Archives of Toxicology

, Volume 87, Issue 5, pp 783–798

Non-melanoma skin cancer in mouse and man

  • Michael Schwarz
  • Peter A. Münzel
  • Albert Braeuning
Review Article


As a frontier organ, skin is exposed to different environmental and/or occupational chemicals which cause cutaneous cancers in experimental animals. In mice, 7,12-dimethylbenz[a]anthrancene (DMBA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are frequently used as skin model tumor initiator and promoter, respectively. The sequential administration of DMBA and TPA leads to the appearance of a large number of benign papillomas, of which some convert later into invasive squamous cell carcinomas (SCC). At the molecular level, initiation of carcinogenesis in mouse skin consists in the mutational activation of the Ha-ras oncoprotein. HA-RAS mutations are rare in human SCC, but HA-RAS-mutated tumors appear in melanoma patients treated with B-raf inhibitors, indicating that initiated, HA-RAS-mutated stem cells also reside in human skin. Similarly, UV-induced human SCC show footprint mutations in the tumor suppressor gene TP53 which are also observed in UV-induced mouse SCC. Strong species differences exist with respect to phorbol ester-mediated tumor promotion. While certain mouse strains are very susceptible, other rodent species are much less sensitive. Likewise, humans appear to be much more resistant to phorbol ester-mediated skin toxicity. Papilloma formation as a result of a chemical insult is uncommon in men, questioning the relevance of this preneoplastic lesion for humans. However, skin tumorigenesis in the experimental situation and in humans appears to follow common molecular mechanisms, even though there are species differences in the morphological correlates to the preneoplastic state. Therefore, we recommend not simply labeling them as irrelevant for human risk assessment.


Papilloma Chemical carcinogenesis Ha-ras signaling Wnt signaling Phorbol ester Squamous cell carcinoma 


  1. Adams CL, Nelson WJ, Smith SJ (1996) Quantitative analysis of cadherin-catenin-actin reorganization during development of cell–cell adhesion. J Cell Biol 135(6 Pt 2):1899–1911PubMedCrossRefGoogle Scholar
  2. Allen TD, Potten CS (1974) Fine-structural identification and organization of the epidermal proliferative unit. J Cell Sci 15(2):291–319PubMedGoogle Scholar
  3. Balmain A, Brown K (1988) Oncogene activation in chemical carcinogenesis. Adv Cancer Res 51:147–182PubMedCrossRefGoogle Scholar
  4. Beaudoin GM 3rd, Sisk JM, Coulombe PA, Thompson CC (2005) Hairless triggers reactivation of hair growth by promoting Wnt signaling. Proc Natl Acad Sci USA 102(41):14653–14658PubMedCrossRefGoogle Scholar
  5. Berenblum I, Shubik P (1947) A new, quantitative, approach to the study of the stages of chemical cartinogenesis in the mouse’s skin. Br J Cancer 1(4):383–391PubMedCrossRefGoogle Scholar
  6. Bertsch S, Marks F (1974) Lack of an effect of tumor-promoting phorbol esters and of epidermal G1 chalone or DNA synthesis in the epidermis of newborn mice. Cancer Res 34(12):3283–3288PubMedGoogle Scholar
  7. Boutwell RK (1964) Some biological aspects of skin carcinogenesis. Prog Exp Tumor Res 19:207–250Google Scholar
  8. Boutwell RK, Verma AK, Ashendel CL, Astrup E (1992) Mouse skin: a useful model system for studying the mechanism of chemical carcinogenesis. In: Hecker E, Fusenig N, Kunz W, Marks F, Thielmann HW (eds) Carcinogenesis: a comprehensive survey, vol 7. Raven Press, New YorkGoogle Scholar
  9. Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Ponten J (1991) A role of sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 88:10124–10128PubMedCrossRefGoogle Scholar
  10. Brown K, Quintanilla M, Ramsden M, Kerr IB, Young S, Balmain A (1986) v-ras genes from Harvey and BALB murine sarcoma viruses can act as initiators of two-stage mouse skin carcinogenesis. Cell 46(3):447–456PubMedCrossRefGoogle Scholar
