Advertisement

Epidermal stem cells and cancer stem cells: Insights into cancer and potential therapeutic strategies

  • L.E. Finlan
    Correspondence
    Corresponding author: Tel.: +44 1382 348018; fax: +44 1382345386.
    Affiliations
    The Wellcome Trust Biocentre, Division of Cell and Developmental Biology, The University of Dundee, Dow Street, Dundee, Scotland DD1 5EH, UK
    Search for articles by this author
  • T.R. Hupp
    Affiliations
    The University of Edinburgh, Division of Oncology, CRUK Cancer Centre Laboratories, South Crewe Road, Edinburgh, EH4 2XU, UK
    Search for articles by this author

      Abstract

      Epithelial keratinocyte regeneration has been exemplified as dependent on a population of cellular progenitors that have retained developmental pluripotency, a latent capacity for proliferation and differentiation with a prolonged lifespan. Recent evidence suggests that the cell populations that regulate the development of normal tissues, and which play vital roles in maintaining the overall homeostasis of the tissue, might be the key target population that is essential for malignant cancer development, thus giving rise to the notion of ‘cancer stem cells’. This review examines the leading research into the relationship between adult stem cells in human skin marked by p63αΔN, their putative importance in cancer development, and how we might exploit our evolving knowledge of adult tissue stem cells to aid cancer treatments in the future. Furthermore, the review examines information regarding ataxia telangiectasia mutated (ATM) kinase and key regulatory events that take place on p53, only within putative keratinocyte stem cells that are transcriptionally regulated by p63αΔN.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Potten C.S.
        • Booth C.
        Keratinocyte stem cells: a commentary.
        J Invest Dermatol. 2002; 119: 888-899
        • Potten C.S.
        • Hume W.J.
        • Reid P.
        • Cairns J.
        The segregation of DNA in epithelial stem cells.
        Cell. 1978; 15: 899-906
        • Cleaver J.E.
        • Crowley E.
        UV damage, DNA repair and skin carcinogenesis.
        Front Biosci. 2002; 7: d1024-d1043
        • de Gruijl F.R.
        • van Kranen H.J.
        • Mullenders L.H.
        UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer.
        J Photochem Photobiol B. 2001; 63: 19-27
        • Hahn W.C.
        • Counter C.M.
        • Lundberg A.S.
        • Beijersbergen R.L.
        • Brooks M.W.
        • Weinberg R.A.
        Creation of human tumour cells with defined genetic elements.
        Nature. 1999; 400: 464-468
        • Hahn W.C.
        • Weinberg R.A.
        Rules for making human tumor cells.
        New Engl J Med. 2002; 347: 1593-1603
        • Zhang W.
        • Remenyik E.
        • Zelterman D.
        • Brash D.E.
        • Wikonkal N.M.
        Escaping the stem cell compartment: sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations.
        Proc Natl Acad Sci USA. 2001; 98: 13948-13953
        • Watt F.M.
        Stem cell fate and patterning in mammalian epidermis.
        Curr Opin Genet Dev. 2001; 11: 410-417
        • Brouard M.
        • Barrandon Y.
        Controlling skin morphogenesis: hope and despair.
        Curr Opin Biotechnol. 2003; 14: 520-525
        • Barrandon Y.
        • Green H.
        Three clonal types of keratinocyte with different capacities for multiplication.
        Proc Natl Acad Sci USA. 1987; 84: 2302-2306
        • Pellegrini G.
        • Dellambra E.
        • Golisano O.
        • et al.
        p63 identifies keratinocyte stem cells.
        Proc Natl Acad Sci USA. 2001; 98: 3156-3161
        • Brash D.E.
        • Ziegler A.
        • Jonason A.S.
        • Simon J.A.
        • Kunala S.
        • Leffell D.J.
        Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.
        J Investig Dermatol Symp Proc. 1996; 1: 136-142
        • Jonason A.S.
        • Kunala S.
        • Price G.J.
        • et al.
        Frequent clones of p53-mutated keratinocytes in normal human skin.
        Proc Natl Acad Sci USA. 1996; 93: 14025-14029
        • Ren Z.P.
        • Hedrum A.
        • Ponten F.
        • et al.
        Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes.
        Oncogene. 1996; 12: 765-773
        • Ren Z.P.
        • Ponten F.
        • Nister M.
