Hernando Eva, Charytonowicz Elizabeth, Dudas Maria E, Menendez Silvia, Matushansky Igor, Mills Joslyn, Socci Nicholas D, Behrendt Nille, Ma Li, Maki Robert G, Pandolfi Pier Paolo, Cordon-Cardo Carlos
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nat Med. 2007 Jun;13(6):748-53. doi: 10.1038/nm1560. Epub 2007 May 13.
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 (approximately 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.
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，且下游效应器同时上调。为了确定异常PI3K-AKT信号在平滑肌肉瘤发病机制中的作用，我们通过将Pten(loxP/loxP)小鼠与Tagln-cre小鼠杂交，在平滑肌细胞谱系中使Pten基因失活。携带Pten等位基因纯合缺失的小鼠出现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，发病非常迅速且发病率升高（约80%）。组成型mTOR激活仅限于平滑肌肉瘤，这表明除了Pten缺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了Tagln-cre/Pten(loxP/loxP)小鼠的肿瘤生长并延长了它们的寿命。我们的数据表明AKT-mTOR途径在平滑肌转化和平滑肌肉瘤发生中具有新的关键作用，并支持通过用新化合物靶向该途径或这些化合物与传统化疗药物联合来治疗某些肉瘤。
