Apoptosis and Pathogenesis of Melanoma and Nonmelanoma Skin Cancer

  • Peter Erb
  • Jingmin Ji
  • Erwin Kump
  • Ainhoa Mielgo
  • Marion Wernli
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 624)

Abstract

Skin cancers, i.e., basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma, belong to the most frequent tumors. Their formation is based on constitutional and/or inherited factors usually combined with environmental factors, mainly UV-irradiation through long term sun exposure. UV-light can randomly induce DNA damage in keratinocytes, but it can also mutate genes essential for control and surveillance in the skin epidermis. Various repair and safety mechanisms exist to maintain the integrity of the skin epidermis. For example, UV-light damaged DNA is repaired and if this is not possible, the DNA damaged cells are eliminated by apoptosis (sunburn cells). This occurs under the control of the p53 suppressor gene. Fas-ligand (FasL), a member of the tumor necrosis superfamily, which is preferentially expressed in the basal layer of the skin epidermis, is a key surveillance molecule involved in the elimination of sunburn cells, but also in the prevention of cell transformation. However, UV light exposure downregulates FasL expression in keratinocytes and melanocytes leading to the loss of its sensor function. This increases the risk that transformed cells are not eliminated anymore. Moreover, important control and surveillance genes can also be direcdy affected by UV-light. Mutation in the p53 gene is the starting point for the formation of SCC and some forms of BCC. Other BCCs originate through UV light mediated mutations of genes of the hedgehog signaling pathway which are essential for the maintainance of cell growth and differentiation. The transcription factor Gli2 plays a key role within this pathway, indeed, Gli2 is responsible for the marked apoptosis resistance of the BCCs. The formation of malignant melanoma is very complex. Melanocytes form nevi and from the nevi melanoma can develop through mutations in various genes. Once the keratinocytes or melanocytes have been transformed they re-express FasL which may allow the expanding tumor to evade the attack of immune effector cells. FasL whichis involved in immune evasion or genes which govern the apoptosis resistance, e.g., Gli2 could therefore be prime targets to prevent tumor formation and growth. Attempts to silence these genes by RNA interference using gene specific short interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) have been functionally successful not only in tissue cultures and tumor tissues, but also in a mouse model. Thus, siRNAs and/or shRNAs may become a novel and promising approach to treat skin cancers at an early stage.

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References

  1. 1.
    Loser K, Mehling A, Locscr S et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med 2006;12(12):1372–1379.PubMedCrossRefGoogle Scholar
  2. 2.
    Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer: new understanding. Arch Dermatol 1997;133(10):1263–1270.PubMedCrossRefGoogle Scholar
  3. 3.
    Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997;88:323–331.PubMedCrossRefGoogle Scholar
  4. 4.
    Naik E, Michalak EM, Villunger A et al. Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J Cell Biol 2007;176(4):415–424.PubMedCrossRefGoogle Scholar
  5. 5.
    Hill LL, Ouhtit A, Loughlin SM et al. Fas ligand: A sensor for DNA damage critical in skin cancer etiology. Science 1999;285(5429):898–900.PubMedCrossRefGoogle Scholar
  6. 6.
    Soehnge H, Ouhtit A, Ananthaswamy ON. Mechanisms of induction of skin cancer by UV radiation. Front Biosci 1997;2:D538–D551.PubMedGoogle Scholar
  7. 7.
    Ziegler A, Jonason AS, LefFell DJ et al. Sunburn and p53 in the onset of skin cancer [see comments]. Nature 1994;372(6508):773–776.PubMedCrossRefGoogle Scholar
  8. 8.
    Jiang W, Ananthaswamy HN, Muller HK et al. p53 protects against skin cancer induction by UV-B radiation. Oncogene 1999;18(29):4247–4253.PubMedCrossRefGoogle Scholar
  9. 9.
    Cohen MM, Jr. The hedgehog signaling network. Am J Med Genet 2003;123A(1):5–28.CrossRefPubMedGoogle Scholar
  10. 10.
    Hahn H, Wicking C, Zaphiropoulous PG et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85(6):841–851.PubMedCrossRefGoogle Scholar
  11. 11.
    Johnson RL, Rothman AL, Xie J et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272(5268):1668–1671.PubMedCrossRefGoogle Scholar
  12. 12.
    Stone DM, Hynes M, Armanini M et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996;384(6605):129–134.PubMedCrossRefGoogle Scholar
  13. 13.
