Visualization and targeting of LGR5+ human colon cancer stem cells

Mariko Shimokawa, Yuki Ohta, Shingo Nishikori, Mami Matano, Ai Takano, Masayuki Fujii, Shoichi Date, Shinya Sugimoto, Takanori Kanai and Toshiro Sato ()
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Mariko Shimokawa: Keio University School of Medicine
Yuki Ohta: Keio University School of Medicine
Shingo Nishikori: Keio University School of Medicine
Mami Matano: Keio University School of Medicine
Ai Takano: Keio University School of Medicine
Masayuki Fujii: Keio University School of Medicine
Shoichi Date: Keio University School of Medicine
Shinya Sugimoto: Keio University School of Medicine
Takanori Kanai: Keio University School of Medicine
Toshiro Sato: Keio University School of Medicine

Nature, 2017, vol. 545, issue 7653, 187-192

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/nature22081

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