  11. Brown K, Buchmann A, Balmain A (1990) Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumor progression. Proc Natl Acad Sci U S A 87(2):538–542PubMedCrossRefGoogle Scholar
  12. Brown K, Strathdee D, Bryson S, Lambie W, Balmain A (1998) The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr Biol 8(9):516–524PubMedCrossRefGoogle Scholar
  13. Buchmann A, Ruggeri B, Klein-Szanto AJ, Balmain A (1991) Progression of squamous carcinoma cells to spindle carcinomas of mouse skin is associated with an imbalance of H-ras alleles on chromosome 7. Cancer Res 51(15):4097–4101PubMedGoogle Scholar
  14. Burns F, Albert R, Altshuler B, Morris E (1983) Approach to risk assessment for genotoxic carcinogens based on data from the mouse skin initiation-promotion model. Environ Health Perspect 50:309–320PubMedCrossRefGoogle Scholar
  15. Burns FJ, Albert RE, Altschuler B (1984) Cancer progression in mouse skin. In: Saga TJ (ed) Mechanisms of tumor promotion, vol 2. CRC Press, Boca Raton, pp 17–39Google Scholar
  16. Cacace AM, Ueffing M, Philipp A, Han EKH, Kolch W, Weinstein IB (1996) PKC epsilon functions as an oncogene by enhancing activation of the Raf kinase. Oncogene 13(12):2517–2526PubMedGoogle Scholar
  17. Cachon-Gonzalez MB, Fenner S, Coffin JM, Moran C, Best S, Stoye JP (1994) Structure and expression of the hairless gene of mice. Proc Natl Acad Sci U S A 91(16):7717–7721PubMedCrossRefGoogle Scholar
  18. Chan EF, Gat U, McNiff JM, Fuchs E (1999) A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet 21(4):410–413PubMedCrossRefGoogle Scholar
  19. Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, Akhurst RJ (1996) TGF-beta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86:531–542PubMedCrossRefGoogle Scholar
  20. Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ, Marinkovich MP, Tao S, Lin Q, Kubo Y, Khavari PA (2003) NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421(6923):639–643PubMedCrossRefGoogle Scholar
  21. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91(2):231–241PubMedCrossRefGoogle Scholar
  22. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278(5338):687–689PubMedCrossRefGoogle Scholar
  23. Dipple A, Pigott M, Moschel RC, Costantino N (1983) Evidence that binding of 7,12-dimethylbenz(a)anthracene to DNA in mouse embryo cell cultures results in extensive substitution of both adenine and guanine residues. Cancer Res 43(9):4132–4135PubMedGoogle Scholar
  24. Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova-Kovacs G, Sibilia M, Baccarini M (2009) Raf-1 addiction in Ras-induced skin carcinogenesis. Cancer Cell 16(2):149–160PubMedCrossRefGoogle Scholar
  25. Fan H, Oro AE, Scott MP, Khavari PA (1997) Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog. Nat Med 3(7):788–792PubMedCrossRefGoogle Scholar
  26. Finch JS, Albino HE, Bowden GT (1996) Quantitation of early clonal expansion of two mutant 61st codon c-Ha-ras alleles in DMBA/TPA treated mouse skin by nested PCR/RFLP. Carcinogenesis 17(12):2551–2557PubMedCrossRefGoogle Scholar
  27. Friedewald WF, Rous P (1944a) The determining influence of tar, benzpyrene, and methylcholanthrene on the character of the benign tumors induced therewith in rabbit skin. J Exp Med 80(2):127–144PubMedCrossRefGoogle Scholar
  28. Friedewald WF, Rous P (1944b) The initiating and promoting elements in tumor production : an analysis of the effects of tar, benzpyrene, and methylcholanthrene on rabbit skin. J Exp Med 80(2):101–126PubMedCrossRefGoogle Scholar
  29. Fujiki H, Suganuma M (1993) Tumor promotion by inhibitors of protein phosphatases 1 and 2A: the okadaic acid class of compounds. Adv Cancer Res 61:143–194PubMedCrossRefGoogle Scholar
