Targeting Self-Renewal in High-Grade Brain Tumors Leads to Loss of Brain Tumor Stem Cells and Prolonged Survival
Targeting Self-Renewal in High-Grade Brain Tumors Leads to Loss of Brain Tumor Stem Cells and Prolonged Survival
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DOI：
10.1016/j.stem.2014.04.007
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发表时间：
2014-08-07
期刊：
影响因子：
23.9
通讯作者：
Liu, Hai-Kun
中科院分区：
文献类型：
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作者：
Zhu, Zhe;Khan, Muhammad Amir;Liu, Hai-Kun
肿瘤干细胞（Cancer stem cells, CSCs）被认为是治疗恶性肿瘤的潜在靶点，但体内支持的证据仍然缺乏。利用核受体无尾子（Tlx）启动子驱动的GFP报告基因，我们发现原发性脑肿瘤中的Tlx（+）细胞大多处于静止状态。谱系追踪表明，在原发肿瘤中，单个Tlx（+）细胞可以自我更新并生成Tlx（-）肿瘤细胞，提示其为脑肿瘤干细胞（BTSCs）。在小鼠原发肿瘤中引入btsc特异性敲除Tlx基因后，我们观察到btsc自我更新的丧失和动物存活的延长，伴随着介导细胞周期阻滞、细胞死亡和神经分化的必要信号通路的诱导。我们的研究证明了靶向胶质母细胞瘤的可行性，并表明BTSCs作为治疗靶点的适用性，从而支持了CSC假说。
Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx(+) cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx(+) cells can self-renew and generate Tlx(-) tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis.