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  • Review Article
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Stem-cell hierarchy in skin cancer

Key Points

  • Cancer is not a cell-autonomous disease, but involves disruption of the complex system of controls exerted by the local microenvironment, as well as hormonal or immune-system components produced by the whole organism.

  • Cancer, like any other tissue that is capable of regeneration or progressive growth, must have cells with self-renewal capacity and a hierarchical architecture.

  • Although many tumours contain cells with the characteristics of stem cells, the identity of the normal cells that acquire the first genetic hits leading to initiation of carcinogenesis has remained elusive. Although expression of stem-cell markers might reflect the tumour cell of origin, it remains possible that these markers are induced by the oncogenic events that occur after the initiation of neoplastic growth.

  • It is likely that there is a continuum of target cells for carcinogenesis, and that combinations of the particular cells in which mutations occur, as well as the specific genes altered, are the main determinants of cell fate and malignant potential.

  • Tumour promoters, which are not in themselves mutagenic, might affect the specific choice of initiated cell that forms a visible lesion and allows the selection of particular target cells.

  • Oncogenic events allow proliferation and self-renewal genetic programmes to be reconciled within the developing tumour.

Abstract

Tumour architecture mimics many of the features of normal tissues, with a cellular hierarchy that regulates the balance between cell renewal and cell death. Although many tumours contain cells with the characteristics of stem cells, the identity of the normal cells that acquire the first genetic hits leading to initiation of carcinogenesis has remained elusive. Identification of the primary cell of origin of cancers and the mechanisms that influence cell-fate decisions will be crucial for the development of novel non-toxic therapies that influence tumour-cell behaviour.

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Figure 1: Cell communication in normal and cancer tissues.
Figure 2: Cell hierarchy in normal tissues and cancer.
Figure 3: A continuum of potential target cells for skin carcinogenesis.
Figure 4: The effect of specific genetic pathways on tumour-cell fate.
Figure 5: Effect of c-MYC overexpression on stem-cell hierarchy.

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References

  1. Donjacour, A. A. & Cunha, G. R. Stromal regulation of epithelial function. Cancer Treat. Res. 53, 335–364 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Paus, R., Peters, E. M., Eichmuller, S. & Botchkarev V, A. Neural mechanisms of hair growth control. J. Invest. Dermatol. Symp. Proc. 2, 61–68 (1997).

    Article  CAS  Google Scholar 

  3. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 7, 57–70 (2000).

    Article  Google Scholar 

  4. Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999). An important demonstration of the crucial role of the stromal environment in the malignant transformation of cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001). Provides evidence that humoral factors produced at distant sites can influence metastatic dissemination of tumour cells.

    Article  CAS  PubMed  Google Scholar 

  6. Szabowski, A. et al. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 103, 745–755 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  8. Kurose, K. et al. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nature Genet. 32, 355–357 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Yuspa, S. H. et al. Regulation of hair follicle development: an in vitro model for hair follicle invasion of dermis and associated connective tissue remodeling. J Invest. Dermatol. 101 (Suppl. 1), 27S–32S (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Gilbert, C. W. & Lajtha, L. G. in Cellular Radiation Biology 118–154 (Williams and Wilkins, Baltimore, Maryland, USA, 1965).

    Google Scholar 

  12. Mackenzie, I. C. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature 226, 653–655 (1970).

    Article  CAS  PubMed  Google Scholar 

  13. Hume, W. J. Keratinocyte proliferative hierarchies confer protective mechanisms in surface epithelia. Br. J. Dermatol. 112, 493–502 (1985).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Cobaleda, C. et al. A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood 95, 1007–1013 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Al–Hajj, M. et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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  PubMed  Google Scholar 

  22. Greaves, M. F. Differentiation-linked leukemogenesis in lymphocytes. Science 234, 697–704 (1986).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Potten, C. S. & Booth, C. Keratinocyte stem cells: a commentary. J. Invest. Dermatol. 119, 888–899 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Kamimura, J., Lee, D., Baden, H. P., Brissette, J. & Dotto, G. P. Primary mouse keratinocyte cultures contain hair follicle progenitor cells with multiple differentiation potential. J. Invest. Dermatol. 109, 534–540 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Ghazizadeh, S. & Taichman, L. B. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 20, 1215–1222 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cotsarelis, G., Sun, T. T. & Lavker, R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 329–337 (1990).

