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Crypt stem cells as the cells-of-origin of intestinal cancer

Nature volume 457, pages 608–611 (2009)Cite this article

Abstract

Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells1. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5+ cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.

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Figure 1: Transformation of non-stem cell populations in Ah-cre/Apc flox/flox intestines through low-dose oral β-NF-induced Apc deletion fails to drive intestinal neoplasia.
Figure 2: Lgr5-EGFP + intestinal stem cells transformed after loss of Apc persist and fuel the rapid formation of β-catenin high microadenomas.
Figure 3: Selective transformation of Lgr5-EGFP + stem cells after loss of Apc efficiently drives adenoma formation throughout the small intestine.
Figure 4: Transformation of Lgr5-EGFP + stem cells drives intestinal neoplasia in both the small intestine and colon.

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Acknowledgements

We thank M. Cozijnsen, J. Korving, C. Nixon, M. Macdonald and B. Doyle for technical help. O.J.S. is funded by Cancer Research UK. N.B. and H.C. are supported by KWF program grant PF-HUBR-2007-3956.

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Author notes

  1. Nick Barker and Rachel A. Ridgway: These authors contributed equally to this work.

Authors and Affiliations

  1. Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht & University Medical Centre Utrecht, Netherlands

    Nick Barker, Johan H. van Es, Marc van de Wetering, Harry Begthel, Maaike van den Born, Esther Danenberg & Hans Clevers

  2. Beatson Institute for Cancer Research, Glasgow G61 1BD, UK

    Rachel A. Ridgway & Owen J. Sansom

  3. Cardiff School of Biosciences, Cardiff CF10 3US, UK

    Alan R. Clarke

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  1. Nick Barker
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Correspondence to Hans Clevers.

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Barker, N., Ridgway, R., van Es, J. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009). https://doi.org/10.1038/nature07602

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