    Grachtchouk M, Mo R, Yu S et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet 2000;24(3):216–217.PubMedCrossRefGoogle Scholar
  14. 14.
    Pavletich NP, Pabo CO. Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers. Science 1993;261(5129):1701–1707.PubMedCrossRefGoogle Scholar
  15. 15.
    Eichberger T, Sander V, Schnidar H et al. Overlapping and distinct transcriptional regulator properties of the GLI1 and GLI2 oncogenes. Genomics 2006;87(5):616–632.PubMedCrossRefGoogle Scholar
  16. 16.
    Marigo V, Johnson RL, Vortkamp A et al. Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Dev Biol 1996;180(1):273–283.PubMedCrossRefGoogle Scholar
  17. 17.
    Lee J, Piatt KA, Censullo P et al. GUI is a target of Sonic hedgehog that induces ventral neural tube development. Development 1997;124(13):2537–2552.PubMedGoogle Scholar
  18. 18.
    Dahmane N, Lee J, Robins P et al. Activation of the transcription factor Glil and the Sonic hedgehog signalling pathway in skin tumours. Nature 1997;389(6653):876–881.PubMedCrossRefGoogle Scholar
  19. 19.
    Nilsson M, Unden AB, Krause D et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci USA 2000;97(7):3438–3443.PubMedCrossRefGoogle Scholar
  20. 20.
    Sheng H, Goich S, Wang A et al. Dissecting the oncogenic potential of Gli:2 deletion of an NH(2)-terminal fragment alters skin tumor phenotype. Cancer Res 2002;62(18):5308–5316.PubMedGoogle Scholar
  21. 21.
    Chiang C, Litingtung Y, Lee E et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996;383(6599):407–413.PubMedCrossRefGoogle Scholar
  22. 22.
    Ding Q, Motoyama J, Gasca S et al. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 1998;125(14):2533–2543.PubMedGoogle Scholar
  23. 23.
    Park HL, Bai C, Platt KA et al. Mouse Glil mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 2000;127(8):1593–1605.PubMedGoogle Scholar
  24. 24.
    Mill P, Mo R, Fu H et al. Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Genes Dev 2003;17(2):282–294.PubMedCrossRefGoogle Scholar
  25. 25.
    Haass NK, Smalley KS, Li L et al. Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res 2005;18(3):150–159.PubMedCrossRefGoogle Scholar
  26. 26.
    Clark WH, Jr., Elder DE, Guerry Dt et al. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 1984;15(12):1147–1165.PubMedCrossRefGoogle Scholar
  27. 27.
    Albino AP, Nanus DM, Mentle IR et al. Analysis of ras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. Oncogene 1989;4(11):1363–1374.PubMedGoogle Scholar
  28. 28.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949–954.PubMedCrossRefGoogle Scholar
  29. 29.
    Omholt K, Platz A, Kanter L et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 2003;9(17):6483–6488.PubMedGoogle Scholar
  30. 30.
    Eskandarpour M, Kiaii S, Zhu C et al. Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells. Int J Cancer 2005;115(1):65–73.PubMedCrossRefGoogle Scholar
  31. 31.
    Hingorani SR, Jacobetz MA, Robertson GP et al. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res 2003;63(17):5198–5202.PubMedGoogle Scholar
  32. 32.
    Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet 2005;365(9460):687–701.PubMedGoogle Scholar
  33. 33.
    Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene 2003;22(20):3113–3122.PubMedCrossRefGoogle Scholar
  34. 34.
    Sharpless E, Chin L. The INK4a/ARF locus and melanoma. Oncogene 2003;22(20):3092–3098.PubMedCrossRefGoogle Scholar
  35. 35.
    Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 1999;96(8):4240–4245.PubMedCrossRefGoogle Scholar
  36. 36.
    Hodgkinson CA, Moore KJ, Nakayama A et al. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 1993;74(2):395–404.PubMedCrossRefGoogle Scholar
  37. 37.
    Salti GI, Manougian T, Farolan M et al. Micropthalmia transcription factor: a new prognostic marker in intermediate-thickness cutaneous malignant melanoma. Cancer Res 2000;60(18):5012–5016.PubMedGoogle Scholar
  38. 38.
    Garraway LA, Widlund HR, Rubin MA et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 2005;436(7047):117–122.PubMedCrossRefGoogle Scholar
  39. 39.
    Kuphal S, Bauer R, Bosserhoff AK. Integrin signaling in malignant melanoma. Cancer Metastasis Rev 2005;24(2):195–222.PubMedCrossRefGoogle Scholar
  40. 40.
