Letter | Published:

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

Nature volume 457, pages 608611 (29 January 2009) | Download Citation

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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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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.

Author information

Author notes

    • Nick Barker
    •  & Rachel A. Ridgway

    These authors contributed equally to this work.

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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Correspondence to Hans Clevers.

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https://doi.org/10.1038/nature07602

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