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.

Cells of origin in cancer

Abstract

Both solid tumours and leukaemias show considerable histological and functional heterogeneity. It is widely accepted that genetic lesions have a major role in determining tumour phenotype, but evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin'. These cells acquire the first genetic hit or hits that culminate in the initiation of cancer. The identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour, and ultimately may lead to preventive therapies for individuals at high risk of developing cancer.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The cell of origin and evolution of a cancer stem cell.
Figure 2: Two models of intertumoral heterogeneity.
Figure 3: Strategies used to identify cells of origin in cancer.
Figure 4: Identification of crypt stem cells as the cell of origin in intestinal cancer by lineage tracing.

References

  1. Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8, 755–768 (2008).

    CAS  Google Scholar 

  2. Marusyk, A. & Polyak, K. Tumor heterogeneity: causes and consequences. Biochim. Biophys. Acta 1805, 105–117 (2010).

    CAS  PubMed  Google Scholar 

  3. Ma, X. J. et al. Gene expression profiles of human breast cancer progression. Proc. Natl Acad. Sci. USA 100, 5974–5979 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Weigelt, B. et al. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc. Natl Acad. Sci. USA 100, 15901–15905 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tlsty, T. D. & Coussens, L. M. Tumor stroma and regulation of cancer development. Annu. Rev. Pathol. 1, 119–150 (2006).

    CAS  PubMed  Google Scholar 

  6. Weinstein, I. B. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Garraway, L. A. & Sellers, W. R. Lineage dependency and lineage-survival oncogenes in human cancer. Nature Rev. Cancer 6, 593–602 (2006).

    CAS  Google Scholar 

  8. Perez-Losada, J. & Balmain, A. Stem-cell hierarchy in skin cancer. Nature Rev. Cancer 3, 434–443 (2003).

    CAS  Google Scholar 

  9. Bailleul, B. et al. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell 62, 697–708 (1990).

    CAS  PubMed  Google Scholar 

  10. Brown, K., Strathdee, D., Bryson, S., Lambie, W. & Balmain, A. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr. Biol. 8, 516–524 (1998).

    CAS  PubMed  Google Scholar 

  11. Ince, T. A. et al. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12, 160–170 (2007).

    CAS  PubMed  Google Scholar 

  12. Sharma, M. K. et al. Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res. 67, 890–900 (2007).

    CAS  PubMed  Google Scholar 

  13. Taylor, M. D. et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8, 323–335 (2005).

    CAS  PubMed  Google Scholar 

  14. Johnson, R. A. et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466, 632–636 (2010). This paper demonstrates integrated genomic and cell-based approaches to identify cells of origin in ependymomas.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sotiriou, C. et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc. Natl Acad. Sci. USA 100, 10393–10398 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lim, E. et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature Med. 15, 907–913 (2009). Identification of an aberrant cell population in preneoplastic tissue, and discovery that mutant- BRCA1 tissue and basal cancers share a gene signature with normal luminal progenitors.

    CAS  PubMed  Google Scholar 

  18. Hayashi, S. & McMahon, A. P. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev. Biol. 244, 305–318 (2002).

    CAS  PubMed  Google Scholar 

  19. Metzger, D. & Chambon, P. Site- and time-specific gene targeting in the mouse. Methods 24, 71–80, (2001).

    CAS  PubMed  Google Scholar 

  20. Hewish, M., Lord, C. J., Martin, S. A., Cunningham, D. & Ashworth, A. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nature Rev. Clin. Oncol. 7, 197–208 (2010).

    Google Scholar 

  21. Narod, S. A. & Foulkes, W. D. BRCA1 and BRCA2: 1994 and beyond. Nature Rev. Cancer 4, 665–676 (2004).

    CAS  Google Scholar 

  22. Fialkow, P. J., Denman, A. M., Jacobson, R. J. & Lowenthal, M. N. Chronic myelocytic leukemia. Origin of some lymphocytes from leukemic stem cells. J. Clin. Invest. 62, 815–823 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jamieson, C. H. et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004). The first functional evidence that cells of origin and cancer-propagating cells in a given malignancy are likely to be distinct.

