Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth.
Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth.
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DOI：
10.1002/stem.188
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发表时间：
2009-10
期刊：
影响因子：
5.2
通讯作者：
Rich, Jeremy N.
中科院分区：
文献类型：
--
作者：
Wang, Hui;Lathia, Justin D.;Wu, Qiulian;Wang, Jialiang;Li, Zhizhong;Heddleston, John M.;Eyler, Christine E.;Elderbroom, Jennifer;Gallagher, Joseph;Schuschu, Jesse;MacSwords, Jennifer;Cao, Yiting;McLendon, Roger E.;Wang, Xiao-Fan;Hjelmeland, Anita B.;Rich, Jeremy N.
胶质母细胞瘤（GBMs）是最常见和最致命的原发性脑肿瘤。最近的研究表明，有限数量的肿瘤细胞（胶质瘤干细胞）在胶质瘤的维持和复发中起着重要作用。我们现在证明，GSCs优先表达白细胞介素6 （IL6）受体白细胞介素6受体α (IL6Rα)和糖蛋白130 （gp130）。利用短发夹rna （short hairpin rna, shRNAs）靶向GSCs中IL6Rα或IL6配体的表达可显著降低生长和神经球形成能力，同时增加细胞凋亡。干扰GSCs中IL6信号会减弱信号转导器和转录3激活因子（STAT3）的激活，而STAT3的小分子抑制剂可能会诱导GSC凋亡。这些数据表明Stat3是GSCs中促存活il - 6信号的下游介质。重要的是，靶向GSCs中IL6Rα或IL6的表达可提高颅内人类胶质瘤移植小鼠的存活率。il - 6在临床上具有重要意义，因为il - 6配体和受体的表达升高与胶质瘤患者的生存率低有关。抗il - 6治疗的潜在效用是通过il - 6抗体治疗的皮下人GSC来源的异种移植物生长减少来证明的。总之，我们的数据表明，IL6信号通过促进GSC的生长和存活来促进胶质瘤恶性肿瘤，并且靶向IL6可能为胶质瘤患者提供益处。
Glioblastomas (GBMs) are the most common and lethal primary brain tumor. Recent studies implicate an important role for a restricted population of neoplastic cells (glioma stem cells; GSCs) in glioma maintenance and recurrence. We now demonstrate that GSCs preferentially express the interleukin 6 (IL6) receptors interleukin 6 receptor alpha (IL6Rα) and glycoprotein 130 (gp130). Targeting IL6Rα or IL6 ligand expression in GSCs utilizing short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription 3 (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis. These data indicate that Stat3 is a downstream mediator of pro-survival IL6 signals in GSCs. Importantly, targeting IL6Rα or IL6 expression in GSCs increases the survival of mice bearing intracranial human glioma xenografts. IL6 is clinically significant as elevated IL6 ligand and receptor expression are associated with poor glioma patient survival. The potential utility of anti-IL6 therapies is demonstrated by decreased growth of subcutaneous human GSC derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for glioma patients.
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影响因子：
11.4
作者：
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