Tumor Biology

, Volume 36, Issue 12, pp 9127–9136 | Cite as

Developing strategies to predict photodynamic therapy outcome: the role of melanoma microenvironment

  • Renzo Emanuel Vera
  • María Julia Lamberti
  • Viviana Alicia Rivarola
  • Natalia Belén Rumie Vittar


Melanoma is among the most aggressive and treatment-resistant human skin cancer. Photodynamic therapy (PDT), a minimally invasive therapeutic modality, is a promising approach to treating melanoma. It combines a non-toxic photoactivatable drug called photosensitizer with harmless visible light to generate reactive oxygen species which mediate the antitumor effects. The aim of this review was to compile the available data about PDT on melanoma. Our comparative analysis revealed a disconnection between several hypotheses generated by in vitro therapeutic studies and in vivo and clinical assays. This fact led us to highlight new preclinical experimental platforms that mimic the complexity of tumor biology. The tumor and its stromal microenvironment have a dynamic and reciprocal interaction that plays a critical role in tumor resistance, and these interactions can be exploited for novel therapeutic targets. In this sense, we review two strategies used by photodynamic researchers: (a) developing 3D culture systems which mimic tumor architecture and (b) heterotypic cultures that resemble tumor microenvironment to favor therapeutic regimen design. After this comprehensive review of the literature, we suggest that new complementary preclinical models are required to better optimize the clinical outcome of PDT on skin melanoma.


Melanoma Photodynamic therapy Tumor microenvironment Monolayer Spheroids 



This work was supported by grants from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Agencia Nacional de Promoción Científica y Tecnológica (PICT), Secretaría de Ciencia y Técnica (SECyT), and Universidad Nacional de Rio Cuarto, Argentina. VR and NBRV are members of the Scientific Researcher Career at CONICET. REV and MJL hold fellowship from CONICET.

Conflicts of interest



  1. 1.
    Lo J, Fisher D. The melanoma revolution: from UV carcinogenesis to a new era in therapeutic. Science. 2014;346:945–9.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Chang C, Murzaku E, Penn L, Abbasi N, Davis P, Berwick M, et al. More skin, more sun, more tan, more melanoma. Am J Public Health. 2014;104:e92–9.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Diao D, Lee T. Sun-protective behaviors in populations at high risk for skin cancer. Psychol Res Behav Manag. 2014;7:9–18.Google Scholar
  4. 4.
    De Giorgi V, Sestini S, Massi D, Lotti T. Melanocytic aggregation in the skin: diagnostic clues from lentigines to melanoma. Dermatol Clin. 2007;25:303–20. vii – viii.CrossRefPubMedGoogle Scholar
  5. 5.
    Bastian B. The molecular pathology of melanoma: an integrated taxonomy of melanocytic, neoplasia. Annu Rev Pathol. 2014;9:239–71.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Miller AJ, Mihm MC. Mechanisms of disease Melanoma. N Engl J Med. 2006;51–65.Google Scholar
  7. 7.
    Markovic SN, Erickson LA, Rao RD, Weenig RH, Pockaj BA, Bardia A, et al. Malignant melanoma in the 21st century, part 2: staging, prognosis, and treatment. Mayo Clin Proc. 2007;82:490–513.CrossRefPubMedGoogle Scholar
  8. 8.
    Markovic SN, Erickson LA, Rao RD, Weenig RH, Pockaj BA, Bardia A, et al. Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc. 2007;82:364–80.CrossRefPubMedGoogle Scholar
  9. 9.
    Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.CrossRefPubMedGoogle Scholar
  10. 10.
    Dar AA, Majid S, De Semir D, Nosrati M, Bezrookove V, Kashani-Sabet M. miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein. J Biol Chem. 2011;286:16606–14.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Van den Hurk K, Niessen HEC, Veeck J, van den Oord JJ, van Steensel MAM, Zur Hausen A, et al. Genetics and epigenetics of cutaneous malignant melanoma: a concert out of tune. Biochim Biophys Acta. 1826;2012:89–102.Google Scholar
  12. 12.
    Lee JT, Herlyn M. Microenvironmental influences in melanoma progression. J Cell Biochem. 2007;101:862–72.CrossRefPubMedGoogle Scholar
  13. 13.
    Bhatia S, Tykodi S, Thompson J. Treatment of metastatic melanoma: an overview. Oncol (willist Park). 2009;23:488–96.Google Scholar
  14. 14.
    Agostinis P, Berg K, Cengel K, Foster T, Girotti A, Gollnick S, et al. Photodynamic therapy of cancer: an update. CA Cancer J Clin. 2011;61:250–81.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Morton C, Szeimies R, Sidoroff A, Braathen L. European guidelines for topical photodynamic therapy part 1: treatment delivery and current indications - actinic keratoses, Bowen’s disease, basal cell carcinoma. J Eur Acad Dermatol Venereol. 2013;27:536–44.CrossRefPubMedGoogle Scholar
  16. 16.
    Dougherty T, Kaufman J, Goldfarb A, Weishaupt K, Boyle D, Mittleman A. Photoradiation therapy for the treatment of malignant tumors. Cancer Res. 1978;38:2628–35.PubMedGoogle Scholar
  17. 17.
    Sheleg S, Zhavrid E, Khodina T, Kochubeev G, Istomin Y, Chalov V, et al. Photodynamic therapy with chlorin e(6) for skin metastases of melanoma. Photodermatol Photoimmunol Photomed. 2004;20:21–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Chetty N, Osborne V, Harland C. Amelanotic melanoma in situ: lack of sustained response to photodynamic therapy. Clin Exp Dermatol. 2008;33:204–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Koderhold G, Jindra R, Koren H, Alth G, Schenk G. Experiences of photodynamic therapy in dermatology. J Photochem Photobiol B. 1996;36:221–3.CrossRefPubMedGoogle Scholar
  20. 20.
    Nelson J, McCullough J, Berns M. Photodynamic therapy of human malignant melanoma xenografts in athymic nude mice. J Natl Cancer Inst. 1988;80:56–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Young A. Chromophores in human skin. Phys Med Biol. 1997;42:789–802.CrossRefPubMedGoogle Scholar
  22. 22.
