Letter | Published:

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

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



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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  1. 1.

    et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003-1007 (2007)

  2. 2.

    , & The intestinal stem cell. Genes Dev. 22, 1856-1864 (2008)

  3. 3.

    Kinetics and possible regulation of crypt cell populations under normal and stress conditions. Bull. Cancer 62, 419-430 (1975)

  4. 4.

    & Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am. J. Anat. 141, 537-561 (1974)

  5. 5.

    & Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. Am. J. Anat. 141, 461-479 (1974)

  6. 6.

    , & The intestinal epithelial stem cell. Bioessays 24, 91-98 (2002)

  7. 7.

    & The stem-cell zone of the small intestinal epithelium. II. Evidence from paneth cells in the newborn mouse. Am. J. Anat. 160, 65-75 (1981)

  8. 8.

    & The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. Am. J. Anat. 160, 51-63 (1981)

  9. 9.

    , , & Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. Dev. Dyn. 233, 1332-1336 (2005)

  10. 10.

    et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA 105, 4283-4288 (2008)

  11. 11.

    & Lessons from hereditary colorectal cancer. Cell 87, 159-170 (1996)

  12. 12.

    et al. Constitutive transcriptional activation by a β-catenin-Tcf complex in APC-/- colon carcinoma. Science 275, 1784-1787 (1997)

  13. 13.

    et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787-1790 (1997)

  14. 14.

    et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241-250 (2002)

  15. 15.

    et al. The intestinal Wnt/TCF signature. Gastroenterology 132, 628-632 (2007)

  16. 16.

    et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 18, 1385-1390 (2004)

  17. 17.

    et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 278, 120-123 (1997)

  18. 18.

    et al. Myc deletion rescues Apc deficiency in the small intestine. Nature 446, 676-679 (2007)

  19. 19.

    et al. Cyclin D1 is not an immediate target of β-catenin following Apc loss in the intestine. J. Biol. Chem. 280, 28463-28467 (2005)

  20. 20.

    et al. Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol. Cell. Biol. 26, 8418-8426 (2006)

  21. 21.

    et al. β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111, 251-263 (2002)

  22. 22.

    et al. EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nature Genet. 39, 1376-1383 (2007)

  23. 23.

    & Bmi1 is expressed in vivo in intestinal stem cells. Nature Genet. 40, 915-920 (2008)

  24. 24.

    et al. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO J. 18, 5931-5942 (1999)

  25. 25.

    & Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730-737 (1997)

  26. 26.

    et al. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339-9344 (2006)

  27. 27.

    , , , & Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983-3988 (2003)

  28. 28.

    , , & A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106-110 (2007)

  29. 29.

    et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111-115 (2007)

  30. 30.

    et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158-10163 (2007)

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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

    • Nick Barker
    •  & Rachel A. Ridgway

    These authors contributed equally to this work.


  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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