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Mechanisms of Disease: from stem cells to colorectal cancer

Nature Clinical Practice Gastroenterology & Hepatology volume 3, pages 267–274 (2006)Cite this article

Abstract

Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of β-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer. A paradigm of abnormal stem cell biology is illustrated by patients with familial adenomatous polyposis, who have mutations in the adenomatous polyposis coli gene. The wild-type protein encoded by this gene is important for the prevention of mass β-catenin accumulation in the nucleus and the subsequent overtranscription of cell cycle proteins. This review discusses the basic mechanisms behind stem cell regulation in the gut and follows their role in the natural history of tumor progression.

Key Points

  • Stem cells are the origin of all intestinal epithelial cells

  • Stem cells are regulated by many intrinsic and extrinsic factors, including the WNT/β-catenin signaling pathway

  • Stem cells have various means of protecting themselves from acquiring DNA mutations but under certain hostile environments produce dysplasia and cancer

  • The cancer stem cell is the key target for many novel therapies

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Figure 1: Schematic of the small intestinal and colonic crypts.
Figure 2: The Wnt signaling pathway.
Figure 3: An adaptation of the Vogelstein adenoma:carcinoma sequence.
Figure 4: A schematic of the 'top-down' and 'bottom-up' models of adenoma histogenesis in the colonic crypt.
Figure 5: Illustration of Cairns' 'immortal strand' hypothesis.

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References

  1. Mayhall EA et al. (2004) The clinical potential of stem cells. Curr Opin Cell Biol 16: 713–720

    Article  CAS  Google Scholar 

  2. Lanza RP (2004) Handbook of Stem Cells: Adult and Fetal Stem Cells. Burlington: Elsevier Academic Press

    Google Scholar 

  3. Cheng H and Leblond CP (1974) Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells. Am J Anat 141: 503–519

    Article  CAS  Google Scholar 

  4. Cheng H and Leblond CP (1974) 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

    Article  CAS  Google Scholar 

  5. Cheng H and Leblond CP (1974) 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

    Article  CAS  Google Scholar 

  6. Niemann C and Watt FM (2002) Designer skin: lineage commitment in postnatal epidermis. Trends Cell Biol 12: 185–192

    Article  CAS  Google Scholar 

  7. Potten CS et al. (1997) The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 78: 219–243

    Article  CAS  Google Scholar 

  8. Ouellette AJ et al. (2000) Characterization of luminal paneth cell α-defensins in mouse small intestine. Attenuated antimicrobial activities of peptides with truncated amino termini. J Biol Chem 275: 33969–33973

    Article  CAS  Google Scholar 

  9. Wright NA and Alison MR (1984) The Biology of Epithelial Cell Populations. Oxford: Clarendon Press

    Google Scholar 

  10. Kirkland SC (1988) Clonal origin of columnar, mucous, and endocrine cell lineages in human colorectal epithelium. Cancer 61: 1359–1363

    Article  CAS  Google Scholar 

  11. Spradling A et al. (2001) Stem cells find their niche. Nature 414: 98–104

    Article  CAS  Google Scholar 

  12. Leedham SJ et al. (2005) Intestinal stem cells. J Cell Mol Med 9: 11–24

    Article  CAS  Google Scholar 

  13. Reya T and Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434: 843–850

    Article  CAS  Google Scholar 

  14. Mao B et al. (2001) LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411: 321–325

    Article  CAS  Google Scholar 

  15. Kohn AD and Moon RT (2005) Wnt and calcium signaling: β-catenin-independent pathways. Cell Calcium 38: 439–446

    Article  CAS  Google Scholar 

  16. He TC et al. (1998) Identification of c-MYC as a target of the APC pathway. Science 281: 1509–1512

    Article  CAS  Google Scholar 

  17. Korinek V et al. (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19: 379–383

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Pinto D et al. (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17: 1709–1713

    Article  CAS  Google Scholar 

  20. Gregorieff A et al. (2005) Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129: 626–638

    Article  CAS  Google Scholar 

  21. Radtke F and Clevers H (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307: 1904–1909

    Article  CAS  Google Scholar 

  22. Wright NA and Alison M (1984) The biology of epithelial cell populations. Oxford: Oxford University Press

    Google Scholar 

  23. Pinto D and Clevers H (2005) Wnt, stem cells and cancer in the intestine. Biol Cell 97: 185–196

    Article  CAS  Google Scholar 

  24. Bhatia M et al. (1997) Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci USA 94: 5320–5325

    Article  CAS  Google Scholar 

  25. Al-Hajj M et al. (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100: 3983–3988

    Article  CAS  Google Scholar 

  26. Hamburger AW and Salmon SE (1977) Primary bioassay of human tumor stem cells. Science 197: 461–463

    Article  CAS  Google Scholar 

  27. Clarke RB (2005) Isolation and characterization of human mammary stem cells. Cell Prolif 38: 375–386

    Article  CAS  Google Scholar 

  28. Galderisi U et al. (2006) Stem cells and brain cancer. Cell Death Differ 13: 5–11

    Article  CAS  Google Scholar 

  29. Vogelstein B et al. (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319: 525–532

    Article  CAS  Google Scholar 

  30. Preston SL et al. (2003) Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Res 63: 3819–3825

    CAS  PubMed  Google Scholar 

  31. Shih IM et al. (2001) Top-down morphogenesis of colorectal tumors. Proc Natl Acad Sci USA 98: 2640–2645

    Article  CAS  Google Scholar 

  32. Kim KM and Shibata D (2002) Methylation reveals a niche: stem cell succession in human colon crypts. Oncogene 21: 5441–5449

