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Roots and stems: stem cells in cancer

Abstract

Cancer develops from normal tissues through the accumulation of genetic alterations that act in concert to confer malignant phenotypes. Although we have now identified some of the genes that when mutated initiate tumor formation and drive cancer progression, the identity of the cell population(s) susceptible to such transforming events remains undefined for the majority of human cancers. Recent work indicates that a small population of cells endowed with unique self-renewal properties and tumorigenic potential is present in some, and perhaps all, tumors. Although our understanding of the biology of these putative cancer stem cells remains rudimentary, the existence of such cells has implications for current conceptualizations of malignant transformation and therapeutic approaches to cancer.

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Figure 1: Potential models of transformation involving stem cells.
Figure 2: Hypothetical model depicting the organization of stem cells in normal organs and tumors.

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References

  1. Al-Hajj, M. & Clarke, M.F. Self-renewal and solid tumor stem cells. Oncogene 23, 7274–7282 (2004).

    CAS  Google Scholar 

  2. Cohnheim, V. Congenitales, quergestreiftes muskelsarkom der nieren. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 65, 64–69 (1875).

    Google Scholar 

  3. Makino, S. Further evidence favoring the concept of the stem cell in ascites tumors of rats. Ann. NY Acad. Sci. 63, 818–830 (1956).

    CAS  Google Scholar 

  4. Bruce, W.R. & Van Der Gaag, H. A Quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199, 79–80 (1963).

    CAS  Google Scholar 

  5. Kleinsmith, L.J. & Pierce, G.B., Jr. Multipotentiality of single embryonal carcinoma cells. Cancer Res. 24, 1544–1551 (1964).

    CAS  Google Scholar 

  6. Park, C.H., Bergsagel, D.E. & McCulloch, E.A. Mouse myeloma tumor stem cells: a primary cell culture assay. J. Natl. Cancer Inst. 46, 411–422 (1971).

    CAS  Google Scholar 

  7. Bishop, J.M. Viral oncogenes. Cell 42, 23–38 (1985).

    CAS  Google Scholar 

  8. Weinberg, R.A. The molecular basis of oncogenes and tumor suppressor genes. Ann. NY Acad. Sci. 758, 331–338 (1995).

    CAS  Google Scholar 

  9. Vogelstein, B. & Kinzler, K.W. Cancer genes and the pathways they control. Nat. Med. 10, 789–799 (2004).

    CAS  Google Scholar 

  10. Masters, J.R. Human cancer cell lines: fact and fantasy. Nat. Rev. Mol. Cell Biol. 1, 233–236 (2000).

    CAS  Google Scholar 

  11. Fuchs, E. & Raghavan, S. Getting under the skin of epidermal morphogenesis. Nat. Rev. Genet. 3, 199–209 (2002).

    CAS  Google Scholar 

  12. Smalley, M. & Ashworth, A. Stem cells and breast cancer: a field in transit. Nat. Rev. Cancer 3, 832–844 (2003).

    CAS  Google Scholar 

  13. Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004).

    CAS  PubMed Central  Google Scholar 

  14. Woodward, W.A., Chen, M.S., Behbod, F. & Rosen, J.M. On mammary stem cells. J. Cell Sci. 118, 3585–3594 (2005).

    CAS  Google Scholar 

  15. Miller, S.J., Lavker, R.M. & Sun, T.T. Interpreting epithelial cancer biology in the context of stem cells: Tumor properties and therapeutic implications. Biochim. Biophys. Acta 1756, 25–52 (2005).

    CAS  Google Scholar 

  16. Crowe, D.L., Parsa, B. & Sinha, U.K. Relationships between stem cells and cancer stem cells. Histol. Histopathol. 19, 505–509 (2004).

    CAS  Google Scholar 

  17. Young, H.E. et al. Adult reserve stem cells and their potential for tissue engineering. Cell Biochem. Biophys. 40, 1–80 (2004).

    CAS  Google Scholar 

  18. Beachy, P.A., Karhadkar, S.S. & Berman, D.M. Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324–331 (2004).

    CAS  Google Scholar 

  19. Valk-Lingbeek, M.E., Bruggeman, S.W. & van Lohuizen, M. Stem cells and cancer: the polycomb connection. Cell 118, 409–418 (2004).

    CAS  Google Scholar 

  20. Tsai, R.Y. A molecular view of stem cell and cancer cell self-renewal. Int. J. Biochem. Cell Biol. 36, 684–694 (2004).

    CAS  Google Scholar 

  21. Goodell, M.A. Multipotential stem cells and 'side population' cells. Cytotherapy 4, 507–508 (2002).

    CAS  Google Scholar 

  22. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    CAS  Google Scholar 

  23. Dontu, G. et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17, 1253–1270 (2003).

    CAS  PubMed Central  Google Scholar 

  24. Dontu, G., Al-Hajj, M., Abdallah, W.M., Clarke, M.F. & Wicha, M.S. Stem cells in normal breast development and breast cancer. Cell Prolif. 36 Suppl 1, 59–72 (2003).

    CAS  Google Scholar 

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

    CAS  PubMed Central  Google Scholar 

  26. 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).

    CAS  Google Scholar 

  27. Setoguchi, T., Taga, T. & Kondo, T. Cancer stem cells persist in many cancer cell lines. Cell Cycle 3, 414–415 (2004).

    CAS  Google Scholar 

  28. Kondo, T., Setoguchi, T. & Taga, T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc. Natl. Acad. Sci. USA 101, 781–786 (2004).

