Skip to main content
Log in

Growth factors in melanoma

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Human melanoma cells in culture are the source of a wide variety of polypeptide growth factors. Melanoma-derived basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF)-A and PDGF-B chains, transforming growth factor (TGF)-α and TGF-β, interleukin (IL)-1α and IL-1β, and melanoma growth stimulatory activity (MGSA) have similar biochemical and functional properties when compared to their counterparts produced by untransformed cells. In contrast to melanoma cells, normal melanocytes, even under optimal growth conditions, express only TGF-β1 and MGSA at detectable levels suggesting that production of the other growth factors is a tumor-associated phenomenon. Recent evidence suggests that at least two of the growth factors, bFGF and MGSA, contribute to autocrine growth stimulation of melanoma cells. Whether PDGF, TGF-α, IL-1, and TGF-β act in an autocrine mode is unclear at present. However, these four growth factors are among those secreted by melanoma cells and, therefore, can be expected to interact with normal cells of the tumor stroma in vivo. Such paracrine effects include not only growth modulation in the context of angiogenesis and stroma formation, but also tissue degradation by proteolytic enzymes, the modification of extracellular matrix composition, and expression of adhesion receptors.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Todaro GJ, DeLarco JE: Growth factors produced by sarcoma virus-transformed cells. Cancer Res 38: 4147–4154, 1978

    Google Scholar 

  2. Clark WH, Elder DE, Guerry D, Epstein ME, Greene MH, VanHorn M: A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 15: 1147–1165, 1984

    Google Scholar 

  3. Clark WH, Elder DE, VanHorn M: The biologic forms of malignant melanoma. Hum Pathol 17: 443–450, 1986

    Google Scholar 

  4. Eisinger M, Marko O: Selective proliferation of normal human melanocytes in vitro in the presence of phorbol ester and cholera toxin. Proc Natl Acad Sci USA 79: 2018–2022, 1982

    Google Scholar 

  5. Herlyn M, Rodeck U, Mancianti ML, Cardillo FM, Lang A, Ross AH, Jambrosic J, Koprowski H: Experssion of melanoma-associated antigens in rapidly dividing human melanocytes in culture. Cancer Res 47: 3057–3061, 1987

    Google Scholar 

  6. Halaban R, Ghosh S, Baird A: bFGF is the putative natural growth factor for human melanocytes. In Vitro Cell Dev Biol 23: 47–52, 1987

    Google Scholar 

  7. Herlyn M, Clark WH, Rodeck U, Mancianti ML, Jambrosic J, Koprowski H: Biology of disease: Biology of tumor progression in human melanocytes. Lab Invest 56: 461–474, 1987

    Google Scholar 

  8. Herlyn M: Human melanoma: Development and progression. Cancer Mets Rev 9: 101–112, 1990

    Google Scholar 

  9. Rodeck U, Herlyn M: Growth regulation in normal and malignant melanocytes. In: Paukovits W, (ed) Growth Regulation and Carcinogenesis Vol. I. CRC Press, 1991, pp 243–250

  10. Herlyn M, Kath R, Williams N, Valyi-Nagy I, Rodeck U: Growth regulatory factors for normal, premalignant, and malignant human cells. Adv Cancer Res 54: 213–234, 1990

    Google Scholar 

  11. DeLarco JE, Todaro GJ: Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci USA 75: 4001–4005, 1978

    Google Scholar 

  12. Derynck R: Transforming growth factor alpha. Cell 54: 593–595, 1988

    Google Scholar 

  13. Derynck R, Roberts AB, Winkler ME, Chen EY, Goeddel DV: Human transforming growth factor-alpha: Precursor structure and expression in E. coli. Cell 38: 287–297, 1984

    Google Scholar 

  14. Todaro GJ, Fryling C, DeLarco JE: Transforming growth factors produced by certain human tumor cells: Polypeptides that interact with epidermal growth factor receptors. Proc Natl Acad Sci USA 77: 5258–5262, 1980

    Google Scholar 

  15. Marquardt H, Todaro G: Human transforming growth factor production by a melanoma cell line, purification, and initial characterization. J Biol Chem 257: 5220–5225, 1982

    Google Scholar 

  16. DeLarco JE, Pigott DA, Lazarus JA: Ectopic peptides released by a human melanoma cell line that modulate the transformed phenotype. Proc Natl Acad Sci USA 82: 5015–5019, 1985

    Google Scholar 

  17. Imanishi K, Yamaguchi K, Suzuki M, Honda S, Yanaihara N, Abe K: Production of transforming growth factor-alpha in human tumor cell lines. Br J Cancer 59: 761–765, 1989

    Google Scholar 

  18. Inagaki H, Katoh M, Kurosawa-Ohsawa K, Tanaka S: A new sandwich enzyme-linked immunosorbent assay (ELISA) for transforming growth factor alpha (TGF-alpha) based upon conformational modification by antibody binding. J Immunol Meth 128: 27–37, 1990

    Google Scholar 

  19. Kim MK, Warren TC, Kimball ES: Purification and characterization of a low molecular weight transforming growth factor from the urine of melanoma patients. J Biol Chem 260: 9237–9243, 1985

    Google Scholar 

  20. Ellis DL, Chow JC, King LE: Detection of urinary TGF-alpha by HFLC and Western blot in patients with melanoma. J Invest Dermatol 95: 27–30, 1990

    Google Scholar 

  21. Hudgins WR, Orth DN, Stromberg K: Variant forms of rat epidermal growth factor present in the urine of nude rats bearing human tumors. Cancer Res 48: 1428–1434, 1988

    Google Scholar 

  22. Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringman TS, Berger WH: Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res 47: 707–712, 1987

    Google Scholar 

  23. Lizonova A, Bizik J, Grofova M, Vaheri A: Coexpression of tumor-associated alpha2-macroglobulin and growth factors in human melanoma cell lines. J Cell Biochem 43: 315–323, 1990

    Google Scholar 

  24. Ellem KA, Cullinan M, Baumann KC, Dunstan A: UVR induction of TGF-alpha: A possible autocrine mechanism for the melanocytic response and for promotion of epidermal carcinogenesis. Carcinogenesis 9: 797–801, 1988

    Google Scholar 

  25. Koprowski H, Herlyn M, Balaban G, Parmiter A, Ross A, Nowell P: Expression of the receptor for epidermal growth factor correlates with increased dosage of chromosome 7 in malignant melanoma. Somat Cell Mol Genet 11: 297–302, 1985

    Google Scholar 

  26. Real FX, Rettig WJ, Chesa PG, Melamed MR, Old LJ, Mendelsohn J: Expression of epidermal growth factor receptor in human cultured cells and tissues: Relationship to cell lineage and stage of differentiation. Cancer Res 46: 4726–4731, 1986

    Google Scholar 

  27. Elder DE, Rodeck U, Thurin J, Cardillo F, Clark WH, Stewart R, Herlyn M: Antigenic profile of tumor progression in human melanocytic nevi and melanomas. Cancer Res 49: 5091–5096, 1989

    Google Scholar 

  28. Rodeck U, Herlyn M, Menssen HD, Furlanetto RW, Koprowski H: Metastatic but not primary melanoma cells grow in vitro independently of exogenous growth factors. Int J Cancer 40: 687–690, 1987

    Google Scholar 

  29. Sauvagio S, Fretts RE, Riopelle RJ, Lagarde AE: Autonomous proliferation of MeWo human melanoma cell lines in serum-free medium: Secretion of growth-stimulating activities. Int J Cancer 37: 123–132, 1986

    Google Scholar 

  30. Singletary SE, Baker FL, Spitzer G, Tucker SL, Tomasovic B, Brock WA, Ajani JA, Kelly AM: Biologic effect of epidermal growth factor on the in vitro growth of human tumors. Cancer Res 47: 403–406, 1987

