EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors

¹ Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA
² National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
³ Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA
⁴ Program of Cancer Genetics, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
⁵ Department of Neurology and Neurological Sciences, Stanford University Medical School, Palo Alto, CA, USA

^* To whom correspondence should be addressed. E-mail: Alonzo.Ross{at}umassmed.edu.

	Abstract

Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/- neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/- cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker, CD133, as well as resistance to oxidative stress and ionizing radiation. The RAS/ERK and PI3K/Akt pathways were activated, and Chk1, the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/- cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, GFAP+, nestin+ tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability.

Key Words: aneuploidy, EGFRvIII, PTEN, glioblastoma, neural precursor cells

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