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Applying the principles of stem-cell biology to cancer

Key Points

  • Not all cancer cells are created equal. There are intrinsic differences among cancer cells from the same patient in terms of their ability to proliferate and form tumours in vivo.

  • A subset of cancer cells have the properties of cancer stem cells, which self-renew to generate additional cancer stem cells and differentiate to generate phenotypically diverse cancer cells with limited proliferative potential. Cancer stem cells are highly enriched for the ability to form tumours following transplantation relative to bulk tumour cells or non-tumorigenic cancer cells.

  • Cancer stem cells have been characterized in the context of human acute myeloid leukaemia, breast cancer and glioblastoma. In each case, surface markers have been identified that distinguish cancer stem cells from cancer cells with more limited proliferative potential, allowing the prospective identification of cancer stem cells.

  • In some cases, cancer stem cells might arise from the mutational transformation of normal stem cells, whereas in other cases mutations might cause restricted progenitors or differentiated cells to acquire properties of cancer stem cells such as self-renewal potential.

  • The neoplastic proliferation of cancer stem cells is likely to be driven by mutations that inappropriately activate pathways that promote the self-renewal of normal stem cells. Examples of these pathways include the WNT, and BMI1-dependent pathways that regulate the self-renewal of haematopoietic stem cells and neural stem cells.

  • Further characterization of cancer stem cells might lead to improved diagnostics and therapies by allowing us to better identify and target cancer stem cells. To cure cancer it is necessary to kill, differentiate or prevent the metastasis of cancer stem cells.

Abstract

Why are tumours heterogeneous, in terms of cell phenotype and proliferative potential, even in cases in which all cells are derived from a single clone? Ongoing mutagenesis can partially explain this heterogeneity, but it also seems that some tumours arise from small populations of 'cancer stem cells' that give rise to phenotypically diverse cancer cells, with less proliferative potential. These cancer stem cells are likely to arise from mutations that dysregulate normal stem-cell self-renewal. Using this information, it might be possible to devise more effective therapies.

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Figure 1: Control of stem-cell self-renewal by the WNT and BMI1 pathways.
Figure 2: Therapeutic implications of cancer stem cells.

References

  1. Sell, S. & Pierce, G. B. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab. Invest. 70, 6–22 (1994).

    CAS  PubMed  Google Scholar 

  2. Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24, 385–428 (2001).

    CAS  Article  PubMed  Google Scholar 

  3. Fearon, E. R., Burke, P. J., Schiffer, C. A., Zehnbauer, B. A. & Vogelstein, B. Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphocytic leukemia. N. Engl. J. Med. 315, 15–24 (1986).

    CAS  PubMed  Google Scholar 

  4. Fialkow, P. J. et al. Clonal development, stem-cell differentiation, and clinical remissions in acute nonlymphocytic leukemia. N. Engl. J. Med. 20, 468–473 (1987).

    Google Scholar 

  5. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Hamburger, A. W. & Salmon, S. E. Primary bioassay of human tumor stem cells. Science 197, 461–463 (1977).

    CAS  PubMed  Google Scholar 

  8. Lapidot, T. et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature 17, 645–648 (1994).

    Google Scholar 

  9. 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). Not all human breast cancer cells are equal in terms of their ability to form tumours in immunocompromised mice, and the tumorigenic subset of cells exhibits properties of cancer stem cells. The tumorigenic cell population represents a minority of cells within the tumours, but can be isolated from most of the patients studied based on a unique surface-marker expression pattern.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Singh, S. K. et al. Identification of a cancer stem cell in human brain tumours. Cancer Res. 63, 5821–5828 (2003). Not all human brain cancer cells are equal in terms of their ability to proliferate in culture, and the more proliferative subset of cells exhibits markers and functions of neural stem cells.

    CAS  PubMed  Google Scholar 

  11. Taipale, J. & Beachy, P. A. The hedgehog and Wnt signaling pathways in cancer. Nature 411, 349–354 (2001).

    CAS  PubMed  Google Scholar 

  12. Zhu, Y. & Parada, L. F. The molecular and genetic basis of neurological tumours. Nature Rev. Cancer 2, 616–626 (2002).

    CAS  Google Scholar 

  13. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003). Haematopoietic stem-cell self-renewal in vivo is dependent on BMI1 , and BMI1 -deficient haematopoietic stem cells do not persist into adulthood.

    CAS  PubMed  Google Scholar 

  14. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003). Proliferation of leukaemic stem cells is dependent on BMI1 , and BMI1 -deficient leukaemia cells fail to induce disease following transplantation. This shows that proliferation of leukaemic stem cells depends on a pathway that is also crucial for the self-renewal of normal haematopoietic stem cells.

    CAS  PubMed  Google Scholar 

  15. Hemmati, H. D. et al. Pediatric brain tumor stem cells. Ann. Neurol. 54, S117 (2003).

    Google Scholar 

  16. Salmon, S. E. et al. Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs. N. Engl. J. Med. 298, 1321–1327 (1978).

    CAS  PubMed  Google Scholar 

  17. McCulloch, E. A. Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture, 1982). Blood 62, 1–13 (1983).

    CAS  PubMed  Google Scholar 

  18. Trott, K. R. Tumour stem cells: the biological concept and its application in cancer treatment. Radiother. Oncol. 30, 1–5 (1994).

    CAS  PubMed  Google Scholar 

  19. Kummermehr, J. & Trott, K. -R. in Stem Cells (ed. Potten, C. S.) 363–399 (Academic Press, New York, 1997).

    Google Scholar 

  20. Bruce, W. R. & Gaag, H. V. D. A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199, 79–80 (1963).

    CAS  PubMed  Google Scholar 

  21. Wodinsky, I., Swiniarski, J. & Kensler, C. J. Spleen colony studies of leukemia L1210. I. Growth kinetics of lymphocytic L1210 cells in vivo as determined by spleen colony assay. Cancer Chemother. Rep. 51, 415–421 (1967).

    Google Scholar 

  22. Ignatova, T. N. et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39, 193–206 (2002).

    PubMed  Google Scholar 

  23. Knudson, A. G. Jr, Strong, L. C. & Anderson, D. E. Heredity and cancer in man. Prog. Med. Genet. 9, 113–158 (1973).

    PubMed  Google Scholar 

  24. Bhatia, M., Wang, J. C., Kapp, U., Bonnet, D. & Dick, J. E. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc. Natl Acad. Sci. USA 94, 5320–5325 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Pereira, D. S. et al. Retroviral transduction of TLS-ERG initiates a leukemogenic program in normal human hematopoietic cells. Proc. Natl Acad. Sci. USA 95, 8239–8244 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kelly, L. M. & Gilliland, D. G. Genetics of myeloid leukemias. Annu. Rev. Genomics Hum. Genet. 3, 179–198 (2002).

    CAS  PubMed  Google Scholar 

  27. Blair, A., Hogge, D. E., Ailles, L. E., Lansdorp, P. M. & Sutherland, H. J. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 89, 3104–3112 (1997).

    CAS  PubMed  Google Scholar 

  28. Jordan, C. T. et al. The interleukin-3 receptor α chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14, 1777–1784 (2000).

    CAS  PubMed  Google Scholar 

  29. Polakis, P. The oncogenic activation of β-catenin. Curr. Opin. Genet. Dev. 9, 15–21 (1999).

    CAS  PubMed  Google Scholar 

  30. 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  Google Scholar 

  31. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003). Soluble Wnt3a can promote the self-renewal of haematopoeitic stem cells in culture.

    CAS  PubMed  Google Scholar 

  32. Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003). Wnt/β-catenin-pathway activation promotes the self-renewal of haematopoietic stem cells in culture.

    CAS  PubMed  Google Scholar 

  33. Wechsler-Reya, R. J. & Scott, M. P. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22, 103–114 (1999).

    CAS  PubMed  Google Scholar 

  34. Taylor, M. D. et al. Mutations in SUFU predispose to medulloblastoma. Nature Genet. 31, 306–310 (2002).

    CAS  PubMed  Google Scholar 

  35. Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci. 6, 21–27 (2003).

    CAS  PubMed  Google Scholar 

  36. Wetmore, C. Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. Curr. Opin. Genet. Dev. 13, 34–42 (2003).

    CAS  PubMed  Google Scholar 

  37. Pear, W. S. et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283–2291 (1996).

    CAS  PubMed  Google Scholar 

  38. 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  Google Scholar 

  39. Henrique, D. et al. Maintenance of neuroepithelial progenitor cells by δ-Notch signalling in the embryonic chick retina. Curr. Biol. 7, 661–670 (1997).

    CAS  PubMed  Google Scholar 

  40. Di Cristofano, A. & Pandolfi, P. P. The multiple roles of PTEN in tumor suppression. Cell 100, 387–390 (2000).

    CAS  PubMed  Google Scholar 

  41. Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the pten tumor suppressor gene in vivo. Science 1, 1 (2001).

    Google Scholar 

  42. Morrison, S. J. Pten-uating neural growth. Nature Med. 8, 16–18 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  44. 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 

  45. 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  Google Scholar 

  46. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. 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  Google Scholar 

  49. 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). References 47–49 show that the Wnt/β-catenin pathway is required to maintain the stem-cell identity of normal gut epithelial stem cells as well as colorectal cancer cells, and that it promotes the proliferation of both cell types by acting through similar downstream pathways.

    CAS  Google Scholar 

  50. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992).

    CAS  PubMed  Google Scholar 

  51. Moser, A. R., Dove, W. F., Roth, K. A. & Gordon, J. I. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J. Cell Biol. 116, 1517–1526 (1992).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  53. Bienz, M. & Clevers, H. Linking colorectal cancer to Wnt signaling. Cell 103, 311–320 (2000).

    CAS  PubMed  Google Scholar 

  54. 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  Google Scholar 

  55. 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  Google Scholar 

  56. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Haegel, H. et al. Lack of β-catenin affects mouse development at gastrulation. Development 121, 3529–3537 (1995).

    CAS  PubMed  Google Scholar 

  58. Brault, V. et al. Inactivation of the β-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128, 1253–1264 (2001).

    CAS  PubMed  Google Scholar 

  59. Yoshikawa, Y., Fujimori, T., McMahon, A. P. & Takada, S. Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev. Biol. 183, 234–242 (1997).

    CAS  PubMed  Google Scholar 

  60. Chung, E. J. et al. Regulation of leukemic cell adhesion, proliferation, and survival by β-catenin. Blood 100, 982–990 (2002).

    CAS  PubMed  Google Scholar 

  61. Qiang, Y. W., Endo, Y., Rubin, J. S. & Rudikoff, S. Wnt signaling in B-cell neoplasia. Oncogene 22, 1536–1545 (2003).

    CAS  PubMed  Google Scholar 

  62. van Kemenade, F. J. et al. Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood 97, 3896–3901 (2001).

    CAS  PubMed  Google Scholar 

  63. Visser, H. P. et al. The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br. J. Haematol. 112, 950–958 (2001).

    CAS  PubMed  Google Scholar 

  64. Ohta, H. et al. Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. J. Exp. Med. 195, 759–770 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    CAS  PubMed  Google Scholar 

  66. Bea, S. et al. BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res. 61, 2409–2412 (2001).

    CAS  PubMed  Google Scholar 

  67. Alkema, M. J., Jacobs, H., van Lohuizen, M. & Berns, A. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmi1 transgenic mice require the Bmi1 RING finger. Oncogene 15, 899–910 (1997).

    CAS  PubMed  Google Scholar 

  68. Haupt, Y., Bath, M. L., Harris, A. W. & Adams, J. M. bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene 8, 3161–3164 (1993).

    CAS  PubMed  Google Scholar 

  69. van der Lugt, N. M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994).

    CAS  PubMed  Google Scholar 

  70. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).

    CAS  PubMed  Google Scholar 

  71. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678–2790 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Lessard, J., Baban, S. & Sauvageau, G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 91, 1216–1224 (1998).

    CAS  PubMed  Google Scholar 

  73. Jacobs, J. J. L. & Lohuizen, M. V. Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim. Biophys. Acta 1602, 151–161 (2002).

    CAS  PubMed  Google Scholar 

  74. Chaudhary, P. M. & Roninson, I. B. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66, 85–94 (1991).

    CAS  PubMed  Google Scholar 

  75. Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Med. 7, 1028–1034 (2001).

    CAS  PubMed  Google Scholar 

  76. Pallis, M. & Russell, N. P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway. Blood 95, 2897–2904 (2000).

    CAS  PubMed  Google Scholar 

  77. Johnstone, R. W., Cretney, E. & Smyth, M. J. P-glycoprotein protects leukemia cells against caspase-dependent, but not caspase-independent, cell death. Blood 93, 1075–1085 (1999).

    CAS  PubMed  Google Scholar 

  78. Bittner, M. et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 406, 536–540 (2000).

    CAS  PubMed  Google Scholar 

  79. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  PubMed  Google Scholar 

  80. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    CAS  PubMed  Google Scholar 

  81. Pomeroy, S. L. et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415, 436–442 (2002).

    CAS  PubMed  Google Scholar 

  82. Shipp, M. A. et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nature Med. 8, 68–74 (2002).

    CAS  PubMed  Google Scholar 

  83. Guzman, M. L. et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc. Natl Acad. Sci. USA 99, 16220–16225 (2002). Shows that it is possible to identify therapeutic agents that kill leukaemic stem cells but not normal haematopoietic stem cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Stephenson, W. T., Poirier, S. M., Rubin, L. & Einhorn, L. H. Evaluation of reproductive capacity in germ-cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. J. Clin. Oncol. 13, 2278–2280 (1995).

    CAS  PubMed  Google Scholar 

  85. 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). References 30, 45, 46 and 85 show that the WNT/ β-catenin pathway regulates the self-renewal of normal epidermal stem cells and that mutations that over-activate this pathway lead to the formation of tumours in the epidermis.

    CAS  PubMed  Google Scholar 

  86. Cui, H., Meng, Y. & Bulleit, R. F. Inhibition of glycogen synthase kinase 3β activity regulates proliferation of cultured cerebellar granule cells. Brain Res. Dev. Brain Res. 111, 177–188 (1998).