    CAS  PubMed  Google Scholar 

  24. Hope, K. J., Jin, L. & Dick, J. E. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nature Immunol. 5, 738–743 (2004).

    CAS  Google Scholar 

  25. Barabe, F., Kennedy, J. A., Hope, K. J. & Dick, J. E. Modeling the initiation and progression of human acute leukemia in mice. Science 316, 600–604 (2007).

    ADS  CAS  PubMed  Google Scholar 

  26. Wei, J. et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13, 483–495 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hong, D. et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 319, 336–339 (2008).

    ADS  CAS  PubMed  Google Scholar 

  28. Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).

    CAS  PubMed  Google Scholar 

  29. Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9. Nature 442, 818–822 (2006).

    ADS  CAS  PubMed  Google Scholar 

  30. Cozzio, A. et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 17, 3029–3035 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Drynan, L. F. et al. Mll fusions generated by Cre-loxP-mediated de novo translocations can induce lineage reassignment in tumorigenesis. EMBO J. 24, 3136–3146 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, W. et al. Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells. Cancer Cell 13, 432–440 (2008). This study highlights the importance of gene dosage when assessing the effects of oncogene expression in candidate cells of origin.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. McCormack, M. P. et al. The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte self-renewal. Science 327, 879–883 (2010).

    ADS  CAS  PubMed  Google Scholar 

  34. Akala, O. O. et al. Long-term haematopoietic reconstitution by Trp53−/−p16Ink4a−/p19Arf−/ multipotent progenitors. Nature 453, 228–232 (2008).

    ADS  CAS  PubMed  Google Scholar 

  35. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    CAS  PubMed  Google Scholar 

  36. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009). Using lineage-tracing studies, this paper demonstrates that colonic stem cells can act as the cell of origin for colon cancer. See also references 37 and 38.

    ADS  CAS  PubMed  Google Scholar 

  37. Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603–607 (2009).

    ADS  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  39. Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro . Cell Stem Cell 6, 25–36 (2010).

    CAS  PubMed  Google Scholar 

  40. Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 25, 55–57 (2000).

    CAS  PubMed  Google Scholar 

  41. Alcantara Llaguno, S. et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15, 45–56 (2009).

    PubMed  PubMed Central  Google Scholar 

  42. Marumoto, T. et al. Development of a novel mouse glioma model using lentiviral vectors. Nature Med. 15, 110–116 (2009).

    CAS  PubMed  Google Scholar 

  43. Merkle, F. T., Mirzadeh, Z. & Alvarez-Buylla, A. Mosaic organization of neural stem cells in the adult brain. Science 317, 381–384 (2007).

    ADS  CAS  PubMed  Google Scholar 

  44. Jacques, T. S. et al. Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. EMBO J. 29, 222–235 (2010).

    CAS  PubMed  Google Scholar 

  45. Wang, Y. et al. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15, 514–526 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bachoo, R. M. et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1, 269–277 (2002).

    CAS  PubMed  Google Scholar 

  47. Bruggeman, S. W. et al. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12, 328–341 (2007).

    CAS  PubMed  Google Scholar 

  48. Schuller, U. et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14, 123–134 (2008). This study demonstrates that descendants of stem cells can act as crucial cellular targets of transformation. See also reference 49.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang, Z. J. et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14, 135–145 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sutter, R. et al. Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas. Oncogene 29, 1845–1856 (2010).

    CAS  PubMed  Google Scholar 

  51. Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1098 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Joseph, N. M. et al. The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell 13, 129–140 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Zheng, H. et al. Induction of abnormal proliferation by nonmyelinating Schwann cells triggers neurofibroma formation. Cancer Cell 13, 117–128 (2008).

    CAS  PubMed  Google Scholar 

  54. Wang, X. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009). This report establishes a new luminal stem cell as a target of prostate carcinogenesis and indicates a hierarchy of stem cells in this tissue.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Leong, K. G., Wang, B. E., Johnson, L. & Gao, W. Q. Generation of a prostate from a single adult stem cell. Nature 456, 804–808 (2008).

    ADS  CAS  PubMed  Google Scholar 

  56. Ma, X. et al. Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation but not by reduced apoptosis. Cancer Res. 65, 5730–5739 (2005).

