Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Neurooncology, University Clinic Heidelberg and German Cancer Consortium (DKTK), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Cell Stem Cell. 2014 Aug 7;15(2):185-98. doi: 10.1016/j.stem.2014.04.007. Epub 2014 May 15.
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.
癌症干细胞（CSCs）被认为是治疗恶性肿瘤的潜在治疗靶点，但体内支持证据仍然缺乏。使用由核受体无尾（Tlx）启动子驱动的 GFP 报告基因，我们证明原发性脑肿瘤中的 Tlx(+)细胞大多处于静止状态。谱系追踪表明，单个 Tlx(+)细胞可以自我更新，并在原发性肿瘤中产生 Tlx(-)肿瘤细胞，提示它们是脑肿瘤干细胞（BTSCs）。在初级小鼠肿瘤中引入 BTSC 特异性 Tlx 基因敲除后，我们观察到 BTSC 的自我更新丧失和动物存活时间延长，同时诱导了介导细胞周期停滞、细胞死亡和神经分化的必需信号通路。我们的研究证明了针对神经胶质瘤的靶向治疗的可行性，并表明 BTSCs 适合作为治疗靶点，从而支持 CSC 假说。
