 2005;The Cancer Genome Atlas Research Network 2008;Parsons et al 2008) and is correlated with poor prognosis in multiple glioma subtypes (Sasaki et al 2001;Smith et al 2001). Furthermore, PTEN loss dramatically enhances gliomagenesis in a number of murine model systems (Hu et al 2005;Wei et al 2006;Kwon et al 2008). Given the central role of PTEN in glioma biology, the identification of alternative mechanisms for PTEN regulation in this tumor entity would be of considerable interest.…”