    Article  Google Scholar 

  29. Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T. T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Rochat, A., Kobayashi, K. & Barrandon, Y. Location of stem cells of human hair follicles by clonal analysis. Cell 76, 1063–1073 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Potten, C. S. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int. Rev. Cytol. 69, 271–318 (1981).

    Article  CAS  PubMed  Google Scholar 

  32. Klein-Szanto, A. J., Ruggeri, B., Bianchi, A. & Conti, C. J. Cellular and molecular changes during mouse skin tumor progression. Recent Results Cancer Res. 128, 193–204 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Frame, S. & Balmain, A. Integration of positive and negative growth signals during Ras pathway activation in vivo. Curr. Opin. Genet. Dev. 10, 106–113 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Hunter, J. A., Savin J. A. & Dahl M V. Clinical Dermatology (Blackwell Science, Oxford, 1995).

    Google Scholar 

  35. Barrandon, Y., Morgan, J. R., Mulligan, R. C. & Green, H. Restoration of growth potential in paraclones of human keratinocytes by a viral oncogene. Proc. Natl Acad. Sci. USA 86, 4102–4106 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell. 3, 565–577 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. 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). See reference 39.

    Article  CAS  PubMed  Google Scholar 

  38. Greenhalgh, D. A. et al. Induction of epidermal hyperplasia, hyperkeratosis, and papillomas in transgenic mice by a targeted v-Ha-ras oncogene. Mol. Carcinog. 7, 99–110 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. 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). This article (together with reference 37) shows that benign tumours that are at risk of malignant conversion are primarily derived from cells located within the hair follicle, whereas papillomas with very low malignant potential can arise from the interfollicular or suprabasal cells. Together, these papers show that the nature of the cell in which tumour initiation occurs is one of the main determinants of malignant potential.

    Article  CAS  PubMed  Google Scholar 

  40. Wang, X. J., Liefer, K. M., Greenhalgh, D. A. & Roop, D. R. 12-O-tetradecanoylphorbol-13-acetate promotion of transgenic mouse epidermis coexpressing transforming growth factor-alpha and v-fos: acceleration of autonomous papilloma formation and malignant conversion via c-Ha-ras activation. Mol. Carcinog. 26, 305–311 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Cairns, J. Mutation selection and the natural history of cancer. Nature 255, 197–200 (1975)

    Article  CAS  PubMed  Google Scholar 

  42. Cairns, J. Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc. Natl Acad. Sci. USA 99, 10567–10570 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Balmain, A., Ramsden, M., Bowden, G. T. & Smith, J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307, 658–660 (1984).

    Article  CAS  PubMed  Google Scholar 

  44. Quintanilla, M., Brown, K., Ramsden, M. & Balmain, A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322, 78–80 (1986).

    Article  CAS  PubMed  Google Scholar 

  45. Hennings, H., Shores, R., Mitchell, P., Spangler, E. F. & Yuspa, S. H. Induction of papillomas with a high probability of conversion to malignancy. Carcinogenesis 6, 1607–1610 (1985).

    Article  CAS  PubMed  Google Scholar 

  46. Tennenbaum, T. et al. The suprabasal expression of α6β4 integrin is associated with a high risk for malignant progression in mouse skin carcinogenesis Cancer Res. 53, 4803–4810 (1993).