    Google Scholar 

  31. Herlyn M, Mancianti ML, Jambrosic J, Bolen JB, Koprowski H: Regulatory factors that determine growth and phenotype of normal human melanocytes. Exp Cell Res 179: 322–331, 1988

    Google Scholar 

  32. Rodeck U, Williams N, Murthy U, Herlyn M: Monoclonal antibody 425 inhibits growth stimulation of carcinoma cells by exogenous EGF and tumor-derived TGF-α. J Cell Biochem 10: 69–80, 1990

    Google Scholar 

  33. Kudlow JE, Khosravi MJ, Kobrin MS, Mak WW: Inability of an anti-epidermal growth factor receptor monoclonal antibody to block ‘autocrine’ growth stimulation in transforming growth factor-secreting melanoma cells. J Biol Chem 259: 11895–11900, 1984

    Google Scholar 

  34. Massague J: The transforming growth factor-beta family. Ann Rev Cell Biol 6: 597–641, 1990

    Google Scholar 

  35. Valverius EM, Walker-Jones D, Bates SE, Stampfer MR, Clark R, McCormick F, Dickson RB, Lippman ME: Production of and responsiveness to transforming growth factor-beta in normal and oncogene-transformed human mammary epithelial cells. Cancer Res 49: 6269–6274, 1989

    Google Scholar 

  36. Arteaga CL, Coffey RJ, Dugger TC, McCutchen CM, Moses HL, Lyons RM: Growth stimulation of human breast cancer cells with anti-transforming growth factor beta antibodies: Evidence for negative autocrine regulation by transforming growth factor beta. Cell Growth Diff 1: 367–374, 1990

    Google Scholar 

  37. Pittelkow MR, Shipley GD: Serum-free culture of normal human melanocytes: growth kinetics and growth factor requirements. J Cell Physiol 140: 565–576, 1989

    Google Scholar 

  38. Newman M: Inhibition of carcinoma and melanoma cell growth by type 1 transforming growth factor beta is dependent on the presence of polyunsaturated fatty acids. Proc Natl Acad Sci USA 87: 5543–5547, 1990

    Google Scholar 

  39. Bodmer S, Strommer K, Frei K, Siepl C, deTribolet N, Heid I, Fontana A: Immunosuppression and transforming growth factor-beta in glioblastoma: Preferential production of transforming growth factor-beta 2. J Immunol 143: 3222–3229, 1989

    Google Scholar 

  40. Heldin C-H, Westermark B: Platelet-derived growth factor: Mechanism of action and possible in vivo function. Cell Regulation 1: 555–566, 1990

    Google Scholar 

  41. Johnsson A, Heldin C-H, Wasteson A, Westermark B, Deuel TF, Huang JS, Seeburg PH, Gray A, Ullrich A, Scrace G, Strrobant P, Waterfield MD: The c-sis gene encodes a precursor of the B chain of platelet-derived growth factor. EMBO J 3: 921–928, 1984

    Google Scholar 

  42. Waterfield MD, Scarce GT, Whittle N, Stroobant P, Johnsson A, Wasteson A, Westermark B, Heldin C-H, Huang JS, Deuel TF: Platelet-derived growth factor is structurally related to the putative transforming protein p28 sis of simian sarcoma virus. Nature 304: 35–39, 1983

    Google Scholar 

  43. Leal F, Williams LT, Robbins KC, Aaronson SA: Evidence that the v-sis gene product transforms by interaction with the receptor for platelet-derived growth factor. Science 230: 327–330, 1985

    Google Scholar 

  44. Johnsson A, Betsholtz C, Heldin C-H, Westermark B: Antibodies against platelet-derived growth factor inhibit acute transformation by simian sarcoma virus. Nature 317: 438–440, 1985

