Molecular Pathogenesis of Melanoma: Established and Novel Pathways

  • Paolo Antonio AsciertoEmail author
  • Maria Libera Ascierto
  • Mariaelena Capone
  • Zendee Elaba
  • Michael J. Murphy
  • Giuseppe Palmieri
Part of the Current Clinical Pathology book series (CCPATH)


Melanoma is the eighth most common malignancy in the USA and has shown a rapid increase in its incidence rate over the past two decades, especially for early-stage disease [1–4] A recent analysis of data from the Surveillance Epidemiology and End Results (SEER) Program indicates that the incidence of melanoma increases with age, showing somewhat different patterns in men and women [3]. This cancer arises from melanocytes, which are specialized pigmented cells that are predominantly found in the skin and eyes, where they produce melanin, the pigment responsible for skin and hair color.


Notch Signaling Mucosal Melanoma Melanocytic Nevus Melanoma Risk NRAS Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Beddingfield III FC. The melanoma epidemic: res ipsa loquitur. Oncologist. 2002;8:459–65.CrossRefGoogle Scholar
  2. 2.
    Gerami P, Gammon B, Murphy M. Melanocytic neoplasms I: molecular diagnosis. In: Murphy MJ, editor. Molecular diagnostics in dermatology and dermatopathology. New York: Springer; 2011.Google Scholar
  3. 3.
    Dennis LK. Analysis of the melanoma epidemic, both apparent and real: data from the 1973 through 1994 surveillance, epidemiology, and end results program registry. Arch Dermatol. 1999;135:275–80.PubMedCrossRefGoogle Scholar
  4. 4.
    Lipsker DM, Hedelin G, Heid E, Grosshans EM, Cribier BJ. Striking increases of thin melanomas contrasts with a stable incidence of thick melanomas. Arch Dermatol. 1999;135:1451–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Gandini S, Sera F, Cattaruzza MS, Pasquini P, Picconi O, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer. 2005;41:45–60.PubMedCrossRefGoogle Scholar
  6. 6.
    Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med. 1999;340:1341–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Jhappan C, Noonan FP, Merlino G. Ultraviolet radiation and cutaneous malignant melanoma. Oncogene. 2003;22:3099–112.PubMedCrossRefGoogle Scholar
  8. 8.
    Eide MJ, Weinstock MA. Association of UV index, latitude, and melanoma incidence in non-White populations – US surveillance, epidemiology, and end results (SEER) program, 1992 to 2001. Arch Dermatol. 2005;141:477–81.PubMedCrossRefGoogle Scholar
  9. 9.
    De Fabo EC, Noonan FP, Fears T, Merlino G. Ultraviolet B but not ultraviolet A radiation initiates melanoma. Cancer Res. 2004;64:6372–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Wang SQ, Setlow R, Berwick M, Polsky D, Marghoob AA, Kopf AW, Bart RS. Ultraviolet A and melanoma: a review. J Am Acad Dermatol. 2001;44: 837–46.PubMedCrossRefGoogle Scholar
  11. 11.
    Moan J, Dahlback A, Setlow RB. Epidemiological support for an hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol. 1999;70:243–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Oliveria S, Dusza S, Berwick M. Issues in the epidemiology of melanoma. Expert Rev Anticancer Ther. 2001;1:453–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Garland C, Garland F, Gorham E. Epidemiologic evidence for different roles of ultraviolet A and B radiation in melanoma mortality rates. Ann Epidemiol. 2003;13:395–404.PubMedCrossRefGoogle Scholar
  14. 14.
    Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.PubMedCrossRefGoogle Scholar
  15. 15.
    Giehl K. Oncogenic Ras in tumor progression and metastasis. Biol Chem. 2005;386:193–205.PubMedCrossRefGoogle Scholar
  16. 16.
    Campbell PM, Der CJ. Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin Cancer Biol. 2004;14:105–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417: 949–54.PubMedCrossRefGoogle Scholar
  18. 18.
    Goodall J, Wellbrock C, Dexter TJ, Roberts K, Marais R, Goding CR. The Brn-2 transcription factor links activated BRAF to melanoma proliferation. Mol Cell Biol. 2004;24:2923–31.PubMedCrossRefGoogle Scholar
  19. 19.
    Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD, Robertson GP. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 2005;65: 2412–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature. 1998;391:298–301.PubMedCrossRefGoogle Scholar
  21. 21.
    Bhatt KV, Spofford LS, Aram G, McMullen M, Pumiglia K, Aplin AE. Adhesion control of cyclin D1 and p27Kip1 levels is deregulated in melanoma cells through BRAF–MEK–ERK signaling. Oncogene. 2005;24:3459–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Gray-Schopfer VC, Cheong SC, Chong H, et al. Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer. 2006;95: 496–505.PubMedCrossRefGoogle Scholar
  23. 23.
    Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436:720–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Huntington JT, Shields JM, Der CJ, et al. Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells: role of BRAF mutation and fibroblast growth factor signaling. J Biol Chem. 2004;279:33168–76.PubMedCrossRefGoogle Scholar
  25. 25.
    Ellerhorst JA, Ekmekcioglu S, Johnson MK, Cooke CP, Johnson MM, Grimm EA. Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma. Oncogene. 2006;25:3956–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Patton EE, Widlund HR, Kutok JL, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol. 2005;15:249–54.PubMedCrossRefGoogle Scholar
  27. 27.
    Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008;132:363–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Michaloglou C, Vredeveld LC, Mooi WJ, Peeper DS. BRAF(E600) in benign and malignant human tumours. Oncogene. 2008;27:877–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Dhomen N, Reis-Filho JS, da Rocha Dias S, et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15:294–303.PubMedCrossRefGoogle Scholar
  30. 30.
    Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005;23: 965–72.PubMedCrossRefGoogle Scholar
  31. 31.
    Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95:581–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006; 106: 375–82.PubMedCrossRefGoogle Scholar
  33. 33.
    Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, Sellers WR, Lengauer C, Stegmeier F. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 2009;69:4286–93.PubMedCrossRefGoogle Scholar
  34. 34.
    Ciuffreda L, Del Bufalo D, Desideri M, et al. Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations. Neoplasia. 2009;11:720–31.PubMedGoogle Scholar
  35. 35.
    Banerji U, Camidge DR, Verheul HM, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16:1613–23.PubMedCrossRefGoogle Scholar
  36. 36.
    Stone S, Ping J, Dayananth P, Tavtigian SV, Katcher H, Parry D, Gordon P, Kamb A. Complex structure and regulation of the P16 (MTS1) locus. Cancer Res. 1995;55:2988–94.PubMedGoogle Scholar
  37. 37.
    Haber DA. Splicing into senescence: the curious case of p16 and p19ARF. Cell. 1997;28(91):555–8.CrossRefGoogle Scholar
  38. 38.
    Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998;92:725–34.PubMedCrossRefGoogle Scholar
  39. 39.
    Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–31.PubMedCrossRefGoogle Scholar
  40. 40.
    Box NF, Terzian T. The role of p53 in pigmentation, tanning and melanoma. Pigment Cell Melanoma Res. 2008;21:525–33.PubMedCrossRefGoogle Scholar
  41. 41.
    Goldstein AM, Landi MT, Tsang S, Fraser MC, Munroe DJ, Tucker MA. Association of MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A mutations. Cancer Epidemiol Biomarkers Prev. 2005;14:2208–12.PubMedGoogle Scholar
  42. 42.
    Bishop DT, Demenais F, Goldstein AM, et al. Melanoma genetics consortium: geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94:894–903.PubMedGoogle Scholar
  43. 43.
    Demenais F. Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families. J Natl Cancer Inst. 2004;96:785–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Puig S, Malvehy J, Badenas C, Ruiz A, et al. Role of the CDKN2A Locus in patients with multiple primary melanomas. J Clin Oncol. 2005;23:3043–51.PubMedCrossRefGoogle Scholar
  45. 45.
    Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst. 2000;92:1006–10.PubMedCrossRefGoogle Scholar
  46. 46.
    Chaudru V, Chompret A, Bressac-de Paillerets B, Spatz A, Avril MF, Demenais F. Influence of genes, nevi, and sun sensitivity on melanoma risk in a ­family sample unselected by family history and in melanoma-prone families. J Natl Cancer Inst. 2004;96:785–95.PubMedCrossRefGoogle Scholar
  47. 47.
