Nature Genetics
25, 55 - 57 (2000)
doi:10.1038/75596
Combined activation of Ras and Akt in neural progenitors induces glioblastoma
formation in miceEric C. Holland1, 2, Joseph Celestino1, Chengkai Dai1, Laura Schaefer1, Raymond E. Sawaya1
& Gregory N. Fuller31
Department of Neurosurgery, MD Anderson Cancer Center
, Houston, Texas, USA. 2
Department of Molecular Genetics, MD Anderson Cancer
Center, Houston, Texas, USA. 3
Department of Pathology, MD Anderson Cancer Center
, Houston, Texas, USA.
Correspondence should be addressed to Eric C. Holland eholland@notes.mdacc.tmc.eduGliomas are the most common primary malignant brain tumours and are classified
into four clinical grades1, 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 proteins6,
7,
8,
9,
10. 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.
|