    CAS  PubMed  Google Scholar 

  47. Cano, A. et al. Expression pattern of the cell adhesion molecules. E-cadherin, P-cadherin and alpha-6 beta-4 intergrins is altered in pre-malignant skin tumors of p53-deficient mice. Int. J. Cancer 65, 254–262 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Argyris, T. S. Promotion of epidermal carcinogenesis by repeated damage to mouse skin. Am. J. Ind. Med. 8, 329–337 (1985).

    Article  CAS  PubMed  Google Scholar 

  49. Morris, R. J., Tryson, K. A. & Wu, K. Q. Evidence that the epidermal targets of carcinogen action are found in the interfollicular epidermis of infundibulum as well as in the hair follicles. Cancer Res. 15, 226–229 (2000).

    Google Scholar 

  50. Reynolds, A. J. & Jahoda, C. A. Cultured dermal papilla cells induce follicle formation and hair growth by transdifferentiation of an adult epidermis. Development 115, 587–593 (1992).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. Levy, L., Broad, S., Diekmann, D., Evans, R. D. & Watt, F. M. Beta1 integrins regulate keratinocyte adhesion and differentiation by distinct mechanisms. Mol. Biol. Cell. 11, 453–466 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, A., Simmons, P. J. & Kaur, P. Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proc. Natl Acad. Sci. USA 95, 3902–3907 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tani, H., Morris, R. J. & Kaur, P. Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc. Natl Acad. Sci. USA 97, 10960–10965 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Van Duuren, B. L., Sivak, A., Katz, C., Seidman, I. & Melchionne, S. The effect of ageing and interval between primary and secondary treatment in two-stage carcinogenesis on mouse skin. Cancer Res. 35, 502–505 (1975). Classic work in which the authors showed that the initiating effect of the carcinogen persists even when the interval between initiation and promotion is more than 1 year.

    CAS  PubMed  Google Scholar 

  56. Jonason, A. S. et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA 93, 14025–14029 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rehman, I. et al. Frequent codon 12 Ki-ras mutations in mouse skin tumors initiated by N-methyl-N′-nitro-N-nitrosoguanidine and promoted by mezerein. Mol. Carcinog. 27, 298–307 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Megosh, L., Halpern, M., Farkash, E. & O'Brien, T. G. Analysis of ras gene mutational spectra in epidermal papillomas from K6/ODC transgenic mice. Mol. Carcinog. 22, 145–149 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Aydinlik, H., Nguyen, T. D., Moennikes, O., Buchmann, A. & Schwarz, M. Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta-catenin-mutated mouse liver tumors. Oncogene 20, 7812–7816 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. Yamasaki, H. et al. Comparative effects of a complete tumor promoter, TPA, and a second-stage tumor promoter, RPA, on intercellular communication, cell differentiation and cell transformation. Carcinogenesis 6, 1173–1179 (1985).

    Article  CAS  PubMed  Google Scholar 

  62. Mackenzie, I. C. & Bickenbach, J. R. Label-retaining keratinocytes and Langerhans cells in mouse epithelia. Cell Tissue Res. 242, 551–556 (1985).

    Article  CAS  PubMed  Google Scholar 

  63. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 95, 605–614 (1998). Shows that the expression of β-catenin in the basal layer induces hair-follicle formation and specific hair tumours. Conversely, deletion of β-catenin (reference 74) in the basal layer induces the targeted cells to adopt an epidermal cell fate.

    Article  CAS  PubMed  Google Scholar 

  64. Niemann, C., Owens, D. M., Hulsken, J., Birchmeier, W. & Watt, F. M. Expression of DeltaNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours. Development 129, 95–109 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genet. 24, 216–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Nilsson, M. et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc. Natl Acad. Sci. USA 97, 3438–3443 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. van Hogerlinden, M., Rozell, B. L., Ahrlund-Richter, L. & Toftgard, R. Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res. 59, 3299–3303 (1999).

    CAS  PubMed  Google Scholar 

  69. Seitz, C. S., Lin, Q., Deng, H. & Khavari, P. A. Alterations in NF-kappaB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kappaB. Proc. Natl Acad. Sci. USA 95, 2307–2312 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dajee, M. et al. NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Toftgard, R. Hedgehog signalling in cancer. Cell. Mol. Life Sci. 57, 1720–1731 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Bonifas, J. M. et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J. Invest. Dermatol. 116, 739–742 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001). See reference 63.

    Article  CAS  PubMed  Google Scholar 

  75. Vassar, R., Rosenberg, M., Ross, S., Tyner, A. & Fuchs, E. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc. Natl Acad. Sci. USA 86, 1563–1567 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Byrne, C. & Fuchs, E. Probing keratinocyte and differentiation specificity of the human K5 promoter in vitro and in transgenic mice. Mol. Cell. Biol. 13, 3176–3190 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lavker, R. M. & Sun, T. T. Epidermal stem cells: properties, markers, and location. Proc. Natl Acad. Sci. USA 97, 13473–13475 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Potten, C. S. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet. 7, 77–88 (1974).

    CAS  PubMed  Google Scholar 

  80. Furstenberger, G., Gross, M., Schweizer, J., Vogt, I. & Marks, F. Isolation, characterization and in vitro cultivation of subfractions of neonatal mouse keratinocytes: effects of phorbol esters. Carcinogenesis 7, 1745–1753 (1986).

    Article  CAS  PubMed  Google Scholar 

  81. Yuspa, S. H., Ben, T., Hennings, H. & Lichti, U. Divergent responses in epidermal basal cells exposed to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 42, 2344–2349 (1982).

    CAS  PubMed  Google Scholar 

  82. Parkinson, E. K., Grabham, P. & Emmerson, A. A subpopulation of cultured human keratinocytes which is resistant to the induction of terminal differentiation-related changes by phorbol, 12-myristate,13-acetate: evidence for an increase in the resistant population following transformation. Carcinogenesis 4, 857–861 (1983).

    Article  CAS  PubMed  Google Scholar 

  83. Morris, R. J., Fischer, S. M. & Slaga, T. J. Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. J. Invest. Dermatol. 84, 277–281 (1985).

    Article  CAS  PubMed  Google Scholar 

  84. Gandarillas, A. & Watt, F. M. c-Myc promotes differentiation of human epidermal stem cells. Genes Dev. 11, 2869–2882 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Waikel, R. L., Kawachi, Y., Waikel, P. A., Wang, X. J. & Roop, D. R. Deregulated expression of c-Myc depletes epidermal stem cells. Nature Genet. 28, 165–168 (2001). Shows that constitutive expression of c-Myc in basal epidermal cells causes depletion of the stem-cell pool, indicating a role for c-Myc as a regulator of epidermal stem-cell maintenance. See also reference 86.

    Article  CAS  PubMed  Google Scholar 

  86. Arnold, I. & Watt, F. M. c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny. Curr. Biol. 11, 558–568 (2001). See reference 85.

    Article  CAS  PubMed  Google Scholar 

  87. Frye, M., Gardner, C., Li, E. R., Arnold, I. & Watt, F. M. Evidence that c-Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment. Development 130, 2793–2808 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Fidler, I. J. The biology of human cancer metastasis. 7th Jan Waldenstrom Lecture. Acta Oncol. 30, 668–675 (1991).

    Article  CAS  PubMed  Google Scholar 

  89. Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Gimbrone, M. A. Jr, Cotran, R. S., Leapman, S. B. & Folkman, J. Tumor growth and neovascularization: an experimental model using the rabbit cornea. J. Natl Cancer Inst. 52, 413–427 (1974).

    Article  PubMed  Google Scholar 

  91. Naumov, G. N., MacDonald, I. C., Chambers, A. F. & Groom, A. C. Solitary cancer cells as a possible source of tumour dormancy? Semin. Cancer Biol. 11, 271–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Holyoake, T. L. et al. Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood 97, 720–728 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. van Rhee, F. et al. Detection of residual leukaemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant. 14, 609–612 (1994).

    CAS  PubMed  Google Scholar 

  94. Yong, A. S. & Goldman, J. M. Relapse of chronic myeloid leukaemia 14 years after allogeneic bone marrow transplantation. Bone Marrow Transplant. 23, 827–828 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Woodruff, M. Interaction of cancer and host (the Walter Hubert Lecture, 1982). Br. J. Cancer 46, 313–322 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Callaway, M. P. & Briggs, J. C. The incidence of later recurrence (greater than 10 years): an analysis of 536 consecutive cases of cutaneous melanoma. Br. J. Plast. Surg. 42, 46–49 (1989).

    Article  CAS  PubMed  Google Scholar 

  97. van de Vijver, M. J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Bernards, R. & Weinberg, R. A. A progression puzzle. Nature 418, 823 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Bruserud, O. & Gjertsen, B. T. New strategies for the treatment of acute myelogenous leukemia: differentiation induction — present use and future possibilities. Stem Cells 18, 57–65 (2000).

    Google Scholar 

  101. Demetri, G. D. et al. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor–gamma ligand troglitazone in patients with liposarcoma. Proc. Natl Acad. Sci. USA 96, 3951–3956 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the authors' laboratory is supported by a grant from the National Cancer Institute's Mouse Models of Human Cancer Consortium. We would like to acknowledge numerous colleagues for useful discussions and comments on the manuscript. J.P.-L is the recipient of a Fellowship support of the 'Ministerio de Educacion y Ciencia' of Spain. A.B. would like to acknowledge the continued encouragement and support of B. Bass Bakar and S. Lloyd.

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DATABASES

LocusLink

α6 integrin

β1 integrin

β-catenin

Cdkn2a

Egfr

GLI1

GLI2

Hras

IκBα

keratin-5

keratin-14

Kras

LEF1

Myc

NF-κB

PTCH

Ras

RAS

Tgf-α

TP53

Glossary

BULGE

Region of the outer root sheath in the hair follicle that lies adjacent to the insertion of the arrector pili muscle, and where the stem cells reside.

ASYMMETRICAL CELL DIVISION

Mitosis in which one stem cell leads to one new daughter stem cell and another cell that differentiates along a particular lineage.

SYMMETRICAL CELL DIVISION

Mitosis in which one stem cell leads to two identical stem cells or two identical more-differentiated cells.

TRANSIT AMPLIFYING CELLS

Skin-cell population defined as cells that are able to divide only 3–5 times before all of their daughters terminally differentiate.

HYPERPLASIA

Enlargement of a tissue or organ due to an increase in the number of cells without cytological or architectural tissue abnormalities. This is normally reversible after the stimulus disappears.

DYSPLASIA

Premalignant lesion that shows signs of increased proliferation, as well as cytological or architectural tissue abnormalities. It can be reversible when the stimulus ceases.

SKIN PAPILLOMA

Benign tumour showing increased proliferation and a high degree of differentiation. The proliferating cells do not penetrate the epithelial basement membrane.

SQUAMOUS INVASIVE CARCINOMA

Malignant epithelial lesion with many cytological and architectural tissue abnormalities; the cells have penetrated the epithelial basement membrane and invaded the dermis.

SPINDLE CARCINOMA

Poorly differentiated carcinoma variant, which is highly aggressive, and in which a high proportion of the cells resemble fibroblasts.

TUMOUR INITIATION

The first step in the process of transformation, usually involving a mutation that converts the target epidermal cell into a latent initiated cell that is capable of undergoing clonal selection to become a tumour.

TUMOUR PROMOTER

An exogenously applied molecule or agent (or endogenous growth factor) that stimulates the growth and selection of the initiated cell that carries the first mutation.

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Perez-Losada, J., Balmain, A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer 3, 434–443 (2003). https://doi.org/10.1038/nrc1095

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