Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Wnt signalling in stem cells and cancer

Abstract

The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The canonical Wnt signalling pathway.
Figure 2: Tissue anatomy of the adult small intestine.
Figure 3: Tissue anatomy of the colonic epithelium.
Figure 4: The hair follicle.
Figure 5: Proposed model of HSC development in the niche.
Figure 6: Normal Wnt signalling influences the proliferation and renewal of stem cells (dark blue) or progenitors (light blue) during development of a variety of tissues.

References

  1. Rijsewijk, F. et al. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 50, 649–657 (1987)

    CAS  PubMed  Article  Google Scholar 

  2. Veeman, M. T., Axelrod, J. D. & Moon, R. T. A second canon. Functions and mechanisms of β-catenin-independent Wnt signaling. Dev. Cell 5, 367–377 (2003)

    CAS  PubMed  Article  Google Scholar 

  3. Eastman, Q. & Grosschedl, R. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr. Opin. Cell Biol. 11, 233–240 (1999)

    CAS  PubMed  Article  Google Scholar 

  4. Giles, R. H., van Es, J. H. & Clevers, H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim. Biophys. Acta 1653, 1–24 (2003)

    CAS  PubMed  Google Scholar 

  5. Porter, E. M., Bevins, C. L., Ghosh, D. & Ganz, T. The multifaceted Paneth cell. Cell. Mol. Life Sci. 59, 156–170 (2002)

    CAS  PubMed  Article  Google Scholar 

  6. Heath, J. P. Epithelial cell migration in the intestine. Cell Biol. Int. 20, 139–146 (1996)

    CAS  PubMed  Article  Google Scholar 

  7. Potten, C. S. Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Phil. Trans. R. Soc. Lond. B 353, 821–830 (1998)

    CAS  Article  Google Scholar 

  8. Potten, C. S., Owen, G. & Booth, D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115, 2381–2388 (2002)

    CAS  PubMed  Article  Google Scholar 

  9. Bjerknes, M. & Cheng, H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 116, 7–14 (1999)

    CAS  PubMed  Article  Google Scholar 

  10. Schmidt, G. H., Winton, D. J. & Ponder, B. A. Development of the pattern of cell renewal in the crypt-villus unit of chimaeric mouse small intestine. Development 103, 785–790 (1988)

    CAS  PubMed  Article  Google Scholar 

  11. Booth, C. & Potten, C. S. Gut instincts: thoughts on intestinal epithelial stem cells. J. Clin. Invest. 105, 1493–1499 (2000)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Roth, K. A., Hermiston, M. L. & Gordon, J. I. Use of transgenic mice to infer the biological properties of small intestinal stem cells and to examine the lineage relationships of their descendants. Proc. Natl Acad. Sci. USA 88, 9407–9411 (1991)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 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)

    CAS  PubMed  Article  Google Scholar 

  14. Korinek, V. et al. Depletion of epithelia stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 1–5 (1998)

    Article  CAS  Google Scholar 

  15. Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Kuhnert, F. et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl Acad. Sci. USA 101, 266–271 (2004)

    ADS  CAS  PubMed  Article  Google Scholar 

  17. 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)

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  19. Rubinfeld, B. et al. Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science 272, 1023–1026 (1996)

    ADS  CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  21. Liu, W. et al. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating β-catenin/TCF signalling. Nature Genet. 26, 146–147 (2000)

    CAS  PubMed  Article  Google Scholar 

  22. 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)

    CAS  PubMed  Article  Google Scholar 

  23. He, T. C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998)

    ADS  CAS  PubMed  Article  Google Scholar 

  24. Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999)

    ADS  CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Niemann, C. & Watt, F. M. Designer skin: lineage commitment in postnatal epidermis. Trends Cell Biol. 12, 185–192 (2002)

    CAS  PubMed  Article  Google Scholar 

  27. van Genderen, C. et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1 deficient mice. Genes Dev. 8, 2691–2703 (1994)

    CAS  PubMed  Article  Google Scholar 

  28. Zhou, P., Byrne, C., Jacobs, J. & Fuchs, E. Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. Genes Dev. 9, 700–713 (1995)

    CAS  PubMed  Article  Google Scholar 

  29. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95, 605–614 (1998)

    CAS  PubMed  Article  Google Scholar 

  30. Lo Celso, C., Prowse, D. M. & Watt, F. M. Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 131, 1787–1799 (2004)

    CAS  PubMed  Article  Google Scholar 

  31. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001)

    CAS  PubMed  Article  Google Scholar 

  32. DasGupta, R. & Fuchs, E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557–4568 (1999)

    CAS  PubMed  Article  Google Scholar 

  33. Niemann, C., Owens, D. M., Hulsken, J., Birchmeier, W. & Watt, F. M. Expression of ΔNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours. Development 129, 95–109 (2002)

    CAS  PubMed  Article  Google Scholar 

  34. Braun, K. M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003)

    CAS  PubMed  Article  Google Scholar 

  35. Merrill, B. J., Gat, U., DasGupta, R. & Fuchs, E. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev. 15, 1688–1705 (2001)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Chan, E. F., Gat, U., McNiff, J. M. & Fuchs, E. A common human skin tumour is caused by activating mutations in β-catenin. Nature Genet. 21, 410–413 (1999)

    CAS  PubMed  Article  Google Scholar 

  37. Till, J. & McCulloch, E. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213–222 (1961)

    ADS  CAS  PubMed  Article  Google Scholar 

  38. Becker, A. J., McCulloch, E. A. & Till, J. E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197, 452–454 (1963)

    ADS  CAS  PubMed  Article  Google Scholar 

  39. Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287, 1442–1446 (2000)

    ADS  CAS  PubMed  Article  Google Scholar 

  40. Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001)

    ADS  CAS  PubMed  Article  Google Scholar 

  41. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001)

    ADS  CAS  PubMed  Article  Google Scholar 

  42. Varnum-Finney, B. et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nature Med. 6, 1278–1281 (2000)

    CAS  PubMed  Article  Google Scholar 

  43. Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol. 2, 172–180 (2001)

    CAS  Article  Google Scholar 

  44. Rattis, F. M., Voermans, C. & Reya, T. Wnt signaling in the stem cell niche. Curr. Opin. Hematol. 11, 88–94 (2004)

    CAS  PubMed  Article  Google Scholar 

  45. Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003)

    ADS  CAS  PubMed  Article  Google Scholar 

  46. Austin, T. W., Solar, G. P., Ziegler, F. C., Liem, L. & Matthews, W. A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells. Blood 89, 3624–3635 (1997)

    CAS  PubMed  Article  Google Scholar 

  47. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003)

    ADS  CAS  PubMed  Article  Google Scholar 

  48. Van Den Berg, D. J., Sharma, A. K., Bruno, E. & Hoffman, R. Role of members of the Wnt gene family in human hematopoiesis. Blood 92, 3189–3202 (1998)

    CAS  PubMed  Article  Google Scholar 

  49. Murdoch, B. et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc. Natl Acad. Sci. USA 100, 3422–3427 (2003)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Cobas, M et al. β-Catenin is dispensable for hematopoiesis and lymphopoiesis. J. Exp. Med. 199, 221–229 (2004)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Xu, Y., Banerjee, D., Huelsken, J., Birchmeier, W. & Sen, J. M. Deletion of β-catenin impairs T cell development. Nature Immunol. 4, 1177–1182 (2003)

    CAS  Article  Google Scholar 

  52. Reya, T. et al. Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Immunity 13, 15–24 (2000)

    CAS  PubMed  Article  Google Scholar 

  53. Ranheim, E., Kwan, H., Reya, T., Weissman, I. L. & Francke, U. Frizzled 9 knockout mice have abnormal B cell development. Blood ahead of print publication, 30 November 2004 (doi:10.1182/blood-2004-06-2334).

  54. van de Wetering, M., de Lau, W. & Clevers, H. WNT signaling and lymphocyte development. Cell 109 (suppl.), S13–S19 (2002)

    CAS  PubMed  Article  Google Scholar 

  55. Cowin, P., Kapprell, H. P. & Franke, W. W. The complement of desmosomal plaque proteins in different cell types. J. Cell Biol. 101, 1442–1454 (1985)

    CAS  PubMed  Article  Google Scholar 

  56. Zheng, X. et al. γ-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells. Blood 103, 3535–3543 (2004)

    CAS  PubMed  Article  Google Scholar 

  57. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    ADS  CAS  PubMed  Article  Google Scholar 

  58. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    ADS  CAS  PubMed  Article  Google Scholar 

  59. Hackney, J. A. et al. A molecular profile of a hematopoietic stem cell niche. Proc. Natl Acad. Sci. USA 99, 13061–13066 (2002)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Jamieson, C. H. et al. Granulocyte/macrophage progenitors in chronic myelogenous leukemia are candidate leukemia stem cells that activate the β-catenin pathway. N. Engl. J. Med. 351, 657–667 (2004)

    CAS  PubMed  Article  Google Scholar 

  61. Muller-Tidow, C. et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol. Cell. Biol. 24, 2890–2904 (2004)

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. McWhirter, J. R. et al. Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia. Proc. Natl Acad. Sci. USA 96, 11464–11469 (1999)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Derksen, P. W. et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc. Natl Acad. Sci. USA 101, 6122–6127 (2004)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Watkins, D. N. et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003)

    ADS  CAS  PubMed  Article  Google Scholar 

  65. Liang, H. et al. Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4, 349–360 (2003)

    CAS  PubMed  Article  Google Scholar 

  66. Smit, L. et al. Wnt activates the Tak1/Nemo-like kinase pathway. J. Biol. Chem. 279, 17232–17240 (2004)

    CAS  PubMed  Article  Google Scholar 

  67. Chenn, A. & Walsh, C. A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002)

    ADS  CAS  PubMed  Article  Google Scholar 

  68. Zechner, D. et al. β-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev. Biol. 258, 406–418 (2003)

    CAS  PubMed  Article  Google Scholar 

  69. Zurawel, R. H., Chiappa, S. A., Allen, C. & Raffel, C. Sporadic medulloblastomas contain oncogenic β-catenin mutations. Cancer Res. 58, 896–899 (1998)

    CAS  PubMed  Google Scholar 

  70. Dahmen, R. P. et al. Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res. 61, 7039–7043 (2001)

    CAS  PubMed  Google Scholar 

  71. Baeza, N., Masuoka, J., Kleihues, P. & Ohgaki, H. AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene 22, 632–636 (2003)

    CAS  PubMed  Article  Google Scholar 

  72. Liu, B. Y., McDermott, S. P., Khwaja, S. S. & Alexander, C. M. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc. Natl Acad. Sci. USA 101, 4158–4163 (2004)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Li, Y. et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl Acad. Sci. USA 100, 15853–15858 (2003)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Med. 10, 55–63 (2004)

    CAS  PubMed  Article  Google Scholar 

  75. Kielman, M. F. et al. Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling. Nature Genet. 32, 594–605 (2002)

    CAS  PubMed  Article  Google Scholar 

  76. Duncan, A. W. et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nature Immunol. 6(3), 314–322 (2005)

    CAS  Article  Google Scholar 

  77. Galceran, J., Sustmann, C., Hsu, S. C., Folberth, S. & Grosschedl, R. LEF1-mediated regulation of Delta-like1 links Wnt and Notch signaling in somitogenesis. Genes Dev. 18, 2718–2723 (2004)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-β-catenin signalling. Nature Genet. 36, 1117–1121 (2004)

    MathSciNet  CAS  PubMed  Article  Google Scholar 

  79. Viti, J., Gulacsi, A. & Lillien, L. Wnt regulation of progenitor maturation in the cortex depends on Shh or fibroblast growth factor 2. J. Neurosci. 23, 5919–5927 (2003)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Lee, H. Y. et al. Instructive role of Wnt/β-catenin in sensory fate specification in neural crest stem cells. Science 303, 1020–1023 (2004)

    ADS  CAS  PubMed  Article  Google Scholar 

  81. Muroyama, Y., Kondoh, H. & Takada, S. Wnt proteins promote neuronal differentiation in neural stem cell culture. Biochem. Biophys. Res. Commun. 313, 915–921 (2004)

    CAS  PubMed  Article  Google Scholar 

  82. Brandon, C., Eisenberg, L. M. & Eisenberg, C. A. WNT signaling modulates the diversification of hematopoietic cells. Blood 96, 4132–4141 (2000)

    CAS  PubMed  Article  Google Scholar 

  83. Zhu, A. J. & Watt, F. M. β-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion. Development 126, 2285–2298 (1999)

    CAS  PubMed  Article  Google Scholar 

  84. Verbeek, S. et al. An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374, 70–74 (1995)

    ADS  CAS  PubMed  Article  Google Scholar 

  85. Okamura, R. M., Sigvardsson, M., Verbeek, S., Clevers, H. & Grosschedl, R. Redundant regulation of T cell differentiation and TCRα gene expression by the transcription factors LEF-1 and TCF-1. Immunity 8, 11–20 (1998)

    CAS  PubMed  Article  Google Scholar 

  86. Mulroy, T., McMahon, J. A., Burakoff, S. J., McMahon, A. P. & Sen, J. Wnt-1 and Wnt-4 regulate thymic cellularity. Eur. J. Immunol. 32, 967–971 (2002)

    CAS  PubMed  Article  Google Scholar 

  87. Hsu, W., Shakya, R. & Costantini, F. Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice. J. Cell Biol. 155, 1055–1064 (2001)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Yamane, T. et al. Wnt signaling regulates hemopoiesis through stromal cells. J. Immunol. 167, 765–772 (2001)

    CAS  PubMed  Article  Google Scholar 

  89. Sancho, E., Batlle, E. & Clevers, H. Signaling pathways in intestinal development and cancer. Annu. Rev. Cell Dev. Biol. 20, 695–723 (2004)

    CAS  PubMed  Article  Google Scholar 

  90. Turksen, K. Revisiting the bulge. Dev Cell. 6, 454–456 (2004)

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank F. Watt and I. Weissman for comments and suggestions, and F. Rattis for help with figures. T.R. is supported by an NIH grant and investigator awards from the Cancer Research Foundation and Ellison Medical Foundation. H.C. is supported by the Center for Biomedical Genetics, Cancer Genomics Consortium, SPINOZA, the Louis Jeantet-Foundation and the Dutch Cancer Foundation KWF.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Tannishtha Reya or Hans Clevers.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Reya, T., Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005). https://doi.org/10.1038/nature03319

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03319

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing