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Combined
activation of Ras and Akt in neural progenitors induces glioblastoma
formation in mice
Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN
Department of Neurosurgery, MD Anderson Cancer Center, Houston,
Texas, USA. eholland@notes.mdacc.tmc.edu
Gliomas are the most common primary malignant brain tumours and are
classified into four clinical grades, with the most aggressive tumours
being grade 4 astrocytomas (also known as glioblastoma multiforme;
GBM).
Frequent
genetic alterations in GBMs (refs 2-5) result in stimulation of common
signal transduction pathways involving Ras, Akt and other
proteins.
It
is not known which of these pathways, if any, are sufficient to induce
GBM formation.
Here
we transfer, in a tissue-specific manner, genes encoding activated
forms of Ras and Akt to astrocytes and neural progenitors in
mice.
We
found that although neither activated Ras nor Akt alone is sufficient
to induce GBM formation, the combination of activated Ras and Akt
induces high-grade gliomas with the histological features of human
GBMs.
These
tumours appear to arise after gene transfer to neural progenitors, but
not after transfer to differentiated astrocytes.
Increased
activity of RAS is found in many human GBMs (ref. 11), and we show
here that Akt activity is increased in most of these tumours, implying
that combined activation of these two pathways accurately models the
biology of this disease.
PMID:
10802656 [PubMed - indexed for MEDLINE]
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