        • Ponten J.
        Two distinct p53 immunohistochemical patterns in human squamous-cell skin cancer, precursors and normal epidermis.
        Int J Cancer. 1996; 69: 174-179
        • Jensen U.B.
        • Lowell S.
        • Watt F.M.
        The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis.
        Development. 1999; 126: 2409-2418
        • Clarke M.F.
        Self-renewal and solid-tumor stem cells.
        Biol Blood Marrow Transplant. 2005; 11: 14-16
        • Beachy P.A.
        • Karhadkar S.S.
        • Berman D.M.
        Tissue repair and stem cell renewal in carcinogenesis.
        Nature. 2004; 432: 324-331
        • Potten C.S.
        Keratinocyte stem cells, label-retaining cells and possible genome protection mechanisms.
        J Investig Dermatol Symp Proc. 2004; 9: 183-195
        • 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. 1989; 86: 4102-4106
        • Owens D.M.
        • Watt F.M.
        Contribution of stem cells and differentiated cells to epidermal tumours.
        Nat Rev Cancer. 2003; 3: 444-451
        • Morris R.J.
        A perspective on keratinocyte stem cells as targets for skin carcinogenesis.
        Differentiation. 2004; 72: 381-386
        • McKeon F.
        p63 and the epithelial stem cell: more than status quo?.
        Genes Dev. 2004; 18: 465-469
        • Yang A.
        • Schweitzer R.
        • Sun D.
        • et al.
        p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.
        Nature. 1999; 398: 714-718
        • Tiberio R.
        • Marconi A.
        • Fila C.
        • et al.
        Keratinocytes enriched for stem cells are protected from anoikis via an integrin signaling pathway in a Bcl-2 dependent manner.
        FEBS Lett. 2002; 524: 139-144
        • Kurata S.
        • Okuyama T.
        • Osada M.
        • et al.
        p51/p63 Controls subunit alpha3 of the major epidermis integrin anchoring the stem cells to the niche.
        J Biol Chem. 2004; 279: 50069-50077
        • Dohn M.
        • Zhang S.
        • Chen X.
        p63alpha and DeltaNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes.
        Oncogene. 2001; 20: 3193-3205
        • Wu G.
        • Nomoto S.
        • Hoque M.O.
        • et al.
        DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development.
        Cancer Res. 2003; 63: 2351-2357
        • Ghioni P.
        • Bolognese F.
        • Duijf P.H.
        • Van Bokhoven H.
        • Mantovani R.
        • Guerrini L.
        Complex transcriptional effects of p63 isoforms: identification of novel activation and repression domains.
        Mol Cell Biol. 2002; 22: 8659-8668
        • Yang A.
        • Kaghad M.
        • Wang Y.
        • et al.
        p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.
        Mol Cell. 1998; 2: 305-316
        • De Laurenzi V.
        • Melino G.
        Evolution of functions within the p53/p63/p73 family.
        Ann NY Acad Sci. 2000; 926: 90-100
        • Koster M.I.
        • Kim S.
        • Mills A.A.
        • DeMayo F.J.
        • Roop D.R.
        p63 is the molecular switch for initiation of an epithelial stratification program.
        Genes Dev. 2004; 18: 126-131
        • Nylander K.
        • Vojtesek B.
        • Nenutil R.
        • et al.
        Differential expression of p63 isoforms in normal tissues and neoplastic cells.
        J Pathol. 2002; 198: 417-427
        • Donehower L.A.
        • Harvey M.
        • Slagle B.L.
        • et al.
        Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.
        Nature. 1992; 356: 215-221
        • Mills A.A.
        • Zheng B.
        • Wang X.J.
        • Vogel H.
        • Roop D.R.
        • Bradley A.
        p63 is a p53 homologue required for limb and epidermal morphogenesis.
        Nature. 1999; 398: 708-713
        • Park B.J.
        • Lee S.J.
        • Kim J.I.
        • et al.
        Frequent alteration of p63 expression in human primary bladder carcinomas.
        Cancer Res. 2000; 60: 3370-3374
        • Yamaguchi K.
        • Wu L.
        • Caballero O.L.
        • et al.
        Frequent gain of the p40/p51/p63 gene locus in primary head and neck squamous cell carcinoma.
        Int J Cancer. 2000; 86: 684-689
        • Hibi K.
        • Trink B.
        • Patturajan M.
        • et al.
        AIS is an oncogene amplified in squamous cell carcinoma.
        Proc Natl Acad Sci USA. 2000; 97: 5462-5467
        • Melino G.
        • Lu X.
        • Gasco M.
        • Crook T.
        • Knight R.A.
        Functional regulation of p73 and p63: development and cancer.
        Trends Biochem Sci. 2003; 28: 663-670
        • Flores E.R.
        • Tsai K.Y.
        • Crowley D.
        • et al.
        p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.
        Nature. 2002; 416: 560-564
        • Barbieri C.E.
        • Barton C.E.
        • Pietenpol J.A.
        Delta Np63 alpha expression is regulated by the phosphoinositide 3-kinase pathway.
        J Biol Chem. 2003; 278: 51408-51414
        • Westfall M.D.
        • Mays D.J.
        • Sniezek J.C.
        • Pietenpol J.A.
        The DeltaNp63alpha phosphoprotein binds the p21 and 14-3-3sigma promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations.
        Mol Cell Biol. 2003; 23: 2264-2276
        • Dellambra E.
        • Golisano O.
        • Bondanza S.
        • et al.
        Downregulation of 14-3-3sigma prevents clonal evolution and leads to immortalization of primary human keratinocytes.
        J Cell Biol. 2000; 149: 1117-1130
        • Taniere P.
        • Martel-Planche G.
        • Saurin J.C.
        • et al.
        TP53 mutations, amplification of P63 and expression of cell cycle proteins in squamous cell carcinoma of the oesophagus from a low incidence area in Western Europe.
        Br J Cancer. 2001; 85: 721-726
        • Park H.R.
        • Min S.K.
        • Cho H.D.
        • Kim K.H.
        • Shin H.S.
        • Park Y.E.
        Expression profiles of p63, p53, survivin, and hTERT in skin tumors.
        J Cutan Pathol. 2004; 31: 544-549
        • Nylander K.
        • Coates P.J.
        • Hall P.A.
        Characterization of the expression pattern of p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions.
        Int J Cancer. 2000; 87: 368-372
        • Lo Muzio L.
        • Santarelli A.
        • Caltabiano R.
        • et al.
        p63 overexpression associates with poor prognosis in head and neck squamous cell carcinoma.
        Hum Pathol. 2005; 36: 187-194
        • Massion P.P.
        • Taflan P.M.
        • Rahman S.M.
        • et al.
        Role of p63 amplification and overexpression in lung cancer development.
        Chest. 2004; 125: 102S
        • Osada M.
        • Ohba M.
        • Kawahara C.
        • et al.
        Cloning and functional analysis of human p51, which structurally and functionally resembles p53.
        Nat Med. 1998; 4: 839-843
        • Di Como C.J.
        • Urist M.J.
        • Babayan I.
        • et al.
        p63 expression profiles in human normal and tumor tissues.
        Clin Cancer Res. 2002; 8: 494-501
        • Westfall M.D.
        • Pietenpol J.A.
        p63: Molecular complexity in development and cancer.
        Carcinogenesis. 2004; 25: 857-864
        • Wang T.Y.
        • Chen B.F.
        • Yang Y.C.
        • et al.
        Histologic and immunophenotypic classification of cervical carcinomas by expression of the p53 homologue p63: a study of 250 cases.
        Hum Pathol. 2001; 32: 479-486
        • Yaar M.
        • Gilchrest B.A.
        Ageing and photoageing of keratinocytes and melanocytes.
        Clin Exp Dermatol. 2001; 26: 583-591
        • Meek D.W.
        Mechanisms of switching on p53: a role for covalent modification?.
        Oncogene. 1999; 18: 7666-7675
        • Levine A.J.
        p53, the cellular gatekeeper for growth and division.
        Cell. 1997; 88: 323-331
        • Li G.
        • Mitchell D.L.
        • Ho V.C.
        • Reed J.C.
        • Tron V.A.
        Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice.
        Am J Pathol. 1996; 148: 1113-1123
        • Nakazawa H.
        • English D.
        • Randell P.L.
        • et al.
        UV and skin cancer: specific p53 gene mutation in normal skin as a biologically relevant exposure measurement.
        Proc Natl Acad Sci USA. 1994; 91: 360-364
        • Ziegler A.
        • Jonason A.S.
        • Leffell D.J.
        • et al.
        Sunburn and p53 in the onset of skin cancer.
        Nature. 1994; 372: 773-776
        • Ziegler A.
        • Jonason A.
        • Simon J.
        • Leffell D.
        • Brash D.E.
        Tumor suppressor gene mutations and photocarcinogenesis.
        Photochem Photobiol. 1996; 63: 432-435
        • Ren Z.P.
        • Ahmadian A.
        • Ponten F.
        • et al.
        Benign clonal keratinocyte patches with p53 mutations show no genetic link to synchronous squamous cell precancer or cancer in human skin.
        Am J Pathol. 1997; 150: 1791-1803
        • Qin J.Z.
        • Bacon P.E.
        • Chaturvedi V.
        • Bonish B.
        • Nickoloff B.J.
        Pathways involved in proliferating, senescent and immortalized keratinocyte cell death mediated by two different TRAIL preparations.
        Exp Dermatol. 2002; 11: 573-583
        • Qin J.Z.
        • Chaturvedi V.
        • Denning M.F.
        • et al.
        Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes.
        Oncogene. 2002; 21: 2991-3002
        • Marchbank A.
        • Su L.J.
        • Walsh P.
        • et al.
        The CUSP DeltaNp63alpha isoform of human p63 is downregulated by solar-simulated ultraviolet radiation.
        J Dermatol Sci. 2003; 32: 71-74
        • Liefer K.M.
        • Koster M.I.
        • Wang X.J.
        • Yang A.
        • McKeon F.
        • Roop D.R.
        Down-regulation of p63 is required for epidermal UV-B-induced apoptosis.
        Cancer Res. 2000; 60: 4016-4020
        • Beattie P.FL.
        • Hupp T.R.
        • Ibbotson S.H.
        The effect of UVA1, UVB and solar simulated radiation (SSR) on p53 activation and p21 Waf1/Cip1.
        Br J Dermatol. 2005;
        • Hall P.A.
        • McKee P.H.
        • Menage H.D.
        • Dover R.
        • Lane D.P.
        High levels of p53 protein in UV-irradiated normal human skin.
        Oncogene. 1993; 8: 203-207
        • Murphy M.
        • Mabruk M.J.
        • Lenane P.
        • et al.
        Comparison of the expression of p53, p21, Bax and the induction of apoptosis between patients with basal cell carcinoma and normal controls in response to ultraviolet irradiation.
        J Clin Pathol. 2002; 55: 829-833
        • Bruins W.
        • Zwart E.
        • Attardi L.D.
        • et al.
        Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389.
        Mol Cell Biol. 2004; 24: 8884-8894
        • Brunner H.G.
        • Hamel B.C.
        • Bokhoven Hv.H.
        P63 gene mutations and human developmental syndromes.
        Am J Med Genet. 2002; 112: 284-290
        • 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. 2003; 36: 59-72
        • Clarke R.B.
        • Spence K.
        • Anderson E.
        • Howell A.
        • Okano H.
        • Potten C.S.
        A putative human breast stem cell population is enriched for steroid receptor-positive cells.
        Dev Biol. 2005; 277: 443-456
        • Hanahan D.
        • Weinberg R.A.
        The hallmarks of cancer.
        Cell. 2000; 100: 57-70
        • Elrick L.J.
        • Jorgensen H.G.
        • Mountford J.C.
        • Holyoake T.L.
        Punish the parent not the progeny.
        Blood. 2005; 105: 1862-1866
        • Johnson R.A.
        • Shepard E.M.
        • Scotto K.W.
        Differential regulation of MDR1 transcription by the p53 family members: role of the DNA binding domain.
        J Biol Chem. 2005;
        • Wu G.
        • Osada M.
        • Guo Z.
        • et al.
        DeltaNp63alpha up-regulates the Hsp70 gene in human cancer.
        Cancer Res. 2005; 65: 758-766
        • Ihrie R.A.
        • Attardi L.D.
        A new Perp in the lineup: linking p63 and desmosomal adhesion.
        Cell Cycle. 2005; 4
        • Ihrie R.A.
        • Marques M.R.
        • Nguyen B.T.
        • et al.
        Perp is a p63-regulated gene essential for epithelial integrity.
        Cell. 2005; 120: 843-856