    Eliason MJ, Hansen CB, Hart M, et al. Multiple primary melanomas in a CDKN2A mutation carrier exposed to ionizing radiation. Arch Dermatol. 2007;143:1409–12.PubMedCrossRefGoogle Scholar
  48. 48.
    Pho L, Grossman D, Leachman SA. Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma. Curr Opin Oncol. 2006;18:173–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Fargnoli MC, Gandini S, Peris K, Maisonneuve P, Raimondi S. MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur J Cancer. 2010;46:1413–20.PubMedCrossRefGoogle Scholar
  50. 50.
    Box NF, Duffy DL, Chen W, Stark M, Martin NG, Sturm RA, Hayward NK. MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. Am J Hum Genet. 2001;69:765–73.PubMedCrossRefGoogle Scholar
  51. 51.
    van der Velden PA, Sandkuijl LA, Bergman W, Pavel S, van Mourik L, Frants RR, Gruis NA. Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma. Am J Hum Genet. 2001;69:774–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Chaudru V, Laud K, Avril MF, Minière A, Chompret A, Bressac-de Paillerets B, Demenais F. Melanocortin-1 receptor (MC1R) gene variants and dysplastic nevi modify penetrance of CDKN2A mutations in French melanoma-prone pedigrees. Cancer Epidemiol Biomarkers Prev. 2005;14:2384–90.PubMedCrossRefGoogle Scholar
  53. 53.
    Goldstein AM, Chaudru V, Ghiorzo P, et al. Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries. Int J Cancer. 2007;121:825–31.PubMedCrossRefGoogle Scholar
  54. 54.
    Meyle KD, Guldberg P. Genetic risk factors for melanoma. Hum Genet. 2009;126:499–510.PubMedCrossRefGoogle Scholar
  55. 55.
    Goldstein AM, Chan M, Harland M, et al. Melanoma Genetics Consortium (GenoMEL). High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:9818–28.PubMedCrossRefGoogle Scholar
  56. 56.
    Haluska FG, Tsao H, Wu H, Haluska FS, Lazar A, Goel V. Genetic alterations in signaling pathways in melanoma. Clin Cancer Res. 2006;12:2301s–7s.PubMedCrossRefGoogle Scholar
  57. 57.
    Stokoe D. PTEN. Curr Biol. 2001;11:R502.PubMedCrossRefGoogle Scholar
  58. 58.
    Dahia PL. PTEN, a unique tumor suppressor gene. Endocr Relat Cancer. 2000;7:115–29.PubMedCrossRefGoogle Scholar
  59. 59.
    Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999;253:210–29.PubMedCrossRefGoogle Scholar
  60. 60.
    Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004;15:177–82.PubMedCrossRefGoogle Scholar
  61. 61.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedCrossRefGoogle Scholar
  62. 62.
    Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13: 2905–27.PubMedCrossRefGoogle Scholar
  63. 63.
    Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355–65.PubMedCrossRefGoogle Scholar
  64. 64.
    Plas DR, Thompson CB. Akt-dependent transformation: there is more to growth than just surviving. Oncogene. 2005;24:7435–42.PubMedCrossRefGoogle Scholar
  65. 65.
    Stiles B, Groszer M, Wang S, Jiao J, Wu H. PTEN less means more. Dev Biol. 2004;273:175–84.PubMedCrossRefGoogle Scholar
  66. 66.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–41.PubMedCrossRefGoogle Scholar
  67. 67.
    Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282:1318–21.PubMedCrossRefGoogle Scholar
  68. 68.
    Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA. 2001;98:11598–603.PubMedCrossRefGoogle Scholar
  69. 69.
    Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene. 2002;21:1299–303.PubMedCrossRefGoogle Scholar
  70. 70.
    Oren M, Damalas A, Gottlieb T, et al. Regulation of p53: intricate loops and delicate balances. Biochem Pharmacol. 2002;64:865–71.PubMedCrossRefGoogle Scholar
  71. 71.
    Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68.PubMedCrossRefGoogle Scholar
  72. 72.
    Romashkova JA, Makarov SS. NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999;401:86–90.PubMedCrossRefGoogle Scholar
  73. 73.
    Wan YS, Wang ZQ, Shao Y, Voorhees JJ, Fisher GJ. Ultraviolet irradiation activates PI 3-kinase/AKT survival pathway via EGF receptors in human skin in vivo. Int J Oncol. 2001;18:461–6.PubMedGoogle Scholar
  74. 74.
    Waldmann V, Wacker J, Deichmann M. Mutations of the activation-associated phosphorylation sites at codons 308 and 473 of protein kinase B are absent in human melanoma. Arch Dermatol Res. 2001;293: 368–72.PubMedCrossRefGoogle Scholar
  75. 75.
    Waldmann V, Wacker J, Deichmann M. Absence of mutations in the pleckstrin homology (PH) domain of protein kinase B (PKB/Akt) in malignant melanoma. Melanoma Res. 2002;12:45–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Davies MA, Stemke-Hale K, Tellez C, et al. A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer. 2008;99:1265–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Krasilnikov M, Adler V, Fuchs SY, Dong Z, Haimovitz-Friedman A, Herlyn M, Ronai Z. Contribution of phosphatidylinositol 3-kinase to radiation resistance in human melanoma cells. Mol Carcinog. 1999;24:64–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Simpson L, Parsons R. PTEN: life as a tumor suppressor. Exp Cell Res. 2001;264:29–41.PubMedCrossRefGoogle Scholar
  79. 79.
    Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Vazquez F, Sellers WR. The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim Biophys Acta. 2000;1470:M21–35.PubMedGoogle Scholar
  81. 81.
    Bonneau D, Longy M. Mutations of the human PTEN gene. Hum Mutat. 2000;16:109–22.PubMedCrossRefGoogle Scholar
  82. 82.
    Maehama T, Taylor GS, Dixon JE. PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem. 2001;70:247–79.PubMedCrossRefGoogle Scholar
  83. 83.
    Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst. 1999;91: 1922–32.PubMedCrossRefGoogle Scholar
  84. 84.
    Tsao H, Zhang X, Benoit E, Haluska FG. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene. 1998;16:3397–402.PubMedCrossRefGoogle Scholar
  85. 85.
    Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457–63.PubMedCrossRefGoogle Scholar
  86. 86.
    Mirmohammadsadegh A, Marini A, Nambiar S, Hassan M, Tannapfel A, Ruzicka T, Hengge UR. Epigenetic silencing of the PTEN gene in melanoma. Cancer Res. 2006;66:6546–52.PubMedCrossRefGoogle Scholar
  87. 87.
    Tsao H, Goel V, Wu H, Yang G, Haluska FG. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004;122:337–41.PubMedCrossRefGoogle Scholar
  88. 88.
    Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003;22:3113–22.PubMedCrossRefGoogle Scholar
  89. 89.
    Dahia PL, Aguiar RC, Alberta J, et al. PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. Hum Mol Genet. 1999;8:185–93.PubMedCrossRefGoogle Scholar
  90. 90.
    Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med. 2006;12:406–14.PubMedCrossRefGoogle Scholar
  91. 91.
    Denat L, Larue L. Malignant melanoma and the role of the paradoxal protein microphthalmia transcription factor. Bull Cancer. 2007;94:81–92.PubMedGoogle Scholar
  92. 92.
    Loercher AE, Tank EM, Delston RB, Harbour JW. MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. J Cell Biol. 2005;168:35–40.PubMedCrossRefGoogle Scholar
  93. 93.
    Carreira S, Goodall J, Aksan I, et al. Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. Nature. 2005;433:764–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Wellbrock C, Marais R. Elevated expression of MITF counteracts B-RAF stimulated melanocyte and melanoma cell proliferation. J Cell Biol. 2005;170:703–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Du J, Widlund HR, Horstmann MA, et al. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell. 2004;6:565–76.PubMedCrossRefGoogle Scholar
  96. 96.
    McGill GG, Horstmann M, Widlund HR, et al. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell. 2002;109:707–18.PubMedCrossRefGoogle Scholar
  97. 97.
    Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005;436:117–22.PubMedCrossRefGoogle Scholar
  98. 98.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.PubMedGoogle Scholar
  99. 99.
    Dorsky RI, Moon RT, Raible DW. Control of neural crest cell fate by the Wnt signalling pathway. Nature. 1998;396:370–3.PubMedCrossRefGoogle Scholar
  100. 100.