    CAS  PubMed  Google Scholar 

  87. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    CAS  PubMed  Google Scholar 

  88. Chiang, C. et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9 (1999).

    CAS  PubMed  Google Scholar 

  89. Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).

    CAS  PubMed  Google Scholar 

  90. Oro, A. E. et al. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276, 817–821 (1997).

    CAS  PubMed  Google Scholar 

  91. Dahmane, N., Lee, J., Robins, P., Heller, P. & Ruiz i Altaba, A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389, 876–881 (1997).

    CAS  PubMed  Google Scholar 

  92. Raffel, C. et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57, 842–845 (1997).

    CAS  PubMed  Google Scholar 

  93. Pietsch, T. et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 57, 2085–2088 (1997).

    CAS  PubMed  Google Scholar 

  94. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    CAS  PubMed  Google Scholar 

  95. Ruiz i Altaba, A., Sanchez, P. & Dahmane, N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. Cancer 2, 361–327 (2002).

    CAS  Google Scholar 

  96. Chepko, G. & Dickson, R. B. Ultrastructure of the putative stem cell niche in rat mammary epithelium. Tissue Cell 35, 83–93 (2003).

    CAS  PubMed  Google Scholar 

  97. Jhappan, C. et al. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev. 6, 345–355 (1992).

    CAS  PubMed  Google Scholar 

  98. Duerr, E. M. et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene 16, 2259–2264 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  100. Liu, C. et al. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837–847 (2002).

    CAS  PubMed  Google Scholar 

  101. Lowe, S. W. & Sherr, C. J. Tumor suppression by Ink4a–Arf: progress and puzzles. Curr. Opin. Genet. Dev. 13, 77–83 (2003).

    CAS  PubMed  Google Scholar 

  102. Pierce, G. B. & Speers, W. C. Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation. Cancer Res. 48, 1996–2004 (1988).

    CAS  PubMed  Google Scholar 

  103. Jain, M. et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297, 102–104 (2002). Even a transient loss of MYC function can lead to an irreversible loss of neoplastic cells. This is consistent with the idea that MYC is required to maintain the state of cancer stem cells, much as it would be expected to be required for normal stem-cell self-renewal. So, targeting pathways that are required for maintenance of stem-cell identity might be used to convert malignancies into benign tumours.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to N. Joseph, T. Ross, A. Dlugosz and E. Fearon for comments on the manuscript. R. P. was the recipient of a postdoctoral fellowship from the Spanish Ministry of Science and Technology and Sean Morrison is an assistant investigator of the Howard Hughes Medical Institute. We apologize to authors whose papers were not referenced due to space constraints.

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Correspondence to Sean J. Morrison.

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Mike Clarke and Sean Morrison own stock in Cancer Stem Cell Genomics, a company that is developing products based on the use of cancer stem cells.

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DATABASES

Cancer.gov

acute myeloid leukaemia

breast cancer

glioblastoma

LocusLink

Bcl2

BMI1

Cd24

Cd44

CD133

Cdkn2a

EZH2

MDR1

PTEN

RAE28

SHH

Notch

Tcf4

THY1

Wnt3a

Glossary

STEM CELL

A self-renewing, typically multipotent, progenitor with the broadest developmental potential in a particular tissue at a particular time.

CANCER STEM CELL

A cancer cell that has the potential to transfer disease or to form tumours following transplantation. Cancer stem cells have the potential to self-renew, forming additional tumorigenic cancer cells of similar phenotype, and to give rise to phenotypically diverse cancer cells with more limited proliferative potential.

SELF-RENEWAL

The process by which a progenitor gives rise to daughter progenitors of equivalent developmental potential. For example, multipotent stem cells self-renew by dividing to generate one or two multipotent daughter cells.

PROGENITOR

Any cell that divides to give rise to other cells. Progenitors include both stem cells and restricted progenitors.

PROSPECTIVE IDENTIFICATION

The ability to reliably predict which cells are stem cells and which are not in vivo or among freshly dissociated cells that have not yet been cultured. This is typically done based on surface-marker expression, such as by isolating highly purified populations of uncultured stem cells by flow cytometry.

RESTRICTED PROGENITOR

A cell that divides to give rise to other cells, but which has a more limited developmental potential than the stem cells in the same tissue from which it arises.

POLYCOMB FAMILY

Polycomb family members repress gene expression by assembling into multimeric protein complexes that alter chromatin structure. Polycomb family members regulate the expression of cell-cycle genes as well as HOX genes, and are known to regulate proliferation and patterning.

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Pardal, R., Clarke, M. & Morrison, S. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3, 895–902 (2003). https://doi.org/10.1038/nrc1232

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