    Google Scholar 

  45. Westermark B, Johnsson A, Paulsson Y, Betsholtz C, Heldin C-H, Herlyn M, Rodeck U, Koprowski H: Human melanoma cell lines of primary and metastatic origin express the genes encoding the chains of platelet-derived growth factor and produce a PDGF-like growth factor. Proc Natl Acad Sci USA 83: 7197–7200, 1987

    Google Scholar 

  46. Chenevix-Trent G, Martin NG, Ellem KA: Gene expression in melanoma cell lines and cultured melanocytes: correlation between levels of c-src-1, c-myc and p53. Cancer Res 50: 1190–1193, 1990

    Google Scholar 

  47. Rakowicz-Szulczynska EM, Rodeck U, Herlyn M, Koprowski H: Chromatin binding of EGF, NGF, and PDGF in cells bearing the appropriate surface receptors. Proc Natl Acad Sci USA 83: 3728–3732, 1987

    Google Scholar 

  48. Rakowicz-Szulczynska EM, Koprowski H: Antagonistic effect of PDGF and NGF on transcription of ribosomal DNA and tumor cell proliferation. Biochem Biophys Res Commun 163: 649–656, 1989

    Google Scholar 

  49. Harsh GR, Keating MT, Escobedo JA, Williams LT: Platelet derived growth factor (PDGF) autocrine components in human tumor cell lines. J Neurooncol 8: 1–12, 1990

    Google Scholar 

  50. Keating MT, Williams LT: Autocrine stimulation of intracellular PDGF receptors in v-sis-transformed cells. Science 239: 914–916, 1988

    Google Scholar 

  51. Goldfarb M: The fibroblast growth factor family. Cell Growth Diff 1: 439–445, 1990

    Google Scholar 

  52. Halaban R, Kwon BS, Ghosh S, Delli-Bovi P, Baird A: bFGF as an autocrine growth factor for human melanomas. Oncogene Res 3: 177–186, 1988

    Google Scholar 

  53. Moscatelli D, Presta M, Joseph-Silverstein J, Rifkin DB: Both normal and tumor cells produce basic fibroblast growth factor. J Cell Physiol 129: 273–276, 1986

    Google Scholar 

  54. Becker D, Meier CB, Herlyn M: Proliferation of human malignant melanomas is inhibited by antisense oligodeoxy-nucleotides targeted against basic fibroblast growth factor. EMBO J 8: 3685–3691, 1989

    Google Scholar 

  55. Dotto GP, Moellmann G, Ghosh S, Edwards M, and Halaban R: Transformation of murine melanocytes by basic fibroblast growth factor cDNA and oncogenes and selective suppression of the transformed phenotype in a reconstituted cutaneous environment. J Cell Biol 109: 3115–3128, 1989

    Google Scholar 

  56. Richmond A, Balentien E, Thomas HG, Flaggs G, Barton DE, Spiess J, Bordoni R, Franke U, Derynck R: Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin. EMBO J 7: 2025–2033, 1988

    Google Scholar 

  57. Richmond A, Thomas HG: Purification of melanoma growth stimulatory activity. J Cell Physiol 129: 375–384, 1986

    Google Scholar 

  58. Schröder JM, Persoon NL, Christophers E: Lipopolysaccharide-stimulated monocytes secrete, apart from neutrophil-activating peptide 1/interleukin 8, a second neutrophil activating protein. NH2-terminal amino acid sequence identity with melanoma growth stimulatory activity. J Exp Med 171: 1091–1100, 1990

    Google Scholar 

  59. Moser B, Clark-Lewis I, Zwahlen R, Baggilioni M: Neutrophil-activating properties of the melanoma growth-stimulatory activity. J Exp Med 171: 1797–1802, 1990

    Google Scholar 

  60. Richmond A, Lawson DH, Nixon DW, Stedman NJ, Stevens S, Chawla RK: Extraction of a melanoma-growth stimulatory activity from culture medium conditioned by the Hs0294 human melanoma cell line. Cancer Res 43: 2106–2112, 1983

