Cancer stem cell definitions and terminology: the devil is in the details

Article metrics

Abstract

The cancer stem cell (CSC) concept has important therapeutic implications, but its investigation has been hampered both by a lack of consistency in the terms used for these cells and by how they are defined. Evidence of their heterogeneous origins, frequencies and their genomic, as well as their phenotypic and functional, properties has added to the confusion and has fuelled new ideas and controversies. Participants in The Year 2011 Working Conference on CSCs met to review these issues and to propose a conceptual and practical framework for CSC terminology. More precise reporting of the parameters that are used to identify CSCs and to attribute responses to them is also recommended as key to accelerating an understanding of their biology and developing more effective methods for their eradication in patients.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Models of cancer stem cell evolution: perturbation of the normal differentiation hierarchy.
Figure 2: Proposed model of cancer stem cell evolution.
Figure 3: Effects of therapies.

References

  1. 1

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

  2. 2

    Clarke, M. F. et al. Cancer stem cells-perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006).

  3. 3

    Nguyen, L. V., Vanner, R., Dirks, P. & Eaves, C. J. Cancer stem cells: an evolving concept. Nature Rev. Cancer 12, 133–143 (2012).

  4. 4

    Schulenburg, A. et al. Neoplastic stem cells: current concepts and clinical perspectives. Crit. Rev. Oncol. Hematol. 76, 2512–2520 (2010).

  5. 5

    Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–81 (1976).

  6. 6

    Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome - biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011).

  7. 7

    Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).

  8. 8

    Stratton, M. R. Exploring the genomes of cancer cells: progress and promise. Science 331, 1553–1558 (2011).

  9. 9

    Magee, J. A., Piskounova, E. & Morrison, S. J. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21, 283–296 (2012).

  10. 10

    Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

  11. 11

    Konopleva, M. Y. & Jordan, C. T. Leukemia stem cells and microenvironment: biology and therapeutic targeting. J. Clin. Oncol. 29, 591–599 (2011).

  12. 12

    Visvader, J. E. & Lindeman, G. J. Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10, 717–728 (2012).

  13. 13

    Gillies, R. J., Verduzco, D. & Gatenby, R. A. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nature Rev. Cancer 12, 487–493 (2012).

  14. 14

    Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

  15. 15

    Ponti, D. et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506–5511 (2005).

  16. 16

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

  17. 17

    Eramo, A. et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 15, 504–514 (2008).

  18. 18

    Han, M. E. et al. Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research. Cell. Mol. Life Sci. 68, 3589–3605 (2011).

  19. 19

    Copley, M. R. Beer, P. A. & Eaves, C. J. Hematopoietic stem cell heterogeneity takes center stage. Cell Stem Cell 10, 690–697 (2012).

  20. 20

    Bixby, S., Kruger, G. M., Mosher, J. T., Joseph, N. M. & Morrison, S. J. Cell-intrinsic differences between stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity. Neuron 35, 643–656 (2002).

  21. 21

    Van Keymeulen, A. & Blanpain, C. Tracing epithelial stem cells during development, homeostasis, and repair. J. Cell Biol. 197, 575–584 (2012).

  22. 22

    Graf, T. & Enver, T. Forcing cells to change lineages. Nature 462, 587–594 (2009).

  23. 23

    Doulatov, S., Notta, F., Laurenti, E. & Dick, J. E. Hematopoiesis: a human perspective. Cell Stem Cell 10, 120–136 (2012).

  24. 24

    Smalley, M. J. et al. Isolation of mouse mammary epithelial subpopulations: a comparison of leading methods. J. Mammary Gland Biol. Neoplasia 17, 91–97 (2012).

  25. 25

    Wagers, A. J. & Conboy, I. M. Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell 122, 659–667 (2005).

  26. 26

    Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

  27. 27

    Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

  28. 28

    Sutherland, H. J., Lansdorp, P. M., Henkelman, D. H., Eaves, A. C. & Eaves, C. J. Functional characterization of individual human hematopoietic stem cells cultured at limiting dilution on supportive marrow stromal layers. Proc. Natl Acad. Sci. USA 87, 3584–3358 (1990).

  29. 29

    Uchida, N. et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14270–14275 (2000).

  30. 30

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

  31. 31

    Kamel-Reid, S. et al. A model of human acute lymphoblastic leukemia in immune-deficient SCID mice. Science 246, 1597–1600 (1989).

  32. 32

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

  33. 33

    Sirard, C. et al. Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis. Blood 87, 1539–1548 (1996).

  34. 34

    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).

  35. 35

    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).

  36. 36

    Stewart, J. M. et al. Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells. Proc. Natl Acad. Sci. USA 108, 6468–6473 (2011).

  37. 37

    Prince, M. E. et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl Acad. Sci. USA 104, 973–978 (2007).