    Article  CAS  Google Scholar 

  33. Novelli MR et al. (1996) Polyclonal origin of colonic adenomas in an XO/XY patient with FAP. Science 272: 1187–1190

    Article  CAS  Google Scholar 

  34. Maskens AP and Dujardin-Loits RM (1981) Kinetics of tissue proliferation in colorectal mucosa during post-natal growth. Cell Tissue Kinet 14: 467–477

    CAS  PubMed  Google Scholar 

  35. Cairnie AB and Millen BH (1975) Fission of crypts in the small intestine of the irradiated mouse. Cell Tissue Kinet 8: 189–196

    CAS  PubMed  Google Scholar 

  36. Wright NA and Al-Nafussi A (1982) The kinetics of villus cell populations in the mouse small intestine. II. Studies on growth control after death of proliferative cells induced by cytosine arabinoside, with special reference to negative feedback mechanisms. Cell Tissue Kinet 15: 611–621

    CAS  PubMed  Google Scholar 

  37. Park HS et al. (1995) Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens. Am J Pathol 147: 1416–1427

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Fearon ER et al. (1987) Clonal analysis of human colorectal tumors. Science 238: 193–197

    Article  CAS  Google Scholar 

  39. Bjerknes M et al. (1997) Clonality of dysplastic epithelium in colorectal adenomas from familial adenomatous polyposis patients. Cancer Res 57: 355–361

    CAS  PubMed  Google Scholar 

  40. Yatabe Y et al. (2001) Investigating stem cells in human colon by using methylation patterns. Proc Natl Acad Sci USA 98: 10839–10844

    Article  CAS  Google Scholar 

  41. Novelli M et al. (2003) X-inactivation patch size in human female tissue confounds the assessment of tumor clonality. Proc Natl Acad Sci USA 100: 3311–3314

    Article  CAS  Google Scholar 

  42. Potten CS et al. (1985) Cell kinetic studies in the epidermis of mouse. III. The percent labelled mitosis (PLM) technique. Cell Tissue Kinet 18: 59–70

    CAS  PubMed  Google Scholar 

  43. Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255: 197–200

    Article  CAS  Google Scholar 

  44. Potten CS et al. (2002) Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 115: 2381–2388

    CAS  PubMed  Google Scholar 

  45. Nakamura M et al. (1994) Musashi, a neural RNA-binding protein required for Drosophila adult external sensory organ development. Neuron 13: 67–81

    Article  CAS  Google Scholar 

  46. Kayahara T et al. (2003) Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine. FEBS Lett 535: 131–135

    Article  CAS  Google Scholar 

  47. Nishimura S et al. (2003) Expression of Musashi-1 in human normal colon crypt cells: a possible stem cell marker of human colon epithelium. Dig Dis Sci 48: 1523–1529

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors receive funding from Cancer Research UK, University Hospitals Leicester National Health Service, CORE, and Barts and the London School of Medicine and Dentistry.

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Authors and Affiliations

  1. Histopathology Unit at the London Research Institute, Cancer Research UK, London, UK

    Stuart AC McDonald, Sean L Preston, Matthew J Lovell, Nicholas A Wright & Janusz AZ Jankowski

  2. affiliated to the Digestive Diseases Centre, University Hospitals Leicester, Leicester, UK

    Stuart AC McDonald & Janusz AZ Jankowski

  3. Centre of Gastroenterology,

    Sean L Preston, Matthew J Lovell & Nicholas A Wright

  4. Department of Clinical Pharmacology,

    Sean L Preston, Matthew J Lovell & Nicholas A Wright

  5. Department of Histopathology at Barts and the London School of Medicine, Queen Mary, University of London, London

    Sean L Preston, Matthew J Lovell & Nicholas A Wright

  6. also affiliated to the Department of Clinical Pharmacology at the University of Oxford, Oxford, UK

    Janusz AZ Jankowski

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Correspondence to Stuart AC McDonald.

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McDonald, S., Preston, S., Lovell, M. et al. Mechanisms of Disease: from stem cells to colorectal cancer. Nat Rev Gastroenterol Hepatol 3, 267–274 (2006). https://doi.org/10.1038/ncpgasthep0473

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  • DOI: https://doi.org/10.1038/ncpgasthep0473

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