    Dorsky RI, Moon RT, Raible DW. Environmental signals and cell fate specification in premigratory neural crest. Bioessays. 2000;22:708–16.PubMedCrossRefGoogle Scholar
  101. 101.
    Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis – a look outside the nucleus. Science. 2000;287:1606–9.PubMedCrossRefGoogle Scholar
  102. 102.
    You L, He B, Xu Z, et al. An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res. 2004;64:5385–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Kashani-Sabet M, Range J, Torabian S, et al. A multi-marker assay to distinguish malignant melanomas from benign nevi. Proc Natl Acad Sci USA. 2009;106:6268–72.PubMedCrossRefGoogle Scholar
  104. 104.
    Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of β-catenin by genetic defects in melanoma cell lines. Science. 1997;275:1790–2.PubMedCrossRefGoogle Scholar
  105. 105.
    Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER. Frequent nuclear/cytoplasmic localization of β-catenin without exon 3 mutations in malignant melanoma. Am J Pathol. 1999;154:325–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Wellbrock C, Rana S, Paterson H, Pickersgill H, Brummelkamp T, Marais R. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS One. 2008;3:2734.CrossRefGoogle Scholar
  107. 107.
    Morgan T. The theory of the gene. Am Nat. 1917;51:513–44.CrossRefGoogle Scholar
  108. 108.
    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Jeffries S, Capobianco AJ. Neoplastic transformation by Notch requires nuclear localization. Mol Cell Biol. 2000;20:3928–41.PubMedCrossRefGoogle Scholar
  110. 110.
    Allman D, Punt JA, Izon DJ, Aster JC, Pear WS. An invitation to T and more: notch signaling in lymphopoiesis. Cell. 2002;109:S1–11.PubMedCrossRefGoogle Scholar
  111. 111.
    Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66:649–61.PubMedCrossRefGoogle Scholar
  112. 112.
    Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, Ball DW. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001;61:3200–5.PubMedGoogle Scholar
  113. 113.
    Gestblom C, Grynfeld A, Ora I, et al. The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas. Lab Invest. 1999;79:67–79.PubMedGoogle Scholar
  114. 114.
    Grynfeld A, Påhlman S, Axelson H. Induced neuroblastoma cell differentiation, associated with transient HES-1 activity and reduced HASH-1 expression, is inhibited by Notch1. Int J Cancer. 2000;88:401–10.PubMedCrossRefGoogle Scholar
  115. 115.
    Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA. 1995;92:6414–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Talora C, Sgroi DC, Crum CP, Dotto GP. Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev. 2002;16:2252–63.PubMedCrossRefGoogle Scholar
  117. 117.
    Shou J, Ross S, Koeppen H, de Sauvage FJ, Gao WQ. Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res. 2001;61:7291–7.PubMedGoogle Scholar
  118. 118.
    Nicolas M, Wolfer A, Raj K, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33:416–21.PubMedCrossRefGoogle Scholar
  119. 119.
    Rangarajan A, Talora C, Okuyama R, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001;20:3427–36.PubMedCrossRefGoogle Scholar
  120. 120.
    Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal differentiation by δ-notch signalling at the boundaries of stem-cell clusters. Curr Biol. 2000;10:491–500.PubMedCrossRefGoogle Scholar
  121. 121.
    Hoek K, Rimm DL, Williams KR, et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res. 2004;64:5270–82.PubMedCrossRefGoogle Scholar
  122. 122.
    Massi D, Tarantini F, Franchi A, et al. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Mod Pathol. 2006;19:246–59.PubMedCrossRefGoogle Scholar
  123. 123.
    Pinnix CC, Lee JT, Liu ZJ, et al. Active Notch1 confers a transformed phenotype to primary human melanocytes. Cancer Res. 2009;69:5312–20.PubMedCrossRefGoogle Scholar
  124. 124.
    Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002;110:751–62.PubMedCrossRefGoogle Scholar
  125. 125.
    Li G, Satyamoorthy K, Herlyn M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 2001;61:3819–25.PubMedGoogle Scholar
  126. 126.
    Liu ZJ, Xiao M, Balint K, et al. Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression. Cancer Res. 2006;66: 4182–90.PubMedCrossRefGoogle Scholar
  127. 127.
    Cheng P, Zlobin A, Volgina V, et al. Notch-1 regulates NF-kB activity in hemopoietic progenitor cells. J Immunol. 2001;167:4458–67.PubMedGoogle Scholar
  128. 128.
    Shin HM, Minter LM, Cho OH, et al. Notch1 augments Nf-kB activity by facilitating its nuclear retention. EMBO J. 2006;25:129–38.PubMedCrossRefGoogle Scholar
  129. 129.
    Weijzen S, Rizzo P, Braid M, et al. Activation of Notch1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med. 2002;8:979–86.PubMedCrossRefGoogle Scholar
  130. 130.
    Kiaris H, Politi K, Grimm LM, et al. Modulation of Notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium. Am J Pathol. 2004;165:695–705.PubMedCrossRefGoogle Scholar
  131. 131.
    Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–10.PubMedCrossRefGoogle Scholar
  132. 132.
    Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25:280–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Yamamoto M, Yamazaki S, Uematsu S, et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature. 2004;430:218–22.PubMedCrossRefGoogle Scholar
  134. 134.
    Kuwata H, Matsumoto M, Atarashi K, Morishita H, Hirotani T, Koga R, Takeda K. IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation. Immunity. 2006;24: 41–51.PubMedCrossRefGoogle Scholar
  135. 135.
    Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U. The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers. Cell. 1993;72:729–39.PubMedCrossRefGoogle Scholar
  136. 136.
    Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell. 2001;7:401–9.PubMedCrossRefGoogle Scholar
  137. 137.
    Basseres DS, Baldwin AS. Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene. 2006;25:6817–30.PubMedCrossRefGoogle Scholar
  138. 138.
    Jost PJ, Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood. 2007;109:2700–7.PubMedGoogle Scholar
  139. 139.
    Cilloni D, Martinelli G, Messa F, Baccarani M, Saglio G. Nuclear factor kB as a target for new drug development in myeloid malignancies. Haematologica. 2007;92:1224–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Dutta J, Fan Y, Gupta N, Fan G, Gélinas C. Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene. 2006;25:6800–16.PubMedCrossRefGoogle Scholar
  141. 141.
    Luo JL, Kamata H, Karin M. The anti-death machinery in IKK/NF-kappaB signaling. J Clin Immunol. 2005;25:541–50.PubMedCrossRefGoogle Scholar
  142. 142.
    Burstein E, Duckett CS. Dying for NF-kappaB? Control of cell death by transcriptional regulation of the apoptotic machinery. Curr Opin Cell Biol. 2003;15:732–7.PubMedCrossRefGoogle Scholar
  143. 143.
    Hayakawa Y, Maeda S, Nakagawa H, et al. Effectiveness of IkappaB kinase inhibitors in murine colitis-associated tumorigenesis. J Gastroenterol. 2009;44:935–43.PubMedCrossRefGoogle Scholar
  144. 144.
    Demchenko YN, Glebov OK, Zingone A, Keats JJ, Bergsagel PL, Kuehl WM. Classical and/or alternative NF-kappaB pathway activation in multiple myeloma. Blood. 2010;115:3541–52.PubMedCrossRefGoogle Scholar
  145. 145.
    Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R. Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer. 2005;15(04):879–90.CrossRefGoogle Scholar
  146. 146.
    Ianaro A, Tersigni M, Belardo G, et al. NEMO-binding domain peptide inhibits proliferation of human melanoma cells. Cancer Lett. 2009;18(274): 331–6.CrossRefGoogle Scholar
  147. 147.
    Amiri KI, Richmond A. Role of nuclear factor-κB in melanoma. Cancer Metast Rev. 2005;24:301–31.CrossRefGoogle Scholar
  148. 148.
    Meyskens Jr FL, Buckmeier JA, McNulty SE, Tohidian NB. Activation of nuclear factor-kappa B in human metastatic melanoma cells and the effect of oxidative stress. Clin Cancer Res. 1999;5: 1197–202.PubMedGoogle Scholar
  149. 149.
    McNulty SE, Tohidian NB, Meyskens Jr FL. RelA, p50 and inhibitor of kappa B alpha are elevated in human metastatic melanoma cells and respond aberrantly to ultraviolet light B. Pigment Cell Res. 2001;14:456–65.PubMedCrossRefGoogle Scholar
  150. 150.
