Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells.
Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells.
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DOI：
10.1158/0008-5472.can-11-3132
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Mulholland DJ;Kobayashi N;Ruscetti M;Zhi A;Tran LM;Huang J;Gleave M;Wu H
PTEN缺失或PI 3 K/AKT信号通路激活与人前列腺癌进展和转移相关。然而，在临床前鼠模型中，单独缺失Pten不能模拟经常伴随人类疾病终末期的显著转移负荷。为了确定在前列腺癌进展中与PTEN丢失合作的其他途径改变，我们调查了人前列腺癌组织微阵列，发现RAS/MAPK途径在原发性和转移性病变中均显著升高。为了对该事件进行建模，我们将条件性可活化K-rasG 12 D/WT小鼠与前列腺条件性Pten缺失模型进行杂交。虽然RAS激活本身不能启动前列腺癌的发展，但它显著加速了由PTEN丢失引起的进展，伴随着上皮向间质转化（EMT）和100%转移率的大转移。一种新的干/祖细胞亚群与间充质的特点是分离的复合突变前列腺，这是高度转移后原位移植。重要的是，通过MEK抑制剂PD 325901抑制RAS/MAPK信号传导，显著降低了从移植的干/祖细胞开始的转移进展。总的来说，我们的研究结果表明，RAS/MAPK信号传导的激活作为对PTEN/PI 3 K/AKT轴改变的增强的第二次打击，并且共靶向两种途径对于预防转移性前列腺癌的发展是非常有效的。
PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated both in primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penetrance. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a MEK inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, our findings indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis and co-targeting both pathways is highly effective gin preventing the development of metastatic prostate cancers.