  38. 38

    Taussig, D. C. et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood 112, 568–575 (2008).

  39. 39

    Taussig, D. C. et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34- fraction. Blood 115, 1976–1984 (2010).

  40. 40

    Goardon, N. et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138–152 (2011).

  41. 41

    Weinberg, O. K. & Arber, D. A. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia 24, 1844–1851 (2010).

  42. 42

    Kong, Y. et al. CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia 22, 1207–1213 (2008).

  43. 43

    Dirks, P. B. Brain tumor stem cells: the cancer stem cell hypothesis writ large. Mol. Oncol. 4, 420–430 (2010).

  44. 44

    Shmelkov, S. V. et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumours. J. Clin. Invest. 118, 2111–2120 (2008).

  45. 45

    Quintana, E. et al. Phenotypic heterogeneity among tumourigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18, 510–523 (2010).

  46. 46

    Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).

  47. 47

    Gupta, P. B., Chaffer, C. L. & Weinberg, R. A. Cancer stem cells: mirage or reality? Nature Med. 15, 1010–1012 (2009).

  48. 48

    Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).

  49. 49

    Roesch, A. et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumour growth. Cell 141, 583–594 (2010).

  50. 50

    Chaffer, C. L. et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. Sci. USA 108, 7950–7955 (2011).

  51. 51

    Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome – biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011).

  52. 52

    Okita, K. & Yamanaka, S. Induced pluripotent stem cells: opportunities and challenges. Philosoph. Trans. R. Soc. B. Biol. Sci. 366, 2198–2207 (2011).

  53. 53

    Akkina, R. et al. Humanized Rag1−/− γc−/− mice support multilineage hematopoiesis and are susceptible to HIV-1 infection via systemic and vaginal routes. PLoS ONE 6, e20169 (2011).

  54. 54

    Strowig, T. et al. Transgenic expression of human signal regulatory protein α in Rag2−/−γc−/− mice improves engraftment of human hematopoietic cells in humanized mice. Proc. Natl Acad. Sci. USA 108, 13218–13223 (2011).

  55. 55

    Wunderlich, M. et al. AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia 24, 1785–1788 (2010).

  56. 56

    Takagi, S. et al. Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood 119, 2768–2777 (2012).

  57. 57

    Lan, P., Tonomura, N., Shimizu, A., Wang, S. & Yang, Y. G. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 108, 487–492 (2006).

  58. 58

    Petzer, A. L. et al. Characterization of primitive subpopulations of normal and leukemic cells present in the blood of patients with newly diagnosed as well as established chronic myeloid leukemia. Blood 88, 2162–2171 (1996).

  59. 59

    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).

  60. 60

    Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570–575 (2012).

  61. 61

    Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526 (2012).

  62. 62

    Schepers, A. G. et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730–735 (2012).

  63. 63

    Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).

  64. 64

    Domanska, U. M. et al. A review on CXCR4/CXCL12 axis in oncology: no place to hide. Eur. J. Cancer 8 Jun 2012 [epub ahead of print].

  65. 65

    Damon, L. E. & Damon, L. E. Mobilization of hematopoietic stem cells into the peripheral blood. Exp. Rev. Hematol. 2, 717–733 (2009).

  66. 66

    Kessans, M. R., Gatesman, M. L. & Kockler, D. R. Plerixafor: a peripheral blood stem cell mobilizer. Pharmacotherapy 30, 485–492 (2010).

  67. 67

    Burger, J. A. & Peled, A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 23, 43–52 (2009).

  68. 68

    Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Med. 12, 1167–1174 (2006).

  69. 69

    Florian, S. et al. Detection of molecular targets on the surface of CD34+/CD38- stem cells in various myeloid malignancies. Leuk. Lymphoma 47, 207–222 (2006).

  70. 70

    Hosen, N. et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc. Natl Acad. Sci. USA 104, 11008–11013 (2007).

  71. 71

    Van Rhenen, A. et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 110, 2659–2666 (2007).

  72. 72

    Jin, L. et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor α chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 5, 31–42 (2009).

  73. 73

    Järås, M. et al. Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc. Natl Acad. Sci. USA 107, 16280–16285 (2010).

  74. 74

    Kemper, K., Grandela, C. & Medema, J. P. Molecular identification and targeting of colorectal cancer stem cells. Oncotarget 1, 387–395 (2010).

  75. 75

    Lorico, A. & Rappa, G. Phenotypic heterogeneity of breast cancer stem cells. J. Oncol. 2011, 135039 (2011).

  76. 76

    Korkaya, H. & Wicha, M. S. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs 21, 299–310 (2007).

  77. 77

    Valent, P. Emerging stem cell concepts for imatinib-resistant chronic myeloid leukaemia: implications for the biology, management, and therapy of the disease. Br. J. Haematol. 142, 361–378 (2008).