    McNulty SE, del Rosario R, Cen D, Meyskens Jr FL, Yang S. Comparative expression of NFkappaB proteins in melanocytes of normal skin vs. benign intradermal naevus and human metastatic melanoma biopsies. Pigment Cell Res. 2004;17:173–80.PubMedCrossRefGoogle Scholar
  151. 151.
    Yang J, Amiri KI, Burke JR, Schmid JA, Richmond A. BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathways. Clin Cancer Res. 2006;12:950–60.PubMedCrossRefGoogle Scholar
  152. 152.
    Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res. 2002;62: 7335–42.PubMedGoogle Scholar
  153. 153.
    Troppmair J, Hartkamp J, Rapp UR. Activation of NF-kappa B by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade. Oncogene. 1998;17:685–90.PubMedCrossRefGoogle Scholar
  154. 154.
    Jo H, Zhang R, Zhang H, et al. NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis. Oncogene. 2000;19: 841–9.PubMedCrossRefGoogle Scholar
  155. 155.
    Richardson PG, Hideshima T, Anderson KC. Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control. 2003;10:361–9.PubMedGoogle Scholar
  156. 156.
    Markovic SN, Geyer SM, Dawkins F, et al. A phase II study of bortezomib in the treatment of metastatic malignant melanoma. Cancer. 2005;103:2584–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Kamijo R, Harada H, Matsuyama T, et al. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science. 1994; 263:1612–5.PubMedCrossRefGoogle Scholar
  158. 158.
    Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Nat Rev Cancer. 2006;6:521–34.PubMedCrossRefGoogle Scholar
  159. 159.
    Grimm EA, Ellerhorst J, Tang CH, Ekmekcioglu S. Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis. Nitric Oxide. 2008;19:133–7.PubMedCrossRefGoogle Scholar
  160. 160.
    Russo PA, Halliday GM. Inhibition of nitric oxide and reactive oxygen species production improves the ability of a sunscreen to protect from sunburn, immunosuppression and photocarcinogenesis. Br J Dermatol. 2006;155:408–15.PubMedCrossRefGoogle Scholar
  161. 161.
    Palmieri G, Capone ME, Ascierto ML, et al. Main roads to melanoma. J Transl Med. 2009;7:86.PubMedCrossRefGoogle Scholar
  162. 162.
    Martin E, Nathan C, Xie QW. Role of interferon regulatory factor 1 in induction of nitric oxide synthase. J Exp Med. 1994;180:977–84.PubMedCrossRefGoogle Scholar
  163. 163.
    Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem. 1994;269:4705–8.PubMedGoogle Scholar
  164. 164.
    Adcock IM, Brown CR, Kwon O, Barnes PJ. Oxidative stress induces NF kappa B DNA binding and inducible NOS mRNA in human epithelial cells. Biochem Biophys Res Commun. 1994;199:1518–24.PubMedCrossRefGoogle Scholar
  165. 165.
    Meyskens Jr FL, McNulty SE, Buckmeier JA, et al. Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes. Free Radic Biol Med. 2001;31:799–808.PubMedCrossRefGoogle Scholar
  166. 166.
    Zhang J, Peng B, Chen X. Expression of nuclear factor kappaB, inducible nitric oxide syntheses, and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands: correlations with the angiogenesis and clinical outcome. Clin Cancer Res. 2005;11:7334–43.PubMedCrossRefGoogle Scholar
  167. 167.
    MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Rev Immunol. 1997;15: 323–50.CrossRefGoogle Scholar
  168. 168.
    Bredt DS. Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res. 1999;31:577–96.PubMedCrossRefGoogle Scholar
  169. 169.
    Geller DA, Billiar TR. Molecular biology of nitric oxide synthases. Cancer Metastasis Rev. 1998;17: 7–23.PubMedCrossRefGoogle Scholar
  170. 170.
    Massi D, Franchi A, Sardi I, et al. Inducible nitric oxide synthase expression in benign and malignant cutaneous melanocytic lesions. J Pathol. 2001;194:194–200.PubMedCrossRefGoogle Scholar
  171. 171.