    CAS  Google Scholar 

  29. Singh, S.K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).

    CAS  Google Scholar 

  30. Hirschmann-Jax, C. et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc. Natl. Acad. Sci. USA 101, 14228–14233 (2004).

    CAS  Google Scholar 

  31. Locke, M., Heywood, M., Fawell, S. & Mackenzie, I.C. Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res. 65, 8944–8950 (2005).

    CAS  Google Scholar 

  32. Patrawala, L. et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res. 65, 6207–6219 (2005).

    CAS  Google Scholar 

  33. Passegue, E., Jamieson, C.H., Ailles, L.E. & Weissman, I.L. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc. Natl. Acad. Sci. USA 100 Suppl 1, 11842–11849 (2003).

    CAS  Google Scholar 

  34. Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001).

    CAS  Google Scholar 

  35. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    CAS  PubMed Central  Google Scholar 

  36. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5, 744–749 (2005).

    CAS  Google Scholar 

  37. Pardal, R., Clarke, M.F. & Morrison, S.J. Applying the principles of stem-cell biology to cancer. Nat. Rev. Cancer 3, 895–902 (2003).

    CAS  Google Scholar 

  38. Vitale-Cross, L., Amornphimoltham, P., Fisher, G., Molinolo, A.A. & Gutkind, J.S. Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis. Cancer Res. 64, 8804–8807 (2004).

    CAS  Google Scholar 

  39. Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet (2005).

  40. Lininger, R.A., Fujii, H., Man, Y.G., Gabrielson, E. & Tavassoli, F.A. Comparison of loss heterozygosity in primary and recurrent ductal carcinoma in situ of the breast. Mod. Pathol. 11, 1151–1159 (1998).

    CAS  Google Scholar 

  41. Prindull, G. Hypothesis: cell plasticity, linking embryonal stem cells to adult stem cell reservoirs and metastatic cancer cells? Exp. Hematol. 33, 738–746 (2005).

    CAS  Google Scholar 

  42. Bates, R.C. & Mercurio, A.M. The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol. Ther. 4, 365–370 (2005).

    CAS  Google Scholar 

  43. Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004).

    CAS  Google Scholar 

  44. 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 Central  Google Scholar 

  45. Harley, C.B. et al. Telomerase, cell immortality, and cancer. Cold Spring Harb. Symp. Quant. Biol. 59, 307–315 (1994).

    CAS  PubMed Central  Google Scholar 

  46. Hahn, W.C. Role of telomeres and telomerase in the pathogenesis of human cancer. J. Clin. Oncol. 21, 2034–2043 (2003).

    CAS  Google Scholar 

  47. Morrison, S.J., Prowse, K.R., Ho, P. & Weissman, I.L. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5, 207–216 (1996).

    CAS  Google Scholar 

  48. Molofsky, A.V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    CAS  PubMed Central  Google Scholar 

  49. Sherr, C.J. The ink4a/arf network in tumour suppression. Nat. Rev. Mol. Cell Biol. 2, 731–737 (2001).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  51. Allsopp, R.C., Cheshier, S. & Weissman, I.L. Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J. Exp. Med. 193, 917–924 (2001).

    CAS  PubMed Central  Google Scholar 

  52. Flores, I., Cayuela, M.L. & Blasco, M.A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309, 1253–1256 (2005).

    CAS  Google Scholar 

  53. Sarin, K.Y. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005).

    CAS  PubMed Central  Google Scholar 

  54. Masutomi, K. et al. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc. Natl. Acad. Sci. USA 102, 8222–8227 (2005).

    CAS  Google Scholar 

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

    CAS  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  57. Al-Hajj, M., Becker, M.W., Wicha, M., Weissman, I. & Clarke, M.F. Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47 (2004).

    CAS  Google Scholar 

  58. Brenton, J.D., Carey, L.A., Ahmed, A.A. & Caldas, C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J. Clin. Oncol. 23, 7350–7360 (2005).

    CAS  Google Scholar 

  59. Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005).

    CAS  Google Scholar 

  60. Abraham, B.K. et al. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin. Cancer Res. 11, 1154–1159 (2005).

    CAS  Google Scholar 

  61. Glinsky, G.V., Berezovska, O. & Glinskii, A.B. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J. Clin. Invest. 115, 1503–1521 (2005).

    CAS  PubMed Central  Google Scholar 

  62. Bosl, G.J. & Motzer, R.J. Testicular germ-cell cancer. N. Engl. J. Med. 337, 242–253 (1997).

    CAS  Google Scholar 

  63. Bhatia, R. et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101, 4701–4707 (2003).

    CAS  Google Scholar 

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Acknowledgements

We apologize to our colleagues whose work could not be cited due to space limitations. We thank R. Weinberg, C. Kim, K. Cichowski, C. Sawyers, M. Brown and B. Vogelstein for comments and discussion. We recognize support from the US National Institutes of Health (R01 CA94074, P50 CA89393, K01 94223 and R01 AG23145), the Tisch Family Fund for Research in Solid Tumors, the US Army Medical Research and Material Command (DAMD17 02 1 0692 and W8IXWH-04-1-0452) and the American Cancer Society (RSG-05-154-01-MGO). The authors are consultants for Novartis Pharmaceuticals, Inc.

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Kornelia Polyak and William C. Hahn are consultants for Novartis Pharmaceuticals, Inc.

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Polyak, K., Hahn, W. Roots and stems: stem cells in cancer. Nat Med 12, 296–300 (2006). https://doi.org/10.1038/nm1379

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