    Google Scholar 

  61. Richmond A, Lawson DH, Nixon DW, Chawla RK: Characterization of autostimulatory and transforming growth factors from human melanoma cells. Cancer Res 45: 6390–6394, 1985

    Google Scholar 

  62. Lawson DH, Thomas HG, Roy RGB, Gordon DS, Chawla RK, Nixon DW, Richmond A: Preperation of a monoclonal antibody to melanoma growth-stimulatory activity released into serum-free culture medium by Hs0294 malignant melanoma cells. J Cell Biochem 34: 169–185, 1987

    Google Scholar 

  63. Bordoni R, Thomas G, Richmond A: Growth factor modulation of melanoma-growth stimulatory activity mRNA expression in human malignant melanoma cells correlates well with cell growth. J Cell Biochem 39: 421–428, 1989

    Google Scholar 

  64. Grob PM, David E, Warren TC, DeLeon RP, Farina PR, Homon CA: Characterization of a receptor for human monocyte-derived neutrophil chemotactic factor/interleukin 8. J Biol Chem 265: 8311–8316, 1990

    Google Scholar 

  65. Gery I, Waksman BH: Potentiation of the T-lymphocytic response to mitogens II. The cellular source of potentiating mediator(s). J Exp Med 136: 143–155, 1972

    Google Scholar 

  66. diGiovine FS, Duff GW: Interleukin 1: the first interleukin. Immunol Today 11: 13–20, 1990

    Google Scholar 

  67. Onozaki K, Matsushima K, Aggarwal BB, Oppenheim JJ: Human interleukin 1 is a cytocidal factor for several tumor cell lines. J Immunol 135: 3962–3968, 1985

    Google Scholar 

  68. Nakai S, Mizuno K, Kaneta M, HGirai Y: A simple, sensitive bioassay for the detection of interleukin-1 using the human melanoma A375 cell line. Biochem Biophys Res Commun 154: 1189–1196, 1988

    Google Scholar 

  69. Mortarini R, Belli F, Parmiani G, Anichini A: Cytokine-mediated modulation of HLA-class II, INCAM-1, LFA-3 and tumor-associated antigen profile of melanoma cells. Int J Cancer 45: 334–341, 1990

    Google Scholar 

  70. Giavazzi R, Garofalo A, Bani MR, Abbate M, Ghezzi P, Boraschi D, Mantovani A, Dejana E: Interleukin 1 induced augmentation of experimental metastases from a human melanoma in nude mice. Cancer Res 50: 44771–44775, 1990

    Google Scholar 

  71. Köck A, Schwarz T, Urbanski A, Peng Z, Vetterlein M, Miksche M, Ansel JC, Kung HF, Luger TA: Expression and release of interleukin-1 by different human melanoma cell lines. J Natl Cancer Inst 81: 36–42, 1988

    Google Scholar 

  72. Bennicelli JL, Elias J, Kern J, Guerry DIV: Production of interleukin 1 activity by cultured human melanoma cells. Cancer Res 49: 930–935, 1989

    Google Scholar 

  73. Rice EG, Bevilacque M: An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science 246: 1303–1306, 1989

    Google Scholar 

  74. Puma P, Buxsen SE, Watson DJ, Kelleher DJ, Johnson GL: Purification of the receptor for nerve growth factor from A875 melanoma cells by affinity chromatography. J Biol Chem 258: 3370–3375, 1983

    Google Scholar 

  75. Ross AH, Herlyn M, Maul GG, Koprowski H, Bothwell M, Chao M, Pleasure D, Sonnenfeld KH: The nerve growth factor receptor in normal and transformed neural crest cells. Ann New York Acad Sci 486: 115–123, 1985

