| Gliomas are the most common central nervous system primary neoplasms in adults. They are classified into two major subtypes: astrocytomas and oligodendrogliomas, based on their morphological and histological similarities to astrocytes and oligodendrocytes. Glioblastoma multiforme (GBM) is the most malignant form of astrocytoma. A variety of genetic and epigenetic alterations have been identified in human GBMs. In particular, AKT is not mutated but activated in approximately 70% of these tumors in association with loss of PTEN and/or activation of receptor tyrosine kinases. Mechanistic justification for the therapeutic blockade of targets downstream of AKT, such as mTOR, in these cancers requires demonstration that the oncogenic effect of PTEN loss is through elevated AKT activity. Previous studies have demonstrated that activated Akt cooperates with KRas activation to induce GBMs from neural progenitors in mice. In the present studies, we conditionally deleted Pten in neural progenitors by the combination of RCAS/tv-a and Cre/Lox system, and present experimental evidence that loss of Pten is similar to Akt activation in the context of glioma formation. Blockade of mTOR in Akt+KRas-induced GBMs resulted in regional apoptosis in these tumors and conversion in the character of the surviving tumor cells from astrocytoma to oligodendroglioma, suggesting that mTOR activity is required for the survival of some cells within these GBMs and that mTOR appears to be required for the maintenance of astrocytic character in the surviving cells. We further delineate the role of S6k1 and eIF4E, two parallel downstream components of mTOR, in glioma formation. In combination with activated KRas, either activated S6k1 or eIF4E overexpression induced intracranial lesions that exhibited partial characteristics of Akt+KRas-induced GBMs, suggesting that both S6k1 and eIF4E recapitulate some oncogenic effects of activated Akt. The higher incidence of S6k1+KRas-lesions relative to that of eIF4E+KRas-lesions may emphasize the importance of S6k1 in glioma initiation. Gene transfer of an anti-apoptotic factor Bcl-2 and activated KRas failed to induce any intracranial abnormality. If the possibility of unsuccessful simultaneous gene transfer of Bcl-2 and KRas into same cells could be ruled out, this result would imply that mTOR activity, instead of survival signals, both of which are downstream signals of activated Akt, is essential for initiating pre-malignant lesions. |
