Akt signaling is required for glioblastoma maintenance in vivo.
Akt signaling is required for glioblastoma maintenance in vivo.
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DOI：
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发表时间：
2011
影响因子：
5.3
通讯作者：
James P. Robinson;M. VanBrocklin;Andrea J. McKinney;H. Gach;S. Holmen
中科院分区：
文献类型：
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作者：
James P. Robinson;M. VanBrocklin;Andrea J. McKinney;H. Gach;S. Holmen
通过在胶质祖细胞中组合表达活化形式的KRas和Akt，可以在小鼠中诱导多形性胶质母细胞瘤（GBM）。我们先前已经证明，KRas是维持这些肿瘤在体内所必需的，因为抑制KRas表达导致凋亡肿瘤消退和显著增加的存活。为了确定这些肿瘤在体内对Akt信号传导的依赖性，我们产生了允许Akt的表达在递送后被控制的病毒载体。比较持续Akt表达的动物和Akt表达被抑制的动物之间的存活率。尽管五分之一的肿瘤对治疗无效，但抑制Akt显著增加了荷瘤小鼠的存活率，近四分之一的小鼠在治疗期后四个月仍处于缓解状态。这些数据表明，Akt是必要的胶质母细胞瘤的激活Ras的情况下，维持和Akt表达的损失导致生存增加，因此，PI 3 K/AKT信号通路是一个可行的治疗靶点在这种情况下。
Glioblastoma multiforme (GBM) can be induced in mice through the combined expression of activated forms of KRas and Akt in glial progenitor cells. We have previously demonstrated that KRas is required for the maintenance of these tumors in vivo as inhibition of KRas expression resulted in apoptotic tumor regression and significantly increased survival. To determine the reliance of these tumors on Akt signaling in vivo, we generated a viral vector that allows the expression of Akt to be controlled post-delivery. Survival rates were compared between those animals with continued Akt expression and animals in which expression of Akt was suppressed. Although a fifth of the tumors were refractory to treatment, inhibition of Akt significantly increased the survival of tumor-bearing mice and nearly a fourth of the mice remained in remission four months after the treatment period. These data suggest that Akt is required for glioblastoma maintenance in the context of activated Ras and that loss of Akt expression results in increased survival; therefore, the PI3K/AKT signaling pathway is a viable therapeutic target in this context.