    CAS  PubMed  Google Scholar 

  57. Korsten, H., Ziel-van der Made, A., Ma, X., van der Kwast, T. & Trapman, J. Accumulating progenitor cells in the luminal epithelial cell layer are candidate tumor initiating cells in a Pten knockout mouse prostate cancer model. PLoS ONE 4, e5662 (2009).

    ADS  PubMed  PubMed Central  Google Scholar 

  58. Mulholland, D. J. et al. LinSca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res. 69, 8555–8562 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Lawson, D. A. et al. Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc. Natl Acad. Sci. USA 107, 2610–2615 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. Goldstein, A. S., Huang, J., Guo, C., Garraway, I. P. & Witte, O. N. Identification of a cell-of-origin for human prostate cancer. Science 329, 568–571 (2010). This study demonstrates through transduction of isolated cell subsets that basal stem/progenitor cells are an important target cell.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  61. Foulkes, W. D. BRCA1 functions as a breast stem cell regulator. J. Med. Genet. 41, 1–5 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nature Rev. Cancer 4, 814–819 (2004).

    CAS  Google Scholar 

  63. Molyneux, G. et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors not from basal stem cells. Cell Stem Cell 7, 403–417 (2010). This study provides in vivo functional evidence that luminal progenitors rather than basal cells are an important target in the genesis of BRCA1-associated breast tumours.

    CAS  PubMed  Google Scholar 

  64. Liu, S. et al. BRCA1 regulates human mammary stem/progenitor cell fate. Proc. Natl Acad. Sci. USA 105, 1680–1685 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bouras, T. et al. Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 3, 429–441 (2008).

    CAS  PubMed  Google Scholar 

  66. Lee, C. W. et al. A functional Notchsurvivin gene signature in basal breast cancer. Breast Cancer Res. 10, R97 (2008).

    ADS  PubMed  PubMed Central  Google Scholar 

  67. Vaillant, F. et al. The mammary progenitor marker CD61/β3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res. 68, 7711–7717 (2008).

    CAS  PubMed  Google Scholar 

  68. Prat, A. et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12, R68 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).

    PubMed  PubMed Central  Google Scholar 

  70. De La, O. J. et al. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc. Natl Acad. Sci. USA 105, 18907–18912 (2008).

    ADS  Google Scholar 

  71. Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105, 18913–18918 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nature Cell Biol. 12, 299–305 (2010).

    CAS  PubMed  Google Scholar 

  73. Owens, D. M. & Watt, F. M. Contribution of stem cells and differentiated cells to epidermal tumours. Nature Rev. Cancer 3, 444–451 (2003).

    CAS  Google Scholar 

  74. 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). The first report indicating that early stem/progenitor cells are targeted for transformation in AML.

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  76. 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).

    ADS  CAS  PubMed  Google Scholar 

  77. Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    CAS  PubMed  Google Scholar 

  78. Curtis, S. J. et al. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell 7, 127–133 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang, L. et al. Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis. Nature 464, 1058–1061 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  80. Martin, S. A. et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17, 235–248 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Forbes, J. F. et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 9, 45–53 (2008).

    PubMed  Google Scholar 

  82. Asselin-Labat, M. L. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 465, 798–802 (2010).

    ADS  CAS  PubMed  Google Scholar 

  83. Ashworth, A. Drug resistance caused by reversion mutation. Cancer Res. 68, 10021–10023 (2008).

    CAS  PubMed  Google Scholar 

  84. Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376, 235–244 (2010).

    CAS  PubMed  Google Scholar 

  85. Lindberg, N., Kastemar, M., Olofsson, T., Smits, A. & Uhrbom, L. Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene 28, 2266–2275 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I am grateful to J. Adams, G. Lindeman and A. Strasser for critical review of the manuscript, P. Dirks for discussion and P. Maltezos for preparation of figures. I apologize to authors whose work could not be cited owing to space limitations. J.E.V. is supported by the National Health and Medical Research Council and the Victorian Breast Cancer Research Consortium.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Additional information

Reprints and permissions information is available at http://www.nature.com/reprints.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Visvader, J. Cells of origin in cancer. Nature 469, 314–322 (2011). https://doi.org/10.1038/nature09781

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09781

This article is cited by

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: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer