Advertisement

The Tumor Microenvironment in Cutaneous Melanoma: Friend or Foe

  • Oddbjørn Straume
  • Cornelia Schuster
Chapter

Abstract

Malignant melanoma is one of the most aggressive and lethal cancers. Even a primary tumor of 1 mm in thickness can metastasize and kill the patient. However, without the interactions with a supporting microenvironment, the tumor cannot grow and thrive. Most of the time, the microenvironment imposes an inhibitory effect on melanoma growth, and the vast majority of mutated neoplastic cells occurring during life will be destroyed. But how is the tumor microenvironment (TME) sometimes co-opted to support tumor growth? Does it not recognize the tumor lesion as a potential threat? Does the TME perceive the tumor as “a wound that needs to heal”? This chapter will describe some important players in the melanoma microenvironment. In addition to the biology of the melanocyte, the different roles played by keratinocytes, fibroblasts, endothelial cells, and immune cells will be discussed.

Keywords

Melanoma Microenvironment Stem cells Tumor plasticity Phenotype switch Keratinocytes Fibroblasts Endothelial cells Immune cells Ulceration 

References

  1. 1.
    Le Douarin NM, Kalcheim C. The neural crest. London: Cambridge University Press; 1999.CrossRefGoogle Scholar
  2. 2.
    Merlino G, Hearing VJ. Biology of melanocytes and primary melanoma. In: Balch CM, editor. Cutaneous melanoma. 5th ed. St. Louis: Quality Medical Publishing, Inc.; 2009.Google Scholar
  3. 3.
    Blake JA, Ziman MR. Pax3 transcripts in melanoblast development. Develop Growth Differ. 2005;47(9):627–35.CrossRefGoogle Scholar
  4. 4.
    Kos R, Reedy MV, Johnson RL, Erickson CA. The winged-helix transcription factor FoxD3 is important for establishing the neural crest lineage and repressing melanogenesis in avian embryos. Development. 2001;128(8):1467–79.PubMedGoogle Scholar
  5. 5.
    Silver DL, Hou L, Pavan WJ. The genetic regulation of pigment cell development. Adv Exp Med Biol. 2006;589:155–69.PubMedCrossRefGoogle Scholar
  6. 6.
    Yasumoto K, Takeda K, Saito H, Watanabe K, Takahashi K, Shibahara S. Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling. EMBO J. 2002;21(11):2703–14.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    O'Connell MP, Marchbank K, Webster MR, Valiga AA, Kaur A, Vultur A, et al. Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discov. 2013;3(12):1378–93.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Meulemans D, Bronner-Fraser M. Gene-regulatory interactions in neural crest evolution and development. Dev Cell. 2004;7(3):291–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Passeron T, Valencia JC, Bertolotto C, Hoashi T, Le Pape E, Takahashi K, et al. SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. Proc Natl Acad Sci U S A. 2007;104(35):13984–9.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Vandamme N, Berx G. Melanoma cells revive an embryonic transcriptional network to dictate phenotypic heterogeneity. Front Oncol. 2014;4:352.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Denecker G, Vandamme N, Akay O, Koludrovic D, Taminau J, Lemeire K, et al. Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression. Cell Death Differ. 2014;21(8):1250–61.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005;436(7047):117–22.PubMedCrossRefGoogle Scholar
  13. 13.
    Tirosh I, Izar B, Prakadan SM, Wadsworth MH 2nd, Treacy D, Trombetta JJ, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352(6282):189–96.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Wehrle-Haller B. The role of kit-ligand in melanocyte development and epidermal homeostasis. Pigment Cell Res. 2003;16(3):287–96.PubMedCrossRefGoogle Scholar
  15. 15.
    Takeda K, Yasumoto K, Takada R, Takada S, Watanabe K, Udono T, et al. Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a. J Biol Chem. 2000;275(19):14013–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Jouneau A, Yu YQ, Pasdar M, Larue L. Plasticity of cadherin-catenin expression in the melanocyte lineage. Pigment Cell Res. 2000;13(4):260–72.PubMedCrossRefGoogle Scholar
  17. 17.
    Haass NK, Smalley KS, Li L, Herlyn M. Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res. 2005;18(3):150–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Rao C, Foernzler D, Loftus SK, Liu S, McPherson JD, Jungers KA, et al. A defect in a novel ADAMTS family member is the cause of the belted white-spotting mutation. Development. 2003;130(19):4665–72.PubMedCrossRefGoogle Scholar
  19. 19.
    Wilkie AL, Jordan SA, Jackson IJ. Neural crest progenitors of the melanocyte lineage: coat colour patterns revisited. Development. 2002;129(14):3349–57.PubMedGoogle Scholar
  20. 20.
    Hoek KS, Eichhoff OM, Schlegel NC, Dobbeling U, Kobert N, Schaerer L, et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res. 2008;68(3):650–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Hoek KS, Schlegel NC, Brafford P, Sucker A, Ugurel S, Kumar R, et al. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment Cell Res. 2006;19(4):290–302.PubMedCrossRefGoogle Scholar
  22. 22.
    Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010;107(3):1124–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;14(12):769–85.PubMedCrossRefGoogle Scholar
  24. 24.
    Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. Cancer Metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell. 2009;15(3):195–206.PubMedCrossRefGoogle Scholar
  25. 25.
    Nishimura EK, Suzuki M, Igras V, Du J, Lonning S, Miyachi Y, et al. Key roles for transforming growth factor beta in melanocyte stem cell maintenance. Cell Stem Cell. 2010;6(2):130–40.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Cheli Y, Giuliano S, Fenouille N, Allegra M, Hofman V, Hofman P, et al. Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells. Oncogene. 2012;31(19):2461–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Landsberg J, Kohlmeyer J, Renn M, Bald T, Rogava M, Cron M, et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature. 2012;490(7420):412–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Hirobe T, Osawa M, Nishikawa S. Hepatocyte growth factor controls the proliferation of cultured epidermal melanoblasts and melanocytes from newborn mice. Pigment Cell Res. 2004;17(1):51–61.PubMedCrossRefGoogle Scholar
  29. 29.
    Brabletz T. To differentiate or not--routes towards metastasis. Nat Rev Cancer. 2012;12(6):425–36.PubMedCrossRefGoogle Scholar
  30. 30.
    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Haass NK, Herlyn M. Normal human melanocyte homeostasis as a paradigm for understanding melanoma. J Investig Dermatol Symp Proc. 2005;10(2):153–63.PubMedCrossRefGoogle Scholar
  32. 32.
    Villanueva J, Herlyn M. Melanoma and the tumor microenvironment. Curr Oncol Rep. 2008;10(5):439–46.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Smalley KS, Lioni M, Noma K, Haass NK, Herlyn M. In vitro three-dimensional tumor microenvironment models for anticancer drug discovery. Expert Opin Drug Discovery. 2008;3(1):1–10.CrossRefGoogle Scholar
  34. 34.
    Li G, Fukunaga M, Herlyn M. Reversal of melanocytic malignancy by keratinocytes is an E-cadherin-mediated process overriding beta-catenin signaling. Exp Cell Res. 2004;297(1):142–51.PubMedCrossRefGoogle Scholar
  35. 35.
    Larue L, Delmas V. The WNT/Beta-catenin pathway in melanoma. Front Biosci. 2006;11:733–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Widlund HR, Horstmann MA, Price ER, Cui J, Lessnick SL, Wu M, et al. Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor. J Cell Biol. 2002;158(6):1079–87.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Delmas V, Beermann F, Martinozzi S, Carreira S, Ackermann J, Kumasaka M, et al. Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev. 2007;21(22):2923–35.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Li G, Satyamoorthy K, Herlyn M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 2001;61(9):3819–25.PubMedGoogle Scholar
  39. 39.
    Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK. Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem. 2001;276(27):24661–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116(Pt 3):499–511.PubMedCrossRefGoogle Scholar
  41. 41.
    Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene. 2001;20(56):8125–35.PubMedCrossRefGoogle Scholar
  42. 42.
    Soong J, Chen Y, Shustef EM, Scott GA. Sema4D, the ligand for Plexin B1, suppresses c-met activation and migration and promotes melanocyte survival and growth. J Invest Dermatol. 2012;132(4):1230–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Stevens L, McClelland L, Fricke A, Williamson M, Kuo I, Scott G. Plexin B1 suppresses c-met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-met. J Invest Dermatol. 2010;130(6):1636–45.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Argast GM, Croy CH, Couts KL, Zhang Z, Litman E, Chan DC, et al. Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells. Oncogene. 2009;28(30):2697–709.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Pinon P, Wehrle-Haller B. Integrins: versatile receptors controlling melanocyte adhesion, migration and proliferation. Pigm cell Melan Res. 2011;24(2):282–94.CrossRefGoogle Scholar
  46. 46.
    Hess AR, Postovit LM, Margaryan NV, Seftor EA, Schneider GB, Seftor RE, et al. Focal adhesion kinase promotes the aggressive melanoma phenotype. Cancer Res. 2005;65(21):9851–60.PubMedCrossRefGoogle Scholar
  47. 47.
    Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L, Herlyn M, et al. Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. Cancer Res. 1990;50(20):6757–64.PubMedGoogle Scholar
  48. 48.
    Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell. 1996;85(5):683–93.PubMedCrossRefGoogle Scholar
  49. 49.
    Petitclerc E, Stromblad S, von Schalscha TL, Mitjans F, Piulats J, Montgomery AM, et al. Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res. 1999;59(11):2724–30.PubMedGoogle Scholar
  50. 50.
    Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;133(3421):571–3.CrossRefGoogle Scholar
  51. 51.
    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.PubMedCrossRefGoogle Scholar
  52. 52.
    Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 2010;70(14):5649–69.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Lee N, Barthel SR, Schatton T. Melanoma stem cells and metastasis: mimicking hematopoietic cell trafficking? Lab Investig. 2014;94(1):13–30.PubMedCrossRefGoogle Scholar
  55. 55.
    Giehl KA, Nagele U, Volkenandt M, Berking C. Protein expression of melanocyte growth factors (bFGF, SCF) and their receptors (FGFR-1, c-kit) in nevi and melanoma. J Cutan Pathol. 2007;34(1):7–14.PubMedCrossRefGoogle Scholar
  56. 56.
    Straume O, Akslen LA. Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am J Pathol. 2002;160(3):1009–19.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Halaban R, Kwon BS, Ghosh S, Delli Bovi P, Baird A. bFGF as an autocrine growth factor for human melanomas. Onco Res. 1988;3(2):177–86.Google Scholar
  58. 58.
    Becker D, Meier CB, Herlyn M. Proliferation of human malignant melanomas is inhibited by antisense oligodeoxynucleotides targeted against basic fibroblast growth factor. EMBO J. 1989;8(12):3685–91.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Shih IM, Herlyn M. Autocrine and paracrine roles for growth factors in melanoma. In Vivo. 1994;8(1):113–23.PubMedGoogle Scholar
  60. 60.
    Smalley KS, Brafford PA, Herlyn M. Selective evolutionary pressure from the tissue microenvironment drives tumor progression. Semin Cancer Biol. 2005;15(6):451–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6(7):506–20.PubMedCrossRefGoogle Scholar
  62. 62.
    Bissell MJ, Hines WC. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 2011;17(3):320–9.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lu C, Vickers MF, Kerbel RS. Interleukin 6: a fibroblast-derived growth inhibitor of human melanoma cells from early but not advanced stages of tumor progression. Proc Natl Acad Sci U S A. 1992;89(19):9215–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Zhou L, Yang K, Andl T, Wickett RR, Zhang Y. Perspective of targeting cancer-associated fibroblasts in melanoma. J Cancer. 2015;6(8):717–26.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Navab R, Strumpf D, To C, Pasko E, Kim KS, Park CJ, et al. Integrin alpha11beta1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer. Oncogene. 2016;35(15):1899–908.PubMedCrossRefGoogle Scholar
  66. 66.
    Anderberg C, Pietras K. On the origin of cancer-associated fibroblasts. Cell Cycle. 2009;8(10):1461–2.PubMedCrossRefGoogle Scholar
  67. 67.
    Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196(4):395–406.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Wandel E, Grasshoff A, Mittag M, Haustein UF, Saalbach A. Fibroblasts surrounding melanoma express elevated levels of matrix metalloproteinase-1 (MMP-1) and intercellular adhesion molecule-1 (ICAM-1) in vitro. Exp Dermatol. 2000;9(1):34–41.PubMedCrossRefGoogle Scholar
  69. 69.
    Taddei ML, Giannoni E, Raugei G, Scacco S, Sardanelli AM, Papa S, et al. Mitochondrial oxidative stress due to complex I dysfunction promotes fibroblast activation and melanoma cell invasiveness. J Sign Trans. 2012;2012:684592.Google Scholar
  70. 70.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Straume O, Akslen LA. Increased expression of VEGF-receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma. Angiogenesis. 2003;6(4):295–301.PubMedCrossRefGoogle Scholar
  72. 72.
    Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst. 2006;98(5):316–25.PubMedCrossRefGoogle Scholar
  73. 73.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.PubMedCrossRefGoogle Scholar
  74. 74.
    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT, Sun YC, et al. Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. J Biol Chem. 2004;279(11):10331–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32.PubMedCrossRefGoogle Scholar
  77. 77.
    Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer. 2015;138(5):1058–66.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Algire GH. An adaptation of the transparent chamber technique to the mouse. JNCI. 1943;4(1):1–11.Google Scholar
  79. 79.
    Straume O, Akslen LA. Expresson of vascular endothelial growth factor, its receptors (FLT-1, KDR) and TSP-1 related to microvessel density and patient outcome in vertical growth phase melanomas. Am J Pathol. 2001;159(1):223–35.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Streit M, Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene. 2003;22(20):3172–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Straume O, Salvesen HB, Akslen LA. Angiogenesis is prognostically important in vertical growth phase melanomas. Int J Oncol. 1999;15(3):595–9.PubMedGoogle Scholar
  82. 82.
    Mahabeleshwar GH, Byzova TV. Angiogenesis in melanoma. Semin Oncol. 2007;34(6):555–65.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med. 1999;77(7):527–43.PubMedCrossRefGoogle Scholar
  86. 86.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4–25.PubMedCrossRefGoogle Scholar
  87. 87.
    Harper SJ, Bates DO. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer. 2008;8(11):880–7.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Claesson-Welsh L. Introduction to symposium on vascular biology, metabolism and cancer. J Intern Med. 2013;273(2):112–3.PubMedCrossRefGoogle Scholar
  89. 89.
    Straume O, Bergheim J, Ernst P. Bevacizumab therapy for POEMS syndrome. Blood. 2006;107(12):4972–3. author reply 3-4PubMedCrossRefGoogle Scholar
  90. 90.
    Straume O, Chappuis PO, Salvesen HB, Halvorsen OJ, Haukaas SA, Goffin JR, et al. Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res. 2002;62(23):6808–11.PubMedGoogle Scholar
  91. 91.
    Akslen LA, Straume O, Geisler S, Sorlie T, Chi JT, Aas T, et al. Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer. Br J Cancer. 2011;105(1):9–12.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Wang Y, Becker D. Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med. 1997;3(8):887–93.PubMedCrossRefGoogle Scholar
  93. 93.
    Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005;16(2):159–78.PubMedCrossRefGoogle Scholar
  94. 94.
    Adamcic U, Skowronski K, Peters C, Morrison J, Coomber BL. The effect of bevacizumab on human malignant melanoma cells with functional VEGF/VEGFR2 autocrine and intracrine signaling loops. Neoplasia. 2012;14(7):612–23.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Corrie P, Goonewardena M, Dunn JA, Middleton MR, Nathan PD, Gore ME, Davidson N, Nicholson S, Kelly CG, Marples M, Danson S, Marshall E, Houston S, Board RE, Waterston AM, Nobes J, Harries M, Barber J, Lorigan P, AVAST-M: Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence. 2013 ASCO Annual Meeting; 2013: ASCO.Google Scholar
  96. 96.
    Schuster C, Eikesdal HP, Puntervoll H, Geisler J, Geisler S, Heinrich D, et al. Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension. PLoS One. 2012;7(6):e38364.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2(7):632–42.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Liu G, Zhang F, Lee J, Dong Z. Selective induction of interleukin-8 expression in metastatic melanoma cells by transforming growth factor-beta 1. Cytokine. 2005;31(3):241–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA. Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J Cell Biol. 2003;162(5):933–43.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Straume O, Shimamura T, Lampa MJ, Carretero J, Oyan AM, Jia D, et al. Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer. Proc Natl Acad Sci U S A. 2012;109(22):8699–704.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry [in process citation]. Am J Pathol. 1999;155(3):739–52.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Seftor RE, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV, et al. Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol. 2012;181(4):1115–25.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    McDonald DM, Munn L, Jain RK. Vasculogenic mimicry: how convincing, how novel, and how significant? Am J Pathol. 2000;156(2):383–8.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444(7122):1083–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Li JL, Sainson RC, Oon CE, Turley H, Leek R, Sheldon H, et al. DLL4-notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 2011;71(18):6073–83.PubMedCrossRefGoogle Scholar
  106. 106.
    Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    McDermott D, Lebbe C, Hodi FS, Maio M, Weber JS, Wolchok JD, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40(9):1056–64.PubMedCrossRefGoogle Scholar
  109. 109.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.PubMedCrossRefGoogle Scholar
  110. 110.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Sapoznik S, Hammer O, Ortenberg R, Besser MJ, Ben-Moshe T, Schachter J, et al. Novel anti-melanoma immunotherapies: disarming tumor escape mechanisms. Clin Dev Immunol. 2012;2012:818214.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Pico de Coana Y, Choudhury A, Kiessling R. Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med. 2015;21(8):482–91.PubMedCrossRefGoogle Scholar
  115. 115.
    Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Naumov GN, Folkman J, Straume O. Tumor dormancy due to failure of angiogenesis: role of the microenvironment. Clin Exp Metastasis. 2009;26(1):51–60.PubMedCrossRefGoogle Scholar
  117. 117.
    Voron T, Marcheteau E, Pernot S, Colussi O, Tartour E, Taieb J, et al. Control of the immune response by pro-angiogenic factors. Front Oncol. 2014;4:70.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Yuan J, Zhou J, Dong Z, Tandon S, Kuk D, Panageas KS, et al. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res. 2014;2(2):127–32.PubMedCrossRefGoogle Scholar
  119. 119.
    Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science. 1996;274(5291):1363–6.PubMedCrossRefGoogle Scholar
  120. 120.
    Seliger B, Ritz U, Abele R, Bock M, Tampe R, Sutter G, et al. Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway. Cancer Res. 2001;61(24):8647–50.PubMedGoogle Scholar
  121. 121.
    Vircow JJ Cellular Pathology. Philadelphia, 1863.Google Scholar
  122. 122.
    Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77(7):1303–10.PubMedCrossRefGoogle Scholar
  123. 123.
    Hussein MR. Tumour-associated macrophages and melanoma tumourigenesis: integrating the complexity. Int J Exp Pathol. 2006;87(3):163–76.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Botti G, Cerrone M, Scognamiglio G, Anniciello A, Ascierto PA, Cantile M. Microenvironment and tumor progression of melanoma: new therapeutic prospectives. J Immunotoxicol. 2013;10(3):235–52.PubMedCrossRefGoogle Scholar
  125. 125.
    Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66(1):1–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappa B and enhanced IRF-3/STAT1 activation). Blood. 2006;107(5):2112–22.PubMedCrossRefGoogle Scholar
  127. 127.
    Varney ML, Olsen KJ, Mosley RL, Bucana CD, Talmadge JE, Singh RK. Monocyte/macrophage recruitment, activation and differentiation modulate interleukin-8 production: a paracrine role of tumor-associated macrophages in tumor angiogenesis. In Vivo. 2002;16(6):471–7.PubMedGoogle Scholar
  128. 128.
    Varney ML, Olsen KJ, Mosley RL, Singh RK. Paracrine regulation of vascular endothelial growth factor--a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor. J Interf Cytokine Res. 2005;25(11):674–83.CrossRefGoogle Scholar
  129. 129.
    McGovern VJ, Shaw HM, Milton GW, McCarthy WH. Ulceration and prognosis in cutaneous malignant melanoma. Histopathology. 1982;6(4):399–407.PubMedCrossRefGoogle Scholar
  130. 130.
    Balch CM, Wilkerson JA, Murad TM, Soong SJ, Ingalls AL, Maddox WA. The prognostic significance of ulceration of cutaneous melanoma. Cancer. 1980;45(12):3012–7.PubMedCrossRefGoogle Scholar
  131. 131.
    Spatz A, Cook MG, Elder DE, Piepkorn M, Ruiter DJ, Barnhill RL. Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas. Eur J Cancer. 2003;39(13):1861–5.PubMedCrossRefGoogle Scholar
  132. 132.
    Eggermont AM, Spatz A, Lazar V, Robert C. Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity? Curr Opin Oncol. 2012;24(2):137–40.PubMedCrossRefGoogle Scholar
  133. 133.
    Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Kashani-Sabet M, Sagebiel RW, Ferreira CM, Nosrati M, Miller JR III. Tumor vascularity in the prognostic assessment of primary cutaneous melanoma. J Clin Oncol. 2002;20(7):1826–31.PubMedCrossRefGoogle Scholar
  135. 135.
    Straume O, Akslen LA. Independent prognostic importance of vascular invasion in nodular melanomas. Cancer. 1996;78(6):1211–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Egger ME, Gilbert JE, Burton AL, McMasters KM, Callender GG, Quillo AR, et al. Lymphovascular invasion as a prognostic factor in melanoma. Am Surg. 2011;77(8):992–7.PubMedGoogle Scholar
  137. 137.
    White RL Jr, Ayers GD, Stell VH, Ding S, Gershenwald JE, Salo JC, et al. Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database. Ann Surg Oncol. 2011;18(13):3593–600.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Elliott B, Scolyer RA, Suciu S, Lebecque S, Rimoldi D, Gugerli O, et al. Long-term protective effect of mature DC-LAMP+ dendritic cell accumulation in sentinel lymph nodes containing micrometastatic melanoma. Clin Cancer Res. 2007;13(13):3825–30.PubMedCrossRefGoogle Scholar
  139. 139.
    Barnhill RL, Katzen J, Spatz A, Fine J, Berwick M. The importance of mitotic rate as a prognostic factor for localized cutaneous melanoma. J Cutan Pathol. 2005;32(4):268–73.PubMedCrossRefGoogle Scholar
  140. 140.
    Winnepenninckx V, Lazar V, Michiels S, Dessen P, Stas M, Alonso SR, et al. Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst. 2006;98(7):472–82.PubMedCrossRefGoogle Scholar
  141. 141.
    Eggermont AM, Suciu S, Testori A, Kruit WH, Marsden J, Punt CJ, et al. Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer. 2012;48(2):218–25.PubMedCrossRefGoogle Scholar
  142. 142.
    Shaw TJ, Martin P. Wound repair at a glance. J Cell Sci. 2009;122(Pt 18):3209–13.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315(26):1650–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263–6.PubMedCrossRefGoogle Scholar
  145. 145.
    Antonio N, Bonnelykke-Behrndtz ML, Ward LC, Collin J, Christensen IJ, Steiniche T, et al. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J. 2015;34(17):2219–36.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Feng Y, Martin P. Inflammation promotes tumour initiation by leukocyte release of trophic factor (PGE2) as revealed by live imaging in zebrafish larvae. Immunology. 2012;137:111.Google Scholar
  147. 147.
    Balch CM. Cutaneous melanoma. 2nd ed. Philadelphia: J. B. Lippincott Company; 1992.Google Scholar
  148. 148.
    Sundberg C, Nagy JA, Brown LF, Feng D, Eckelhoefer IA, Manseau EJ, et al. Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. Am J Pathol. 2001;158(3):1145–60.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G. Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle. 2006;5(22):2592–601.PubMedCrossRefGoogle Scholar
  150. 150.
    Geukes Foppen MH, Donia M, Svane IM, Haanen JB. Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol Oncol. 2015;9(10):1918–35.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Centre for Cancer Biomarkers CCBIOUniversity of BergenBergenNorway

Personalised recommendations