Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.
Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.
复制标题
DOI：
10.1038/cddis.2016.268
复制
发表时间：
2016-10-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
尤文肉瘤(ES)是由EWS/FLI1(EF)融合蛋白引起的第二常见的儿童骨癌。为了了解EF的表达如何改变骨前体细胞的分化，ES是如何产生的，以及它可以通过哪些抑制机制被靶向，需要通过基因定义的ES模型来了解。我们在小鼠体内使用间充质PRX1介导的条件性EF表达来研究骨发育，并建立可靠的肉瘤模型。EF的表达抑制了早期软骨细胞和成骨细胞的分化，这是由于信号通路的改变，如Hedgehog、WNT或生长因子信号。表达EF的间充质干细胞(MSCs)具有较强的自我更新能力，尽管细胞凋亡率较高，但仍保持未分化状态。通过在MSCs中强制表达BCL2家族成员来阻断细胞凋亡，促进了移植到免疫低下小鼠的有效和快速的肉瘤形成。机制上，BCL2家族成员和CDK4的高表达，而P53和Ink4a蛋白的低表达在尤文样肉瘤的发生中起协同作用。在功能上，MCL1或CDK4的敲除或它们的联合药物抑制导致已建立的人ES细胞系和EF转化的小鼠MSCs的生长停滞和凋亡。联合靶向生存和细胞周期进展通路可以对抗这种侵袭性的儿童癌症。
Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.
登录
查看更多内容
影响因子：
11.2
作者：
Hauer, Kristina;Calzada-Wack, Julia;Richter, Guenther H. S.
通讯作者：
Richter, Guenther H. S.
影响因子：
11.2
作者：
Baird, K;Davis, S;Meltzer, PS
通讯作者：
Meltzer, PS
影响因子：
7.2
作者：
Long, Fanxin;Ornitz, David M.
通讯作者：
Ornitz, David M.
影响因子：
--
作者：
Hong, Sung-Hyeok;Youbi, Sarah. E.;Toretsky, Jeffrey A.
通讯作者：
Toretsky, Jeffrey A.
影响因子：
5.3
作者：
Miyagawa, Yoshitaka;Okita, Hajime;Kiyokawa, Nobutaka
通讯作者：
Kiyokawa, Nobutaka