    Danen EH, Ten Berge PJ, Van Muijen GN et al. Emergence of alpha 5 beta 1 fibronectin-and alpha v beta 3 vitronectin-receptor expression in melanocytic tumour progression. Histopathology 1994;24(3):249–256.PubMedCrossRefGoogle Scholar
  41. 41.
    Petitclerc E, Stromblad S, von Schalscha TL et al. Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res 1999;59(11):2724–2730.PubMedGoogle Scholar
  42. 42.
    Miller AJ, Mihm Jr MC, Melanoma. N Engl J Med 2006;355(1):51–65.PubMedCrossRefGoogle Scholar
  43. 43.
    Boon T, Coulie PG, Van den Eynde BJ et al. Human T-cell responses against melanoma. Annu Rev Immunol 2006;24:175–208.PubMedCrossRefGoogle Scholar
  44. 44.
    Bhardwaj A, Aggarwal BB. Receptor-mediated choreography of life and death. J Clin Immunol 2003;23(5):317–332.PubMedCrossRefGoogle Scholar
  45. 45.
    Emery JG, McDonnell P, Burke MB et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273(23):14363–14367.PubMedCrossRefGoogle Scholar
  46. 46.
    Nagata S. Fas ligand-induccd apoptosis. Annu Rev Genet 1999;33:29–55.PubMedCrossRefGoogle Scholar
  47. 47.
    Krammer PH. CD95’s deadly mission in the immune system. Nature 2000;407(6805):789–795.PubMedCrossRefGoogle Scholar
  48. 48.
    Kirkin V, Joos S, Zornig M. The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta 2004;1644(2–3):229–249.PubMedGoogle Scholar
  49. 49.
    Li HL, Zhu H, Xu CJ et al. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94(4):491–501.PubMedCrossRefGoogle Scholar
  50. 50.
    Friesen C, Fulda S, Debatin KM. Cytotoxic drugs and the CD95 pathway. Leukemia 1999;13(11):1854–1858.PubMedCrossRefGoogle Scholar
  51. 51.
    Hahne M, Rimoldi D, Schroter M et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape [see comments]. Science 1996;274(5291):1363–1366.PubMedCrossRefGoogle Scholar
  52. 52.
    Igney FH, Krammer PH. Death and anti-death: Tumor resistance to apoptosis. Nat Rev Cancer 2002;2(4):277–288.PubMedCrossRefGoogle Scholar
  53. 53.
    Griffith TS, Chin WA, Jackson GC et al. Intracellular regulation of TRAJL-induced apoptosis in human melanoma cells. J Immunol 1998;161(6):2833–2840.PubMedGoogle Scholar
  54. 54.
    Zhang XD, Franco A, Myers K et al. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 1999;59(11):2747–2753.PubMedGoogle Scholar
  55. 55.
    McCarthy MM, DiVito KA, Sznol M et al. Expression of Tumor Necrosis Factor-Related Apoptosis-inducing Ligand Receptors 1 and 2 in Melanoma. Clin Cancer Res 2006;12(12):3856–3863.PubMedCrossRefGoogle Scholar
  56. 56.
    Soubrane C, Mouawad R, Antoine EC et al. A comparative study of Fas and Fas-ligand expression during melanoma progression. Brit J Dermatol 2000;143(2):307–312.CrossRefGoogle Scholar
  57. 57.
    Zhuang L, Lee CS, Scolyer RA et al. Progression in melanoma is associated with decreased expression of death receptors for tumor necrosis factor-related apoptosis-inducing ligand. Human Pathology 2006;37(10):1286–1294.PubMedCrossRefGoogle Scholar
  58. 58.
    Helmbach H, Rossmann E, Kern MA et al. Drug-resistance in human melanoma. Int J Cancer 2001;93(5):617–622.PubMedCrossRefGoogle Scholar
  59. 59.
    Buechner SA, Wernli M, Harr T et al. Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide. J Clin Invest 1997;100(11):2691–2696.PubMedCrossRefGoogle Scholar
  60. 60.
    GutierrezSteil C, WroneSmith T, Sun XM et al. Sunlight-induced basal cell carcinoma tumor cells and ultraviolet-B-irradiated psoriatic plaques express Fas ligand (CD95L). J Clin Invest 1998;101(1):33–39.CrossRefGoogle Scholar
  61. 61.
