Cancer and Metastasis Reviews

, Volume 12, Issue 3–4, pp 219–226 | Cite as

Growth factor independence and growth regulatory pathways in human melanoma development

  • Ulrich Rodeck


This review concentrates on growth autonomy of tumor cells in relation to tumor progression. Human malignant melanoma serves as an example for progressive growth factor independence at subsequent stages of tumor progression. Mechanisms by which malignant cells acquire growth factor independence are discussed. In melanoma, deregulation of growth regulatory pathways has been described on four levels: 1) aberrant production of autocrine growth factors that substitute for exogenous growth factors (basic fibroblast growth factor [bFGF]); 2) alterations in the response to negative autocrine growth factors (interleukin [IL]-6 and transforming growth factor [TGF]-β); 3) overexpression of epidermal growth factor receptors (EGF-R); and 4) alterations of cellular protooncogenes involved in signal transduction (RAS, MYB) and growth suppression (p53). In addition to bFGF and IL-6, multiple other growth factor genes are activated in malignant melanoma cells but not normal melanocytes. These include both chains of platelet-derived growth factor (PDGF), TGF-α, IL-1, IL-8, and tumor necrosis factor (TNF)-α. Of these, PDGF-B has been investigated in more detail. Melanoma-derived PDGF clearly does not act in a direct autocrine mode, but has important paracrine effects on normal tissue constituents, notably fibroblasts and endothelial cells, that are essential for tumor developmentin vivo. It is speculated that other melanoma-derived growth factors with as yet undefined functions similarly exert such paracrine or ‘indirect’ autocrine effects that cannot be sufficiently addressed in studies on cultured cells.

Key words

melanoma cell lines tumor progression growth factors autocrine paracrine 


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  1. 1.
    Nowell PC: The clonal evolution of tumor cell populations. Science 194: 23–28, 1976Google Scholar
  2. 2.
    Doolittle RF, Hunkapiller MW, Hood LE, Devare SG, Robbins KC, Aaronson SA, Antoniades HN: Simian sarcoma virus oncogene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221: 275–277, 1983Google Scholar
  3. 3.
    Waterfield MD, Scrace GT, Whittle N, Stroobant P, Johnsson A, Wasteson A, Westermark B, Heldin CH, Huang JS, Deuel TF: Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature 304: 35–39, 1983Google Scholar
  4. 4.
    Roussel MF, Rettenmier CW, Look AT, Sherr CJ: Cell surface expression of v-fms-coded glycoproteins is required for transformation. Mol Cell Biol 4: 1999–2009, 1984Google Scholar
  5. 5.
    Rettenmier CW, Chen JH, Roussel MF, Sherr CJ: The product of the c-fms protooncogene: a glycoprotein with associated tyrosine kinase activity. Science 228: 320–322, 1985Google Scholar
  6. 6.
    Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD: Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307: 521–527, 1984Google Scholar
  7. 7.
    Westermark B, Heldin CH: Platelet-derived growth factor in autocrine transformation. Cancer Res 51: 5087–5092, 1991Google Scholar
  8. 8.
    Clark WJ, Elder DE, Guerry D, Epstein MN, Greene MH, Van HM: A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 15: 1147–1165, 1984Google Scholar
  9. 9.
    Clark WJ, Elder DE, Van HM: The biologic forms of malignant melanoma. Hum Pathol 17: 443–450, 1986Google Scholar
  10. 10.
    Rodeck U, Herlyn M, Menssen HD, Furlanetto RW, Koprowski H: Metastatic but not primary melanoma cell lines growin vitro independently of exogenous growth factors. Int J Cancer 40: 687–690, 1987Google Scholar
  11. 11.
    Mancianti ML, Herlyn M, Weil D, Jambrosic J, Rodeck U, Becker D, Diamond L, Clark WH, Koprowski H: Growth and phenotypic characteristics of human nevus cells in culture. J Invest Dermatol 90: 134–141, 1988Google Scholar
  12. 12.
    Herlyn M, Rodeck U, Mancianti M, Cardillo FM, Lang A, Ross AH, Jambrosic J, Koprowski H: Expression of melanoma-associated antigens in rapidly dividing human melanocytes in culture. Cancer Res 47: 3057–3061, 1987Google Scholar
  13. 13.
    Westermark B, Johnsson A, Paulsson Y, Betsholtz C, Heldin C-H, Herlyn M, Rodeck U, Koprowski H: Human melanoma cells of primary and metastatic origin express the genes encoding the constituent chains of PDGF and produce a PDGF-like growth factor. Proc Natl Acad Sci USA 83: 7197–7200, 1986Google Scholar
  14. 14.
    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, 1985Google Scholar
  15. 15.
    Rodeck U, Bossler A, Graeven U, Fox F, Nowell P, Kari C: Transforming growth factor-β production and responsiveness in normal human melanocytes and melanoma cells. Submitted, 1993Google Scholar
  16. 16.
    Moscatelli D, Presta M, Joseph SJ, Rifkin DB: Both normal and tumor cells produce basic fibroblast growth factor. J Cell Physiol 129: 273–276, 1986Google Scholar
  17. 17.
    Bennicelli JL, Elias J, Kern J, Guerry D: Production of interleukin 1 activity by cultured human melanoma cells. Cancer Res 49: 930–935, 1989Google Scholar
  18. 18.
    Shabon U, Bennicelli JL, Guerry D, Koprowski H, Ricciardi RP: Human melanoma cells transcribe interleukin 1 genes identical to those of monocytes. Cancer Res 51: 3334–3335, 1991Google Scholar
  19. 19.
    Colombo P, Maccalli C, Mattei S, Melani C, Radrizzani M, Parmiani G: Expression of cytokine genes, including IL-6, in human malignant melanoma cell lines. Melanoma Res 2: 181–189, 1992Google Scholar
  20. 20.
    Rodeck U, Melber K, Kath R, Menssen HD, Varello M, Atkinson B, Herlyn M: Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. J Invest Dermatol 97: 20–26, 1991Google Scholar
  21. 21.
    Albino AP, Davis BM, Nanus DM: Induction of growth factor RNA expression in human malignant melanoma: markers of transformation. Cancer Res 51: 4815–4820, 1991Google Scholar
  22. 22.
    Linnenbach AJ, Huebner K, Reddy EP, Herlyn M, Parmiter AH, Nowell PC, Koprowski H: Structural alteration in the MYB protooncogene and deletion within the gene encoding the alpha-type protein kinase C in human melanoma cell lines. