Skip to main content
SpringerLink
Log in

The Tumor Microenvironment in Cutaneous Melanoma: Friend or Foe

  • Chapter
  • First Online:
Biomarkers of the Tumor Microenvironment

  • 1229 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Le Douarin NM, Kalcheim C. The neural crest. London: Cambridge University Press; 1999.

    Book  Google Scholar 

  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. Blake JA, Ziman MR. Pax3 transcripts in melanoblast development. Develop Growth Differ. 2005;47(9):627–35.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  5. Silver DL, Hou L, Pavan WJ. The genetic regulation of pigment cell development. Adv Exp Med Biol. 2006;589:155–69.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Meulemans D, Bronner-Fraser M. Gene-regulatory interactions in neural crest evolution and development. Dev Cell. 2004;7(3):291–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Vandamme N, Berx G. Melanoma cells revive an embryonic transcriptional network to dictate phenotypic heterogeneity. Front Oncol. 2014;4:352.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wehrle-Haller B. The role of kit-ligand in melanocyte development and epidermal homeostasis. Pigment Cell Res. 2003;16(3):287–96.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Wilkie AL, Jordan SA, Jackson IJ. Neural crest progenitors of the melanocyte lineage: coat colour patterns revisited. Development. 2002;129(14):3349–57.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  29. Brabletz T. To differentiate or not--routes towards metastasis. Nat Rev Cancer. 2012;12(6):425–36.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  32. Villanueva J, Herlyn M. Melanoma and the tumor microenvironment. Curr Oncol Rep. 2008;10(5):439–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  35. Larue L, Delmas V. The WNT/Beta-catenin pathway in melanoma. Front Biosci. 2006;11:733–42.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pinon P, Wehrle-Haller B. Integrins: versatile receptors controlling melanocyte adhesion, migration and proliferation. Pigm cell Melan Res. 2011;24(2):282–94.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  50. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;133(3421):571–3.

    Article  Google Scholar 

  51. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.

    Article  CAS  PubMed  Google Scholar 

  52. Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 2010;70(14):5649–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    Article  CAS  PubMed  Google Scholar 

  54. Lee N, Barthel SR, Schatton T. Melanoma stem cells and metastasis: mimicking hematopoietic cell trafficking? Lab Investig. 2014;94(1):13–30.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Shih IM, Herlyn M. Autocrine and paracrine roles for growth factors in melanoma. In Vivo. 1994;8(1):113–23.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  61. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6(7):506–20.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  66. Anderberg C, Pietras K. On the origin of cancer-associated fibroblasts. Cell Cycle. 2009;8(10):1461–2.

    Article  CAS  PubMed  Google Scholar 

  67. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196(4):395–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  73. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  76. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32.

    Article  CAS  PubMed  Google Scholar 

  77. Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer. 2015;138(5):1058–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Algire GH. An adaptation of the transparent chamber technique to the mouse. JNCI. 1943;4(1):1–11.

    Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Streit M, Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene. 2003;22(20):3172–9.

    Article  CAS  PubMed  Google Scholar 

  81. Straume O, Salvesen HB, Akslen LA. Angiogenesis is prognostically important in vertical growth phase melanomas. Int J Oncol. 1999;15(3):595–9.

    CAS  PubMed  Google Scholar 

  82. Mahabeleshwar GH, Byzova TV. Angiogenesis in melanoma. Semin Oncol. 2007;34(6):555–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  85. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med. 1999;77(7):527–43.

    Article  CAS  PubMed  Google Scholar 

  86. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4–25.

    Article  CAS  PubMed  Google Scholar 

  87. Harper SJ, Bates DO. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer. 2008;8(11):880–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Claesson-Welsh L. Introduction to symposium on vascular biology, metabolism and cancer. J Intern Med. 2013;273(2):112–3.

    Article  CAS  PubMed  Google Scholar 

  89. Straume O, Bergheim J, Ernst P. Bevacizumab therapy for POEMS syndrome. Blood. 2006;107(12):4972–3. author reply 3-4

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. McDonald DM, Munn L, Jain RK. Vasculogenic mimicry: how convincing, how novel, and how significant? Am J Pathol. 2000;156(2):383–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  115. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  121. Vircow JJ Cellular Pathology. Philadelphia, 1863.

    Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  123. Hussein MR. Tumour-associated macrophages and melanoma tumourigenesis: integrating the complexity. Int J Exp Pathol. 2006;87(3):163–76.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  129. McGovern VJ, Shaw HM, Milton GW, McCarthy WH. Ulceration and prognosis in cutaneous malignant melanoma. Histopathology. 1982;6(4):399–407.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  135. Straume O, Akslen LA. Independent prognostic importance of vascular invasion in nodular melanomas. Cancer. 1996;78(6):1211–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  142. Shaw TJ, Martin P. Wound repair at a glance. J Cell Sci. 2009;122(Pt 18):3209–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  144. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. Balch CM. Cutaneous melanoma. 2nd ed. Philadelphia: J. B. Lippincott Company; 1992.

    Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway

    Oddbjørn Straume & Cornelia Schuster

Authors
  1. Oddbjørn Straume
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cornelia Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oddbjørn Straume .

Editor information

Editors and Affiliations

  1. Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Lars A. Akslen

  2. Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Randolph S. Watnick

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Straume, O., Schuster, C. (2017). The Tumor Microenvironment in Cutaneous Melanoma: Friend or Foe. In: Akslen, L., Watnick, R. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-319-39147-2_21

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-39147-2_21

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-39145-8

  • Online ISBN: 978-3-319-39147-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation