Neuron Glia Biology



Overexpression of c-MYC promotes an undifferentiated phenotype in cultured astrocytes and allows elevated Ras and Akt signaling to induce gliomas from GFAP-expressing cells in mice


ANDREW B. LASSMAN a1, CHENGKAI DAI a3p1, GREGORY N. FULLER a4, ANDREW J. VICKERS a5 and ERIC C. HOLLAND a1a2a3c1
a1 Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY
a2 Department of Surgery (Neurosurgery), Memorial Sloan-Kettering Cancer Center, New York, NY
a3 Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY
a4 Department of Pathology, MD Anderson Cancer Center, Houston, TX
a5 Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY

Article author query
lassman ab   [PubMed][Google Scholar] 
dai c   [PubMed][Google Scholar] 
fuller gn   [PubMed][Google Scholar] 
vickers aj   [PubMed][Google Scholar] 
holland ec   [PubMed][Google Scholar] 

Abstract

The c-MYC protooncogene is overexpressed in the most malignant primary brain tumor, glioblastoma multiforme (GBM), and has been correlated with the undifferentiated character of several cell types. However, the role of Myc activity in the generation of GBMs is not known. In this report, we show that gene transfer of c-MYC to GFAP-expressing astrocytes in vitro promotes the outgrowth of GFAP-negative, nestin-expressing cells with progenitor-like morphology, growth characteristics and gene-expression pattern. In addition, gene transfer of c-MYC to GFAP-expressing astrocytes in vivo induces GBMs when co-expressed with activated Ras and Akt. Without c-MYC, Ras+Akt induces GBMs from nestin-expressing CNS progenitors but is insufficient in GFAP-expressing differentiated astrocytes. The ability of Myc activity to enhance the oncogenic effects of Ras+Akt appears to be limited to GFAP-expressing astrocytes because nestin-expressing progenitors show no increase in GBM formation with the addition of MYC to Ras+Akt. These studies indicate that one role of MYC activity in the formation of gliomas might be to either promote or reinforce an undifferentiated phenotype required for glioma cells to respond to the oncogenic effects of elevated Ras and Akt activity.


Key Words: Glioblastoma multiforme (GBM); brain tumor; mouse model; oncogene; RCAS/tv-a.

Correspondence:
c1 Eric C. Holland, MD, PhD, Departments of Surgery (Neurosurgery), Neurology, and Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. phone: +1 212 639 3017; fax: +1 646 422 2062. email: hollande@mskcc.org
p1 Current address: Whitehead Institute, Massachusetts Institute of Technology, Boston, MA