    Google Scholar 

  76. Walker MJ: Role of hormones and growth factors in melanomas. Sem Oncol 15: 512–523, 1988

    Google Scholar 

  77. Ghanem GE, Comunale G, Libert A, Vercammen-Grandjean A, Lejeune FJ: Evidence for alpha-melanocyte-stimulating hormone (alpha-MSH) receptors on human melanoma cells. Int J Cancer 41: 248–255, 1988

    Google Scholar 

  78. Siegrist W, Solca F, Stutz S, Giuffre S, Carrel J, Girard J, Eberle AN: Characterization of receptors for alpha-melanocyte-stimulating hormone on human melanoma cells. Cancer Res 49: 6352–6358, 1989

    Google Scholar 

  79. Tatro JB, Atkins M, Mier JW, Hardarson S, Wolfe H, Smith T, Entwistle ML, Reichlin S: Melanotropin receptors demonstrated in situ in human melanoma. J Clin Invest 85: 1825–1832, 1990

    Google Scholar 

  80. Ghanem G, Verstegen J, Libert A, Arnould R, Lejeune F: Alpha-melanocyte-stimulating hormone immunoreactivity in human melanoma metastases extracts. Pigment Cell Res 2: 519–523, 1989

    Google Scholar 

  81. Ellem KA, Kay GF: The nature of conditioning nutrients for malignant melanoma cultures. J Cell Sci 62: 249–266, 1983

    Google Scholar 

  82. Lerner AB, McGuire JS: Melanocyte stimulating hormone and adrenocorticotropic hormone: their relationship to pigmentation. N Engl J Med 270: 539–546, 1964

    Google Scholar 

  83. Fuller BB, Meyskens FL: Endocrine responsiveness in human melanocytes and melanoma cells in culture. J Natl Cancer Inst 66: 799–802, 1981

    Google Scholar 

  84. Bogdahn U, Apfel R, Hahn M, Gerlach M, Behl C, Hoppe J, Martin R: Autocrine tumor cell growth-inhibiting activities from human malignant melanoma. Cancer Res 49: 5358–5363, 1989

    Google Scholar 

  85. Weilbach FX, Bogdahn U, Poot M, Apfel R, Behl C, Drenkard D, Martin R, Hoehn H: Melanoma-inhibiting activity inhibits cell proliferation by prolongation of the S-phase and arrest of cells in the G2 compartment. Cancer Res 50: 6981–6986, 1990

    Google Scholar 

  86. Pichon F, Lagarde AE: Autoregulation of MeWo metastatic melanoma growth: characterization of intracellular (FGF, MGSA) and secreted (PDGF) growth factors. J Cell Physiol 140: 344–358, 1989

    Google Scholar 

  87. Herlyn M, Malkowicz SB: Regulatory pathways in tumor progression. Lab Invest, in press, 1991

  88. Ignotz RA, Endo R, Massague J: Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-β. J Biol Chem 262: 6443–6446, 1987

    Google Scholar 

  89. Ignotz RA, Heino J, Massague J: Regulation of cell adhesion receptors by TGF-β. Regulation of vitronectin receptor and LFA-1. J Biol Chem 264: 389–392, 1989

    Google Scholar 

  90. Ignotz RA, Massague J: TGF-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261: 4337–4345, 1986

    Google Scholar 

  91. Keski-Oja J, Blasi F, Leof EB, Moses HL: Regulation of the synthesis and activity of urokinase plasminogen activator in A549 human lung carcinoma cells by transforming growth factor-β. J Cell Biol 106: 451–459, 1988

    Google Scholar 

  92. Keski-Oja J, Raghow R, Sawdey M, Loskutoff DJ, Postlethwaite AE, Kang AH, Moses HL: Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-β. J Biol Chem 263: 3111–3115, 1986

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodeck, U., Herlyn, M. Growth factors in melanoma. Cancer Metast Rev 10, 89–101 (1991). https://doi.org/10.1007/BF00049407

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00049407

Key words

Navigation