    Bachmann F, Buechner SA, Wernli M et al. Ultraviolet light downregulates CD95 ligand and trail receptor expression facilitating actinic keratosis and squamous cell carcinoma formation. J Invest Dermatol 2001;117(1):59–66.PubMedCrossRefGoogle Scholar
  62. 62.
    Stander S, Schwarz T. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed in normal skin and cutaneous inflammatory diseases, but not in chronically UV-exposed skin and nonmelanoma skin cancer. Am J Dermatopathol 2005;27(2):116–121.PubMedCrossRefGoogle Scholar
  63. 63.
    Hallermalm K, De Geer A, Kiessling R et al. Secretion of Fas Ligand Shields Tumor Cells from Fas-Mediated Killing by Cytotoxic Lymphocytes. Cancer Res 2004;64(18):6775–6782.PubMedCrossRefGoogle Scholar
  64. 64.
    Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999;11(2):255–260.PubMedCrossRefGoogle Scholar
  65. 65.
    LeBlanc HN, Ashkenazi A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differentiation 2003;10(1):66–75.CrossRefGoogle Scholar
  66. 66.
    Zhang XD, Nguyen T, Thomas WD et al. Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. Febs Lett 2000;482(3):193–199.PubMedCrossRefGoogle Scholar
  67. 67.
    Schneider P, Thome M, Burns K et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappa B. Immunity 1997;7(6):831–836.PubMedCrossRefGoogle Scholar
  68. 68.
    Kim K, Fisher MJ, Xu SQ et al. Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin Cancer Res 2000;6(2):335–346.PubMedGoogle Scholar
  69. 69.
    Kurbanov BM, Fecker LF, Geilen CC et al. Resistance of melanoma cells to TRAIL does not result from upregulation of antiapoptotic proteins by NF-[kappa]B but is related to downregulation of initiator caspases and DR4. Oncogene 2006.Google Scholar
  70. 70.
    Thomas WD, Hersey P. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T-cell killing of target cells. J Immunol 1998;161(5):2195–2200.PubMedGoogle Scholar
  71. 71.
    Walczak H, Miller RE, Ariail K et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo [see comments]. Nat Med 1999;5(2):157–163.PubMedCrossRefGoogle Scholar
  72. 72.
    Kagawa S, He C, Gu J et al. Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Cancer Res 2001;61(8):3330–3338.PubMedGoogle Scholar
  73. 73.
    Ji J, Wernli M, Mielgo A et al. Fas-ligand gene silencing in basal cell carcinoma tissue with small interfering RNA. Gene Ther 2005;12(8):678–684.PubMedCrossRefGoogle Scholar
  74. 74.
    Ji J, Wernli M, Bucchner S et al. Fas ligand downregulation with antiscnsc oligonucleotides in cells and in cultured tissues of normal skin epidermis and basal cell carcinoma. J Invest Dermatol 2003;120(6):1094–1099.PubMedCrossRefGoogle Scholar
  75. 75.
    Regl G, Kasper M, Schnidar H et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res 2004;64(21):7724–7731.PubMedCrossRefGoogle Scholar
  76. 76.
    Bullani RR, Huard B, Viard-Leveugle I et al. Selective Expression of FLIP in Malignant Melanocytic Skin Lesions 2001;117(2):360–364.Google Scholar
  77. 77.
    Zeise E, Weichenthal M, Schwarz T et al. Resistance of Human Melanoma Cells Against the Death Ligand TRAIL Is Reversed by Ultraviolet-B Radiation via Downregulation of FLIP. J Investig Dermatol 2004;123(4):746–754.PubMedCrossRefGoogle Scholar
  78. 78.
    Chawla-Sarkar M, Bae SI, Reu FJ et al. Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ 2004;11(8):915–923.PubMedCrossRefGoogle Scholar
  79. 79.
    Ivanov VN, Hei TK. Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression. Experimental Cell Research 2006;312(20):4120–4138.PubMedCrossRefGoogle Scholar
  80. 80.
    Young-Ho Kim YJL. Time sequence of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cisplatin treatment is responsible for a complex pattern of synergistic cytotoxicity. Journal of Cellular Biochemistry 2006;98(5):1284–1295.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Peter Erb
    • 1
  • Jingmin Ji
    • 1
  • Erwin Kump
    • 1
  • Ainhoa Mielgo
    • 2
  • Marion Wernli
    • 1
  1. 1.Institute for Medical MicrobiologyUniversity of BaselBaselSwitzerland
  2. 2.Moores Cancer CenterUniversity of California San DiegoLa JollaUSA

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