mTOR promotes urvival and astrocytic characteristics induced by Pten/Akt signaling in glioblastoma

被引:147
作者
Hu, XY
Pandolfi, PP
Li, Y
Koutcher, JA
Rosenblum, M
Holland, EC
机构
[1] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10021 USA
[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA
[4] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
[5] Mem Sloan Kettering Canc Ctr, Dept Surg Neurosurg & Neurol, New York, NY 10021 USA
来源
NEOPLASIA | 2005年 / 7卷 / 04期
关键词
Pten; Akt; mTOR; glioblastoma; survival;
D O I
10.1593/neo.04595
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Combined activation of Ras and Akt leads to the formation of astrocytic glioblastoma multiforme (GBM) in mice. In human GBMs, AKT is not mutated but is 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., We demonstrate here that loss of Pten is similar to AM activation in the context of glioma formation in mice. We further delineate the role of mTOR activity downstream of Akt in the maintenance of Akt+KRas-induced GBMs. Blockade of mTOR results in regional apoptosis in these tumors and conversion in the character of surviving tumor cells from astrocytoma to oligodendroglioma. These data suggest that mTOR activity is required for the survival of some cells within these GBMs, and mTOR appears required for the maintenance of astrocytic character in the surviving cells. Furthermore, our study provides the first example of conversion between two distinct tumor types usually thought of as belonging to specific lineages, and provides evidence for signal transduction-mediated transdifferentiation between glioma subtypes.
引用
收藏
页码:356 / 368
页数:13
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