    Xie K, Huang S, Dong Z, Juang SH, Gutman M, Xie QW, Nathan C, Fidler IJ. Transfection with the inducible nitric oxide syntheses gene suppresses tumorigenicity and abrogates metastasis by K-1735 murine melanoma cells. J Exp Med. 1995;181: 1333–43.PubMedCrossRefGoogle Scholar
  172. 172.
    Xie K, Wang Y, Huang S, et al. Nitric oxide-mediated apoptosis of K-1735 melanoma cells is associated with downregulation of Bcl-2. Oncogene. 1997;15:771–9.PubMedCrossRefGoogle Scholar
  173. 173.
    Messmer UK, Ankarcrona M, Nicotera P, Brüne B. p53 expression in nitric oxide induced apoptosis. FEBS Lett. 1994;355:23–6.PubMedCrossRefGoogle Scholar
  174. 174.
    Rudin CM, Thompson CB. Apoptosis and disease: regulation and clinical relevance of programmed cell death. Annu Rev Med. 1997;48:267–81.PubMedCrossRefGoogle Scholar
  175. 175.
    Williams GT, Smith CA. Molecular regulation of apoptosis: genetic controls on cell death. Cell. 1993;74:777–9.PubMedCrossRefGoogle Scholar
  176. 176.
    Krammer PH. The CD95(APO-1/Fas)/CD95L system. Toxicol Lett. 1998;102–103:131–7.PubMedCrossRefGoogle Scholar
  177. 177.
    Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol. 1999;17:2941–53.PubMedGoogle Scholar
  178. 178.
    Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13:555–62.PubMedCrossRefGoogle Scholar
  179. 179.
    Brune B, Mohr S, Messmer UK. Protein thiol modification and apoptotic cell death as cGMP-independent nitric oxide (NO) signaling pathways. Rev Physiol Biochem Pharmacol. 1996;127:1–30.PubMedCrossRefGoogle Scholar
  180. 180.
    Tschugguel W, Pustelnik T, Lass H, et al. Inducible nitric oxide synthase (iNOS) expression may predict distant metastasis in human melanoma. Br J Cancer. 1999;79:1609–12.PubMedCrossRefGoogle Scholar
  181. 181.
    Ahmed B, Van den Oord JJ. Expression of the inducible isoform of nitric oxide synthase in pigment cell lesions of the skin. Br J Dermatol. 2000;142: 432–40.PubMedCrossRefGoogle Scholar
  182. 182.
    Ekmekcioglu S, Ellerhorst J, Smid CM, et al. Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res. 2000;6:4768–75.PubMedGoogle Scholar
  183. 183.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.PubMedCrossRefGoogle Scholar
  184. 184.
    Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev. 2006;20:2149–82.PubMedCrossRefGoogle Scholar
  185. 185.
    Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene. 2003;22:3138–51.PubMedCrossRefGoogle Scholar
  186. 186.
    Miller AJ, Mihm MC. Melanoma. N Engl J Med. 2006;355:51–65.PubMedCrossRefGoogle Scholar
  187. 187.
    Bevona C, Goggins W, Quinn T. Cutaneous melanomas associated with nevi. Arch Dermatol. 2003;139: 1620–4.PubMedCrossRefGoogle Scholar
  188. 188.
    Rasheed S, Mao Z, Chan JMC, Chan LS. Is melanoma a stem cell tumor? Identification of neurogenic proteins in trans-differentiated cells. J Transl Med. 2005;3:14.PubMedCrossRefGoogle Scholar
  189. 189.
    Zabierowski SE, Herlyn M. Melanoma stem cells: the dark seed of melanoma. J Clin Oncol. 2008;26: 2890–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Paolo Antonio Ascierto
    • 1
    Email author
  • Maria Libera Ascierto
    • 1
  • Mariaelena Capone
    • 1
  • Zendee Elaba
    • 2
  • Michael J. Murphy
    • 3
  • Giuseppe Palmieri
    • 4
  1. 1.Unit of Medical Oncology and Innovative TherapyIstituto Nazionale Tumori Fondazione “G. Pascale”NaplesItaly
  2. 2.Department of PathologyHartford HospitalHartfordUSA
  3. 3.Department of DermatologyUniversity of Connecticut Health CenterFarmingtonUSA
  4. 4.Unit of Cancer GeneticsInstitute of Biomolecular Chemistry, National Research Council (CNR)SassariItaly

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