  30. Fujiki H, Suganuma M (2005) Translational research on TNF-alpha as an endogenous tumor promoter and green tea as cancer preventive in humans. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 23(1):3–30PubMedGoogle Scholar
  31. Fujiki H, Suganuma M (2009) Carcinogenic aspects of protein phosphatase 1 and 2A inhibitors. Prog Mol Subcell Biol 46:221–254PubMedCrossRefGoogle Scholar
  32. Furstenberger G, Kopp-Schneider A (1995) Malignant progression of papillomas induced by the initiation–promotion protocol in NMRI mouse skin. Carcinogenesis 16(1):61–69PubMedCrossRefGoogle Scholar
  33. Furstenberger G, Berry DL, Sorg B, Marks F (1981) Skin tumor promotion by phorbol esters is a two-stage process. Proc Natl Acad Sci U S A 78(12):7722–7726PubMedCrossRefGoogle Scholar
  34. Furstenberger G, Kinzel V, Schwarz M, Marks F (1985a) Partial inversion of the initiation-promotion sequence of multistage tumorigenesis in the skin of NMRI mice. Science 230(4721):76–78PubMedCrossRefGoogle Scholar
  35. Furstenberger G, Schweizer J, Marks F (1985b) Development of phorbol ester responsiveness in neonatal mouse epidermis: correlation between hyperplastic response and sensitivity to first-stage tumor promotion. Carcinogenesis 6(2):289–294PubMedCrossRefGoogle Scholar
  36. Gailani MR, Stahle Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R (1996) The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 14(1):78–81PubMedCrossRefGoogle Scholar
  37. Gat U, DasGupta R, Degenstein L, Fuchs E (1998) De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 95(5):605–614PubMedCrossRefGoogle Scholar
  38. Ghazizadeh S, Taichman LB (2001) Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J 20(6):1215–1222PubMedCrossRefGoogle Scholar
  39. Goerttler K, Loehrke H, Schweizer J, Hesse B (1980a) Positive two-stage carcinogenesis in female Sprague-Dawley rats using 7,12-dimethylbenz(a)anthracene (dmba) as initiator and 12-o-tetradecanoylphorbol-13-acetate (tps) as promotor. Results of a pilot study. Virchows Arch A Pathol Anat Histol 385(2):181–186PubMedCrossRefGoogle Scholar
  40. Goerttler K, Loehrke H, Schweizer J, Hesse B (1980b) Two-stage tumorigenesis of dermal melanocytes in the back skin of the Syrian golden hamster using systemic initiation with 7,12-dimethylbenz(a)anthracene and topical promotion with 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 40(1):155–161PubMedGoogle Scholar
  41. Goerttler K, Loehrke H, Hesse B, Schweizer J (1984) Skin tumor formation in the European hamster (Cricetus cricetus L.) after topical initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Carcinogenesis 5(4):521–524PubMedCrossRefGoogle Scholar
  42. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85(6):841–851PubMedCrossRefGoogle Scholar
  43. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, Da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281(5382):1509–1512PubMedCrossRefGoogle Scholar
  44. He J, Sheng T, Stelter AA, Li C, Zhang X, Sinha M, Luxon BA, Xie J (2006) Suppressing Wnt signaling by the hedgehog pathway through sFRP-1. J Biol Chem 281(47):35598–35602PubMedCrossRefGoogle Scholar
  45. Hecker E (1963) Über die Wirkstoffe des Crotonöls. Z Krebsforsch 65:325–333CrossRefGoogle Scholar
  46. Hecker E (1981) Cocarcinogenesis and tumor promoters of the diterpene ester type as possible carcinogenic risk factors. J Cancer Res Clin Oncol 99(1–2):103–124PubMedCrossRefGoogle Scholar
  47. Hecker E (1987) Three stage carcinogenesis in mouse skin–recent results and present status of an advanced model system of chemical carcinogenesis. Toxicol Pathol 15(2):245–258PubMedCrossRefGoogle Scholar
  48. Hennings H, Spangler EF, Shores R, Mitchell P, Devor D, Shamsuddin AK, Elgjo KM, Yuspa SH (1986) Malignant conversion and metastasis of mouse skin tumors: a comparison of Sencar and CD-1 mice. Environ Health Perspect 68:69–74PubMedCrossRefGoogle Scholar
  49. Hennings H, Glick AB, Lowry DT, Krsmanovic LS, Sly LM, Yuspa SH (1993) FVB/N mice: an inbred strain sensitive to the chemical induction of squamous cell carcinomas in the skin. Carcinogenesis 14(11):2353–2358PubMedCrossRefGoogle Scholar
  50. Hickey TA, Worobec SM, West DP, Kinghorn AD (1981) Irritant contact dermatitis in humans from phorbol and related esters. Toxicon 19(6):841–850PubMedCrossRefGoogle Scholar
  51. Holsti P (1959) Tumor promoting effects of some long chain fatty acids in experimental skin carcinogenesis in the mouse. Acta Pathol Microbiol Scand 46(1):51–58PubMedCrossRefGoogle Scholar
  52. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W (2001) beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105(4):533–545PubMedCrossRefGoogle Scholar
  53. Hunter T (1997) Oncoprotein networks. Cell 88(3):333–346PubMedCrossRefGoogle Scholar
  54. Ingham PW (1998) Transducing Hedgehog: the story so far. EMBO J 17(13):3505–3511PubMedCrossRefGoogle Scholar
  55. Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, Cotsarelis G (2005) Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11(12):1351–1354PubMedCrossRefGoogle Scholar
  56. Jansen LA, Mesnil M, Jongen WM (1996) Inhibition of gap junctional intercellular communication and delocalization of the cell adhesion molecule E-cadherin by tumor promoters. Carcinogenesis 17(7):1527–1531PubMedCrossRefGoogle Scholar
  57. Jensen PJ, Telegan B, Lavker RM, Wheelock MJ (1997) E-cadherin and P-cadherin have partially redundant roles in human epidermal stratification. Cell Tissue Res 288(2):307–316PubMedCrossRefGoogle Scholar
  58. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272(5268):1668–1671PubMedCrossRefGoogle Scholar
  59. Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, Leffell DJ, Tarone RE, Brash DE (1996) Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci USA 93(24):14025–14029PubMedCrossRefGoogle Scholar
  60. Kajino Y, Yamaguchi A, Hashimoto N, Matsuura A, Sato N, Kikuchi K (2001) beta-Catenin gene mutation in human hair follicle-related tumors. Pathol Int 51(7):543–548PubMedCrossRefGoogle Scholar
  61. Kallassy M, Toftgard R, Ueda M, Nakazawa K, Vorechovsky I, Yamasaki H, Nakazawa H (1997) Patched (ptch)-associated preferential expression of smoothened (smoh) in human basal cell carcinoma of the skin. Cancer Res 57(21):4731–4735PubMedGoogle Scholar
  62. Kemp CJ, Donehower LA, Bradley A, Balmain A (1993) Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell 74:813–822PubMedCrossRefGoogle Scholar
  63. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D, Rapp UR (1993) Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 364(6434):249–252PubMedCrossRefGoogle Scholar
  64. Kopp-Schneider A, Portier CJ (1992) Birth and death/differentiation rates of papillomas in mouse skin. Carcinogenesis 13(6):973–978PubMedCrossRefGoogle Scholar
  65. Kraemer KH (1997) Sunlight and skin cancer: another link revealed. Proc Natl Acad Sci U S A 94(1):11–14PubMedCrossRefGoogle Scholar
  66. Kress S, Sutter C, Strickland PT, Mukhtar H, Schweizer J, Schwarz M (1992) Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin. Cancer Res 52:6400–6403PubMedGoogle Scholar
  67. Kwa RE, Campana K, Moy RL (1992) Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol 26(1):1–26PubMedCrossRefGoogle Scholar
  68. Lazar AJ, Calonje E, Grayson W, Dei Tos AP, Mihm MC Jr, Redston M, McKee PH (2005) Pilomatrix carcinomas contain mutations in CTNNB1, the gene encoding beta-catenin. J Cutan Pathol 32(2):148–157PubMedCrossRefGoogle Scholar
  69. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16(1):64–67PubMedCrossRefGoogle Scholar
  70. Lustig B, Behrens J (2003) The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 129(4):199–221PubMedGoogle Scholar
  71. Lutz WK, Beland PE, Candrian R, Fekete T, Fischer WH (1996) Dose-time response in mouse skin tumor induction by 7, 12-dimethylbenz[a]anthracene and 12-O-tetradecanoyl-phorbol-13-acetate. Regul Toxicol Pharmacol 23(1 Pt 1):44–48PubMedCrossRefGoogle Scholar
  72. Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, Huber M, Hohl D, Cano A, Birchmeier W, Huelsken J (2008) Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452(7187):650–653PubMedCrossRefGoogle Scholar
  73. Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3(6):459–465PubMedCrossRefGoogle Scholar
  74. Manoukian AS, Woodgett JR (2002) Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv Cancer Res 84:203–229PubMedCrossRefGoogle Scholar
  75. Marais R, Light Y, Mason C, Paterson H, Olson MF, Marshall CJ (1998) Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C. Science 280(5360):109–112PubMedCrossRefGoogle Scholar
  76. Marks F, Furstenberger G (1990) The conversion stage of skin carcinogenesis. Carcinogenesis 11(12):2085–2092PubMedCrossRefGoogle Scholar
  77. Marks F, Schwarz M, Fürstenberger G (1995) Promotion and cocarcinogenesis. In: Arcos JC, Argus MF, Woo YT (eds) Chemical induction of cancer. Birkhäuser, Boston, pp 123–160CrossRefGoogle Scholar
  78. Marte BM, Downward J (1997) PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 22(9):355–358PubMedCrossRefGoogle Scholar
  79. Martinez VD, Becker-Santos DD, Vucic EA, Lam S, Lam WL (2011) Induction of human squamous cell-type carcinomas by arsenic. J Skin Cancer 2011:454157PubMedGoogle Scholar
  80. McGrath JA, McMillan JR, Shemanko CS, Runswick SK, Leigh IM, Lane EB, Garrod DR, Eady RA (1997) Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nat Genet 17(2):240–244PubMedCrossRefGoogle Scholar
  81. Miller SJ, Sun TT, Lavker RM (1993) Hair follicles, stem cells, and skin cancer. J Invest Dermatol 100(3):288S–294SPubMedCrossRefGoogle Scholar
  82. Moolgavkar SH (1983) Model for human carcinogenesis: action of environmental agents. Environ Health Perspect 50:285–291PubMedCrossRefGoogle Scholar
  83. Moraitis AN, Giguere V (2003) The co-repressor hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation. J Biol Chem 278(52):52511–52518PubMedCrossRefGoogle Scholar
  84. Mottram JC (1944) A developing factor in experimental blastogenesis. J Pathol Bacteriol 56(2):181–187CrossRefGoogle Scholar
  85. Mueller MM (2006) Inflammation in epithelial skin tumours: old stories and new ideas. Eur J Cancer 42(6):735–744PubMedCrossRefGoogle Scholar
  86. Nishizuka Y (1988) The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334(6184):661–665PubMedCrossRefGoogle Scholar
  87. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH Jr, Scott MP (1997) Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276(5313):817–821PubMedCrossRefGoogle Scholar
  88. Owens DM, Watt FM (2003) Contribution of stem cells and differentiated cells to epidermal tumours. Nat Rev Cancer 3(6):444–451PubMedCrossRefGoogle Scholar
  89. Palmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM (2008) The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis. PLoS ONE 3(1):e1483PubMedCrossRefGoogle Scholar
  90. Perez-Losada J, Balmain A (2003) Stem-cell hierarchy in skin cancer. Nat Rev Cancer 3(6):434–443PubMedCrossRefGoogle Scholar
  91. Poland A, Palen D, Glover E (1982) Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 300:271–273PubMedCrossRefGoogle Scholar
  92. Potten CS (1974) The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet 7(1):77–88PubMedGoogle Scholar
  93. Potter GB, Beaudoin GM 3rd, DeRenzo CL, Zarach JM, Chen SH, Thompson CC (2001) The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor. Genes Dev 15(20):2687–2701PubMedCrossRefGoogle Scholar
  94. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464(7287):427–430PubMedCrossRefGoogle Scholar
  95. Quintanilla M, Brown K, Ramsden M, Balmain A (1986) Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322(6074):78–80PubMedCrossRefGoogle Scholar
  96. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370(6490):527–532PubMedCrossRefGoogle Scholar
  97. Rose-John S, Furstenberger G, Krieg P, Besemfelder E, Rincke G, Marks F (1988) Differential effects of phorbol esters on c-fos and c-myc and ornithine decarboxylase gene expression in mouse skin in vivo. Carcinogenesis 9(5):831–835PubMedCrossRefGoogle Scholar
  98. Rous P, Kidd JG (1941) Conditional neoplasms and subthreshold neoplastic states : a study of the tar tumors of rabbits. J Exp Med 73(3):365–390PubMedCrossRefGoogle Scholar
  99. Ruggeri B, DiRado M, Zhang SY, Bauer B, Goodrow T, Klein-Szanto AJP (1993) Benzo[a]pyrene-induced murine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene. Proc Natl Acad Sci USA 90:1013–1017PubMedCrossRefGoogle Scholar
  100. Rundhaug JE, Fischer SM (2010) Molecular mechanisms of mouse skin tumor promotion. Cancers (Basel) 2(2):436–482CrossRefGoogle Scholar
  101. Saitoh A, Hansen LA, Vogel JC, Udey MC (1998) Characterization of Wnt gene expression in murine skin: possible involvement of epidermis-derived Wnt-4 in cutaneous epithelial-mesenchymal interactions. Exp Cell Res 243(1):150–160PubMedCrossRefGoogle Scholar
  102. Schweizer J, Marks F (1977) Induction of the formation of new hair follicles in mouse tail epidermis by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 37(11):4195–4201PubMedGoogle Scholar
  103. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88(5):593–602PubMedCrossRefGoogle Scholar
  104. Shubik P (1950) Studies on the promoting phase in the stages of carcinogenesis in mice, rats, rabbits, and guinea pigs. Cancer Res 10(1):13–17PubMedGoogle Scholar
  105. Sidransky D (1996) Is human patched the gatekeeper of common skin cancers? Nat Genet 14(1):7–8PubMedCrossRefGoogle Scholar
  106. Silva-Vargas V, Lo Celso C, Giangreco A, Ofstad T, Prowse DM, Braun KM, Watt FM (2005) Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev Cell 9(1):121–131PubMedCrossRefGoogle Scholar
  107. Sisskin EE, Barrett JC (1981) Hyperplasia of Syrian hamster epidermis induced by single but not multiple treatments with 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 41(1):346–350PubMedGoogle Scholar
  108. Slaga TJ (1986) SENCAR mouse skin tumorigenesis model versus other strains and stocks of mice. Environ Health Perspect 68:27–32PubMedCrossRefGoogle Scholar
  109. Slaga TJ, Fischer SM, Nelson K, Gleason GL (1980) Studies on the mechanism of skin tumor promotion: evidence for several stages in promotion. Proc Natl Acad Sci U S A 77(6):3659–3663PubMedCrossRefGoogle Scholar
  110. Slaga TJ, DiGiovanni J, Winberg LD, Budunova IV (1995) Skin carcinogenesis: characteristics, mechanisms, and prevention. Prog Clin Biol Res 391:1–20PubMedGoogle Scholar
  111. Slusarski DC, Corces VG, Moon RT (1997) Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature 390(6658):410–413PubMedCrossRefGoogle Scholar
  112. Stenback F, Arranto A (1985) Initiation and promotion in young and old animals. Implications for human tumour formation. IARC Sci Publ 58:151–166PubMedGoogle Scholar
  113. Stern MC, Gimenez-Conti I, Budunova I, Coghlan L, Fischer SM, DiGiovanni J, Slaga TJ, Conti CJ (1998) Analysis of two inbred strains of mice derived from the SENCAR stock with different susceptibility to skin tumor progression. Carcinogenesis 19(1):125–132PubMedCrossRefGoogle Scholar
  114. Strutt DI, Weber U, Mlodzik M (1997) The role of RhoA in tissue polarity and Frizzled signalling. Nature 387(6630):292–295PubMedCrossRefGoogle Scholar
  115. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R (2012) RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366(3):207–215PubMedCrossRefGoogle Scholar
  116. Suganuma M, Okabe S, Kurusu M, Iida N, Ohshima S, Saeki Y, Kishimoto T, Fujiki H (2002) Discrete roles of cytokines, TNF-alpha, IL-1, IL-6 in tumor promotion and cell transformation. Int J Oncol 20(1):131–136PubMedGoogle Scholar
  117. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong MQ, Frangou CG, Yates JR 3rd, Wright PE, Han J (2007) PRAK is essential for ras-induced senescence and tumor suppression. Cell 128(2):295–308PubMedCrossRefGoogle Scholar
  118. Suzuki A, Itami S, Ohishi M, Hamada K, Inoue T, Komazawa N, Senoo H, Sasaki T, Takeda J, Manabe M, Mak TW, Nakano T (2003) Keratinocyte-specific Pten deficiency results in epidermal hyperplasia, accelerated hair follicle morphogenesis and tumor formation. Cancer Res 63(3):674–681PubMedGoogle Scholar
  119. Tokar EJ, Benbrahim-Tallaa L, Ward JM, Lunn R, Sams RL 2nd, Waalkes MP (2010) Cancer in experimental animals exposed to arsenic and arsenic compounds. Crit Rev Toxicol 40(10):912–927PubMedCrossRefGoogle Scholar
  120. Trakul N, Menard RE, Schade GR, Qian Z, Rosner MR (2005) Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. J Biol Chem 280(26):24931–24940PubMedCrossRefGoogle Scholar
  121. Trempus CS, Morris RJ, Bortner CD, Cotsarelis G, Faircloth RS, Reece JM, Tennant RW (2003) Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol 120(4):501–511PubMedCrossRefGoogle Scholar
  122. Trempus CS, Morris RJ, Ehinger M, Elmore A, Bortner CD, Ito M, Cotsarelis G, Nijhof JG, Peckham J, Flagler N, Kissling G, Humble MM, King LC, Adams LD, Desai D, Amin S, Tennant RW (2007) CD34 expression by hair follicle stem cells is required for skin tumor development in mice. Cancer Res 67(9):4173–4181PubMedCrossRefGoogle Scholar
  123. Udell CM, Rajakulendran T, Sicheri F, Therrien M (2011) Mechanistic principles of RAF kinase signaling. Cell Mol Life Sci 68(4):553–565PubMedCrossRefGoogle Scholar
  124. Watt FM (1998) Epidermal stem cells: markers, patterning and the control of stem cell fate. Philos Trans R Soc Lond B Biol Sci 353(1370):831–837PubMedCrossRefGoogle Scholar
  125. Wiriyachitra P, Hajiwangoh H, Boonton P, Adolf W, Opferkuch HJ, Hecker E (1985) Investigations of medicinal plants of euphorbiaceae and thymelaeaceae occurring and used in Thailand; II. Cryptic irritants of the diterpene ester type from three Excoecaria species. Planta Med 5:368–371PubMedCrossRefGoogle Scholar
  126. Woodworth CD, Michael E, Smith L, Vijayachandra K, Glick A, Hennings H, Yuspa SH (2004) Strain-dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte. Carcinogenesis 25(9):1771–1778PubMedCrossRefGoogle Scholar
  127. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391(6662):90–92PubMedCrossRefGoogle Scholar
  128. Xie Z, Chang S, Oda Y, Bikle DD (2006) Hairless suppresses vitamin D receptor transactivation in human keratinocytes. Endocrinology 147(1):314–323PubMedCrossRefGoogle Scholar
  129. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445(7128):656–660PubMedCrossRefGoogle Scholar
  130. Yuspa SH (1986) Cutaneous chemical carcinogenesis. J Am Acad Dermatol 15(5 Pt 1):1031–1044PubMedCrossRefGoogle Scholar
  131. Zayed SM, Farghaly M, Soliman SM, Gotta H, Sorg B, Hecker E (2001) Dietary cancer risk from conditional cancerogens (tumor promoters) in produce of livestock fed on species of spurge (Euphorbiaceae). V. Skin irriitant and tumor-promoting diterpene ester toxins of the tigliane and ingenane type in the herbs Euphorbia nubica and Euphorbia helioscopia contaminating fodder of livestock. J Cancer Res Clin Oncol 127(1):40–47PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Michael Schwarz
    • 1
  • Peter A. Münzel
    • 1
  • Albert Braeuning
    • 1
  1. 1.Institute of Experimental and Clinical Pharmacology and ToxicologyUniversity of TübingenTübingenGermany

Personalised recommendations