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


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

    Article  ADS  CAS  Google Scholar 

  2. Barker, N., van de Wetering, M. & Clevers, H. The intestinal stem cell. Genes Dev. 22, 1856-1864 (2008)

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Cheng, H. & Leblond, C. P. 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)

    Article  CAS  Google Scholar 

  5. Cheng, H. & Leblond, C. P. 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)

    Article  CAS  Google Scholar 

  6. Marshman, E., Booth, C. & Potten, C. S. The intestinal epithelial stem cell. Bioessays 24, 91-98 (2002)

    Article  Google Scholar 

  7. Bjerknes, M. & Cheng, H. 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)

    Article  CAS  Google Scholar 

  8. Bjerknes, M. & Cheng, H. 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)

    Article  CAS  Google Scholar 

  9. Ireland, H., Houghton, C., Howard, L. & Winton, D. J. Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. Dev. Dyn. 233, 1332-1336 (2005)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  11. Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159-170 (1996)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Van der Flier, L. G. et al. The intestinal Wnt/TCF signature. Gastroenterology 132, 628-632 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  19. Sansom, O. J. 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)

    Article  CAS  Google Scholar 

  20. Muncan, V. 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)

    Article  CAS  Google Scholar 

  21. Batlle, E. 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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nature Genet. 40, 915-920 (2008)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983-3988 (2003)

    Article  ADS  CAS  Google Scholar 

  28. O’Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106-110 (2007)

    Article  ADS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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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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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).

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