Visualization and targeting of LGR5+ human colon cancer stem cells
Visualization and targeting of LGR5+ human colon cancer stem cells
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DOI：
10.1038/nature22081
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发表时间：
2017-05-11
期刊：
影响因子：
64.8
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
--
作者：
Shimokawa, Mariko;Ohta, Yuki;Sato, Toshiro
癌症干细胞（CSC）理论强调了一种自我更新的癌细胞亚群，它促进了肿瘤的生长。人类CSCs的存在主要是由异种移植的前瞻性分离的细胞支持，但其克隆动力学和可塑性仍不清楚。在这里，我们表明人LGR 5（+）结直肠癌细胞在生长的癌组织中充当CSC。用他莫昔芬诱导的Cre基因敲入LGR 5等位基因的谱系追踪实验揭示了LGR 5（+）肿瘤细胞的自我更新和分化能力。LGR 5-iCaspase 9敲入类器官中LGR 5（+）CSC的选择性消融导致肿瘤消退，随后由重新出现的LGR 5（+）CSC驱动肿瘤再生长。KRT 20敲入报告基因标记在肿瘤组织中不断减少的分化癌细胞，同时恢复为LGR 5（+）CSC并有助于LGR 5（+）CSC消融后的肿瘤再生长。我们还表明，联合化疗增强了LGR 5（+）CSC的靶向作用。这些数据提供了对CSC可塑性及其作为人类结直肠癌治疗靶点的潜力的见解。
The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5(+) colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5(+) tumour cells. Selective ablation of LGR5(+) CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5(+) CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5(+) CSCs and contributing to tumour regrowth after LGR5(+) CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5(+) CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.