  78. 78

    Tu, L. C., Foltz, G., Lin, E., Hood, L. & Tian, Q. Targeting stem cells-clinical implications for cancer therapy. Curr. Stem Cell Res. Ther. 4, 147–153 (2009).

  79. 79

    Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).

  80. 80

    Curtin, J. C. & Lorenzi, M. V. Drug discovery approaches to target Wnt signaling in cancer stem cells. Oncotarget 1, 563–577 (2010).

  81. 81

    Pannuti, A. et al. Targeting Notch to target cancer stem cells. Clin. Cancer Res. 16, 3141–3152 (2010).

  82. 82

    Martelli, A. M. et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells. Curr. Med. Chem. 18, 2715–2726 (2011).

  83. 83

    Allan, E. K., Holyoake, T. L., Craig, A. R. & Jørgensen, H. G. Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukemia 25, 985–994 (2011).

  84. 84

    Takebe, N., Harris, P. J., Warren, R. Q. & Ivy, S. P. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nature Rev. Clin. Oncol. 8, 97–106 (2011).

  85. 85

    de Sousa, E. M., Vermeulen, L., Richel, D. & Medema, J. P. Targeting Wnt signaling in colon cancer stem cells. Clin. Cancer Res. 17, 647–653 (2011).

  86. 86

    Wei, L. et al. Hsp27 participates in the maintenance of breast cancer stem cells through regulation of epithelial-mesenchymal transition and nuclear factor-κB. Breast Cancer Res. 13, R101 (2011).

  87. 87

    Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia. Nature 478, 524–528 (2011).

  88. 88

    Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukemia. Nature 478, 529–533 (2011).

  89. 89

    Skrtic, M. et al. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20, 674–688 (2011).

  90. 90

    Sachlos, E. et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149, 1284–1297 (2012).

  91. 91

    Valent, P. Targeting of leukemia-initiating cells to develop curative drug therapies: straightforward but nontrivial concept. Curr. Cancer Drug Targets 11, 56–71 (2011).

  92. 92

    Barnes, D. J. & Melo, J. V. Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia. Cell Cycle 5, 2862–2866 (2006).

  93. 93

    Irish, J. M., Kotecha, N. & Nolan, G. P. Mapping normal and cancer cell signalling networks: towards single-cell proteomics. Nature Rev. Cancer 6, 146–155 (2006).

  94. 94

    Ho, M. M., Hogge, D. E. & Ling, V. MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid Leukemia. Exp. Hematol. 36, 433–442 (2008).

  95. 95

    Rosen, D. B. et al. Distinct patterns of DNA damage response and apoptosis correlate with Jak/Stat and PI3 kinase response profiles in human myelogenous Leukemia. PLoS ONE 5, e12405 (2010).

  96. 96

    de Jonge, H. J. et al. Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML. Leukemia 25, 1825–1833 (2011).

  97. 97

    Eppert, K. et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nature Med. 17, 1086–1093 (2011).

  98. 98

    Melo, J. V. & Ross, D. M. Minimal residual disease and discontinuation of therapy in chronic myeloid leukemia: can we aim at a cure? Hematol. Am. Soc. Hematol. Educ. Program 2011, 136–142 (2011).

  99. 99

    Liu, Y., Hernandez, A. M., Shibata, D. & Cortopassi, G. A. BCL2 translocation frequency rises with age in humans. Proc. Natl Acad. Sci. USA 91, 8910–8914 (1994).

  100. 100

    Limpens, J. et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 85, 2528–2536 (1995).

  101. 101

    Biernaux, C., Loos, M., Sels, A., Huez, G. & Stryckmans, P. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 86, 3118–3122 (1995).

  102. 102

    Cazzaniga, G. et al. Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia. Blood 118, 5559–5564 (2011).

  103. 103

    Leary, R. J. et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci. Transl. Med. 2, 20ra14 (2010).

Download references

Acknowledgements

The Year 2011 Working Conference on Cancer Stem Cells was supported by a Cancer Stem Cell Grant of the Medical University of Vienna, Austria. The authors would like to thank S. Sonnleitner and K. Krassel for their helpful technical support. H.E.J. was supported by the EU 6th FP to MSCNET (LSHC-CT-2006-037602). M.C. is supported by a Fellowship from the Scottish Funding Council (SCD/04) and J.V.M. by the NIHR Biomedical Research Centre Funding Scheme, UK.

Author information

Correspondence to Peter Valent or Connie Eaves.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1

Classification of therapies according to their effects (PDF 427 kb)

Supplementary information S2

Overview of Mechanisms of CSC Resistance to Therapy and Strategies to Overcome Resistance (PDF 199 kb)

Related links

Related links

FURTHER INFORMATION

Peter Valent's homepage

Connie Eaves' homepage

Rights and permissions

Reprints and Permissions

About this article

Further reading