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, Toshiro Sato

Research output: Contribution to journalArticle

135 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)187-192
Number of pages6
JournalNature
Volume545
Issue number7653
DOIs
Publication statusPublished - 2017 May 11

Fingerprint

Neoplastic Stem Cells
Colonic Neoplasms
Neoplasms
Colorectal Neoplasms
Organoids
Heterologous Transplantation
Tamoxifen
Alleles
Drug Therapy

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Shimokawa, M., Ohta, Y., Nishikori, S., Matano, M., Takano, A., Fujii, M., ... Sato, T. (2017). Visualization and targeting of LGR5 + human colon cancer stem cells. Nature, 545(7653), 187-192. https://doi.org/10.1038/nature22081

Visualization and targeting of LGR5 + human colon cancer stem cells. / Shimokawa, Mariko; Ohta, Yuki; Nishikori, Shingo; Matano, Mami; Takano, Ai; Fujii, Masayuki; Date, Shoichi; Sugimoto, Shinya; Kanai, Takanori; Sato, Toshiro.

In: Nature, Vol. 545, No. 7653, 11.05.2017, p. 187-192.

Research output: Contribution to journalArticle

Shimokawa, M, Ohta, Y, Nishikori, S, Matano, M, Takano, A, Fujii, M, Date, S, Sugimoto, S, Kanai, T & Sato, T 2017, 'Visualization and targeting of LGR5 + human colon cancer stem cells', Nature, vol. 545, no. 7653, pp. 187-192. https://doi.org/10.1038/nature22081
Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M et al. Visualization and targeting of LGR5 + human colon cancer stem cells. Nature. 2017 May 11;545(7653):187-192. https://doi.org/10.1038/nature22081
Shimokawa, Mariko ; Ohta, Yuki ; Nishikori, Shingo ; Matano, Mami ; Takano, Ai ; Fujii, Masayuki ; Date, Shoichi ; Sugimoto, Shinya ; Kanai, Takanori ; Sato, Toshiro. / Visualization and targeting of LGR5 + human colon cancer stem cells. In: Nature. 2017 ; Vol. 545, No. 7653. pp. 187-192.
@article{8dea641f5c434ffda9023fa49054a672,
title = "Visualization and targeting of LGR5 + human colon cancer stem cells",
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.",
author = "Mariko Shimokawa and Yuki Ohta and Shingo Nishikori and Mami Matano and Ai Takano and Masayuki Fujii and Shoichi Date and Shinya Sugimoto and Takanori Kanai and Toshiro Sato",
year = "2017",
month = "5",
day = "11",
doi = "10.1038/nature22081",
language = "English",
volume = "545",
pages = "187--192",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "7653",

}

TY - JOUR

T1 - Visualization and targeting of LGR5 + human colon cancer stem cells

AU - Shimokawa, Mariko

AU - Ohta, Yuki

AU - Nishikori, Shingo

AU - Matano, Mami

AU - Takano, Ai

AU - Fujii, Masayuki

AU - Date, Shoichi

AU - Sugimoto, Shinya

AU - Kanai, Takanori

AU - Sato, Toshiro

PY - 2017/5/11

Y1 - 2017/5/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85019245514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019245514&partnerID=8YFLogxK

U2 - 10.1038/nature22081

DO - 10.1038/nature22081

M3 - Article

VL - 545

SP - 187

EP - 192

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 7653

ER -