Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga, Japan.
Nature. 2017 May 11;545(7653):187-192. doi: 10.1038/nature22081. Epub 2017 Mar 29.
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.
癌症干细胞（CSC）理论强调了肿瘤生长所依赖的自我更新的癌细胞亚群。人类 CSC 的存在主要得到了前瞻性分离细胞的异种移植的支持，但它们的克隆动力学和可塑性仍不清楚。在这里，我们表明人 LGR5 结直肠癌细胞在生长的肿瘤组织中充当 CSC。使用 tamoxifen 诱导型 Cre 敲入 LGR5 的谱系追踪实验揭示了 LGR5 肿瘤细胞的自我更新和分化能力。在 LGR5-iCaspase9 敲入类器官中选择性消融 LGR5 CSC 会导致肿瘤消退，随后由重新出现的 LGR5 CSC 驱动肿瘤重新生长。KRT20 敲入报告标记不断减少的分化癌细胞在肿瘤组织中，而在 LGR5 CSC 消融后恢复为 LGR5 CSC 并有助于肿瘤重新生长。我们还表明，联合化疗增强了对 LGR5 CSC 的靶向作用。这些数据为 CSC 的可塑性及其作为人类结直肠癌治疗靶点的潜力提供了深入了解。