    Witz IP. The tumor microenvironment: the making of a paradigm. Cancer Microenviron. 2009;2:9–17.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Li X, Naylor M, Le H, Nordquist R, Teague T, Howard C, et al. Clinical effects of in situ photoimmunotherapy on late-stage melanoma patients: a preliminary study. Cancer Biol Ther. 2010;10:1081–7.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Naylor M, Chen W, Teague T, Perry L, Nordquist R. In situ photoimmunotherapy: a tumour-directed treatment for melanoma. Br J Dermatol. 2006;155:1287–92.CrossRefPubMedGoogle Scholar
  25. 25.
    Paiva M, Joo J, Abrahao M, Ribeiro J, Cervantes O, Sercarz J. Update on laser photochemotherapy: an alternative for cancer treatment. Anticancer Agents Med Chem. 2011;11:772–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Huang Y, Vecchio D, Avci P, Yin R, Garcia-diaz M, Hamblin MR. Melanoma resistance to photodynamic therapy: new insights. Biol Chem. 2014;394:239–50.Google Scholar
  27. 27.
    Duc GHT, editor. Melanomas | From Early Detection to Treatment. InTech; 2013.Google Scholar
  28. 28.
    Maduray K, Karsten A, Odhav B, Nyokong T. In vitro toxicity testing of zinc tetrasulfophthalocyanines in fibroblast and keratinocyte cells for the treatment of melanoma cancer by photodynamic therapy. J Photochem Photobiol B Biol. 2011;103:98–104.CrossRefGoogle Scholar
  29. 29.
    Krestyn E, Kolarova H, Bajgar R, Tomankova K. Photodynamic properties of ZnTPPS4, ClAlPcS2 and ALA in human melanoma G361 cells. Toxicol InVitro. 2010;24:286–91.CrossRefGoogle Scholar
  30. 30.
    Kolarova H, Tomankova K, Bajgar R, Kolar P, Kubinek R. Photodynamic and sonodynamic treatment by phthalocyanine on cancer cell lines. Ultrasound Med Biol. 2009;35:1397–404.CrossRefPubMedGoogle Scholar
  31. 31.
    Karmakova T, Feofanov A, Nazarova A, Grichine A, Yakubovskaya R, Luk’yanets E, et al. Distribution of metal-free sulfonated phthalocyanine in subcutaneously transplanted murine tumors. J Photochem Photobiol B Biol. 2004;75:81–7.CrossRefGoogle Scholar
  32. 32.
    Barge J, Decréau R, Julliard M, Hubaud JC, Sabatier AS, Grob JJ, et al. Killing efficacy of a new silicon phthalocyanine in human melanoma cells treated with photodynamic therapy by early activation of mitochondrion-mediated apoptosis. Exp Dermatol. 2004;13:33–44.CrossRefPubMedGoogle Scholar
  33. 33.
    Sparsa A, Bellaton S, Naves T, Jauberteau M, Bonnetblanc J, Sol V, et al. Photodynamic treatment induces cell death by apoptosis or autophagy depending on the melanin content in two B16 melanoma cell lines. Oncol Rep. 2013;29:1196–200.PubMedGoogle Scholar
  34. 34.
    Breusing N, Grimm S, Mvondo D, Flaccus A, Biesalski HK, Grune T. Light-induced cytotoxicity after aminolevulinic acid treatment is mediated by heme and not by iron. J Photochem Photobiol B Biol. 2010;99:36–43.CrossRefGoogle Scholar
  35. 35.
    Ickowicz Schwartz D, Gozlan Y, Greenbaum L, Babushkina T, Katcoff DJ, Malik Z. Differentiationdependent photodynamic therapy regulated by porphobilinogen deaminase in B16 melanoma. Br J Cancer. 2004;90:1833–41.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Da̧browski JM, Pereira MM, Arnaut LG, Monteiro CJP, Peixoto AF, Karocki A, et al. Synthesis, photophysical studies and anticancer activity of a new halogenated water-soluble porphyrin. Photochem Photobiol. 2007;83:897–903.CrossRefPubMedGoogle Scholar
  37. 37.
    Nowak-Sliwinska P, Karocki A, Elas M, Pawlak A, Stochel G, Urbanska K. Verteporfin, photofrin II, and merocyanine 540 as PDT photosensitizers against melanoma cells. Biochem Biophys Res Commun. 2006;349:549–55.CrossRefPubMedGoogle Scholar
  38. 38.
    Kolarova H, Macecek J, Nevrelova P, Huf M, Tomecka M, Bajgar R, et al. Photodynamic therapy with zinc-tetra(p-sulfophenyl)porphyrin bound to cyclodextrin induces single strand breaks of cellular DNA in G361 melanoma cells. Toxicol In Vitro. 2005;19:971–4.CrossRefPubMedGoogle Scholar
  39. 39.
    Szurko A, Krämer-Marek G, Wideł M, Ratuszna A, Habdas J, Kuś P. Photodynamic effects of two water soluble porphyrins evaluated on human malignant melanoma cells in vitro. Acta Biochim Pol. 2003;50:1165–74.PubMedGoogle Scholar
  40. 40.
    Ježek P, Nekvasil M, Škobisová E, Urbánková E, Jirsa M, Zadinová M, et al. Experimental photodynamic therapy with meso-tetrakisphenylporphyrin (TPP) in liposomes leads to disintegration of human amelanotic melanoma implanted to nude mice. Int J Cancer. 2003;103:693–702.CrossRefPubMedGoogle Scholar
  41. 41.
    Chang C, Yu J, Wei F. In vitro and in vivo photosensitizing applications of Photofrin® in malignant melanoma cells. Chang Gung Med J. 2007;31:260–7.Google Scholar
  42. 42.
    Kleemann B, Loos B, Lang D, Scriba T, Davids L. St John’s Wort (Hypericum perforatum L.) photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death. PLoS ONE. 2014;9(7), e103762.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Mazor O, Brandis A, Plaks V, Neumark E, Rosenbach-Belkin V, Salomon Y, et al. WST11, a novel watersoluble bacteriochlorophyll derivative; cellular uptake, pharmacokinetics, biodistribution and vasculartargeted photodynamic activity using melanoma tumors as a model. Photochem Photobiol. 2005;81:342–51.CrossRefPubMedGoogle Scholar
  44. 44.
    Nagata S, Obana A, Gohto Y, Nakajima S. Necrotic and apoptotic cell death of human malignant melanoma cells following photodynamic therapy using an amphiphilic photosensitizer, ATX-S10(Na). Lasers Surg Med. 2003;33:64–70.CrossRefPubMedGoogle Scholar
  45. 45.
    Ropp S, Guy J, Berl V, Bischoff P, Lepoittevin J-P. Synthesis and photocytotoxic activity of new α-methylene-γ-butyrolactone-psoralen heterodimers. Bioorg Med Chem. 2004;12:3619–25.CrossRefPubMedGoogle Scholar
  46. 46.
    Donnelly R, McCarron P, Woolfson A. Derivatives of 5-aminolevulinic Acid for photodynamic therapy. Perspect Med Chem. 2008;1:49–63.Google Scholar
  47. 47.
    Haddad R, Kaplan O, Greenberg R, Siegal A, Skornick Y, Kashtan H. Photodynamic therapy of murine colon cancer and melanoma using systemic aminolevulinic acid as a photosensitizer. Int J Surg Investig. 2000;2:171–8.PubMedGoogle Scholar
  48. 48.
    Robertson CA, Abrahamse H, Evans D. The in vitro PDT efficacy of a novel metallophthalocyanine (MPc) derivative and established 5-ALA photosensitizing dyes against human metastatic melanoma cells. Lasers Surg Med. 2010;42:766–76.CrossRefPubMedGoogle Scholar
  49. 49.
    Lr B, Weissenberger J, Vallan C, Kato M. Bern C-. 5-aminolaevulinic acid photodynamic therapy in a transgenic mouse model of skin melanoma. Exp Dermatol. 2005;14:429–37.CrossRefGoogle Scholar
  50. 50.
    Chen Y, Zheng W, Li Y, Zhong J, Ji J, Shen P. Apoptosis induced by methylene-blue-mediated photodynamic therapy in melanomas and the involvement of mitochondrial dysfunction revealed by proteomics. Cancer Sci. 2008;99:2019–27.PubMedGoogle Scholar
  51. 51.
    Wagner M, Suarez ER, Theodoro TR, Machado Filho CDAS, Gama MFM, Tardivo JP, et al. Methylene blue photodynamic therapy in malignant melanoma decreases expression of proliferating cell nuclear antigen and heparanases. Clin Exp Dermatol. 2012;37:527–33.CrossRefPubMedGoogle Scholar
  52. 52.
    Rapozzi V, Zorzet S, Zacchigna M, Della Pietra E, Cogoi S, Xodo LE. Anticancer activity of cationic porphyrins in melanoma tumour-bearing mice and mechanistic in vitro studies. Mol Cancer. 2014;13:75.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hao E, Friso E, Miotto G, Jori G, Soncin M, Fabris C, et al. Synthesis and biological investigations of tetrakis(p-carboranylthio-tetrafluorophenyl)chlorin (TPFC). Org Biomol Chem. 2008;6:3732–40.CrossRefPubMedGoogle Scholar
  54. 54.
    Chen L, Fiedorl L, Pavlofsky F, Brumfeldl V, Salomon Y, Scherz A. Serine conjugates of chlorophyll and bacteriochlorophyll : photocytotoxicity in witro and tissue distribution in mice bearing melanoma tumors. Photochem Photobiol. 1996;64:174–81.CrossRefPubMedGoogle Scholar
  55. 55.
    Zilbersteins J, Bromberg A, Frantz A, Rosenbach-belkin V, Kritzmann A. Light-dependent oxygen consumption in bacteriochlorophyll-serine-treated melanoma tumors: on-line determination using a tissue-inserted oxygen microsensor. Photochem Photobiol. 1997;65:1012–9.CrossRefGoogle Scholar
  56. 56.
    Toledo F, Wahl G. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6:909–23.CrossRefPubMedGoogle Scholar
  57. 57.
    Beaumont K, Mohana-Kumaran N, Haass N. Modeling melanoma in vitro and in vivo. Healthcare. 2013;2:27–46.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Fabris C, Vicente MGH, Hao E, Friso E, Borsetto L, Jori G, et al. Tumour-localizing and -photosensitising properties of meso-tetra(4-nido-carboranylphenyl)porphyrin (H2TCP). J Photochem Photobiol B Biol. 2007;89:131–8.CrossRefGoogle Scholar
  59. 59.
    Tsai T, Ji H, Chiang P, Chou R, Chang W, Chen C. ALA-PDT results in phenotypic changes and decreased cellular invasion in surviving cancer cells. Lasers Surg Med. 2009;41:305–15.CrossRefPubMedGoogle Scholar
  60. 60.
    Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA. Spheroid-based drug screen: considerations and practical approach. Nat Protoc. 2009;4:309–24.CrossRefPubMedGoogle Scholar
  61. 61.
    Fennema E, Rivron N, Rouwkema J, van Blitterswijk C, de Boer J. Spheroid culture as a tool for creating 3D complex tissues. Trends Biotechnol. 2013;31:108–15.CrossRefPubMedGoogle Scholar
  62. 62.
    Rofstad E, Wahl A, Brustad T. Radiation response of multicellular spheroids initiated from five human melanoma xenograft lines. Relationship to the radioresponsiveness in vivo. Br J Radiol. 1986;59:1023–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Kastl A, Dieckmann S, Wähler K, Völker T, Kastl L, Merkel A, et al. Rhenium complexes with visible-lightinduced anticancer activity. ChemMedChem. 2013;8:924–7.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Barbugli P a., Alves CP, Espreafico EM, Tedesco AC. Photodynamic therapy utilizing liposomal ClAlPc in human melanoma 3D cell cultures. Exp Dermatol. 2015;70:n/a – n/a.Google Scholar
  65. 65.
    Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R. Interaction of tumor cells with the microenvironment. Cell Commun Signal. 2011;9:18.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ruiter D, Bogenrieder T, Elder D, Herlyn M. Melanoma-stroma interactions: structural and functional aspects. Lancet Oncol. 2002;3:35–43.CrossRefPubMedGoogle Scholar
  67. 67.
    Labrousse A, Ntayi C, Hornebeck W, Bernard P. Stromal reaction in cutaneous melanoma. Crit Rev Oncol Hematol. 2004;49:269–75.CrossRefPubMedGoogle Scholar
  68. 68.
    Villanueva J, Herlyn M. Melanoma and the tumor microenvironment. Curr Oncol Rep. 2008;10:439–46.CrossRefPubMedGoogle Scholar
  69. 69.
    Hsu M, Meier F, Herlyn M. Melanoma development and progression: a conspiracy between tumor and host. Differentiation. 2002;70:522–36.CrossRefPubMedGoogle Scholar
  70. 70.
    Rumie Vittar N, Lamberti M, Pansa M, Vera R, Rodriguez M, Cogno I, et al. Ecological photodynamic therapy: new trend to disrupt the intricate networks within tumor ecosystem. Biochim Biophys Acta. 1835;2013:86–9.Google Scholar
  71. 71.
    Haass N, Smalley K, Li L, Herlyn M. Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res. 2005;18:150–9.CrossRefPubMedGoogle Scholar
  72. 72.
    Kästle M, Grimm S, Nagel R, Breusing N, Grune T. Combination of PDT and inhibitor treatment affects melanoma cells and spares keratinocytes. Free Radic Biol Med. 2011;50:305–12.CrossRefPubMedGoogle Scholar
  73. 73.
    Berking C, Herlyn M. Human skin reconstruct models: a new application for studies of melanocyte and melanoma biology. Histol Histopathol. 2001;16:669–74.PubMedGoogle Scholar
  74. 74.
    Vörsmann H, Groeber F, Walles H, Busch S, Beissert S, Walczak H, et al. Development of a human three-dimensional organotypic skin-melanoma spheroid model for in vitro drug testing. Cell Death Dis. 2013;4, e719.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Renzo Emanuel Vera
    • 1
  • María Julia Lamberti
    • 1
  • Viviana Alicia Rivarola
    • 1
  • Natalia Belén Rumie Vittar
    • 1
  1. 1.Biología MolecularUniversidad Nacional de Río CuartoRío CuartoArgentina

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