The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas
The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas
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DOI：
10.1038/nm1560
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发表时间：
2007-06-01
期刊：
影响因子：
82.9
通讯作者：
Cordon-Cardo, Carlos
中科院分区：
文献类型：
--
作者：
Hernando, Eva;Charytonowicz, Elizabeth;Cordon-Cardo, Carlos
我们分析了一组肉瘤中的PI3K-AKT信号级联，发现在大多数平滑肌肉瘤中，胰岛素受体底物-2 （IRS2）和磷酸化AKT显著诱导，并伴有下游效应物的上调。为了确定异常的PI3K-AKT信号在平滑肌肉瘤发病中的作用，我们通过将Pten（loxP/loxP）小鼠与Tagln-cre小鼠杂交，在平滑肌细胞系中基因灭活Pten。携带Pten等位基因纯合缺失的小鼠发生广泛的平滑肌细胞增生和腹部平滑肌肉瘤，与其他动物模型相比，发病非常快，发病率升高（接近80%）。组构性mTOR激活仅限于平滑肌肉瘤，这表明除了Pten丢失外，还需要其他分子事件。雷帕霉素衍生物依维莫司显著减缓Tagln-cre/ Pten（loxP/loxP）小鼠的肿瘤生长，延长其寿命。我们的数据显示，AKT-mTOR通路在平滑肌转化和平滑肌肉瘤发生中发挥了新的关键作用，并支持通过使用新化合物或将这些化合物与传统化疗药物联合靶向该通路来治疗选定的肉瘤。
We analyzed the PI3K-AKT signaling cascade in a cohort of sarcomas and found a marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT and a concomitant upregulation of downstream effectors in most leiomyosarcomas. To determine the role of aberrant PI3K-AKT signaling in leiomyosarcoma pathogenesis, we genetically inactivated Pten in the smooth muscle cell lineage by cross-breeding Pten(loxP/loxP) mice with Tagln-cre mice. Mice carrying homozygous deletion of Pten alleles developed widespread smooth muscle cell hyperplasia and abdominal leiomyosarcomas, with a very rapid onset and elevated incidence (similar to 80%) compared to other animal models. Constitutive mTOR activation was restricted to the leiomyosarcomas, revealing the requirement for additional molecular events besides Pten loss. The rapamycin derivative everolimus substantially decelerated tumor growth on Tagln-cre/ Pten(loxP/loxP) mice and prolonged their lifespan. Our data show a new and critical role for the AKT-mTOR pathway in smooth muscle transformation and leiomyosarcoma genesis, and support treatment of selected sarcomas by the targeting of this pathway with new compounds or combinations of these with conventional chemotherapy agents.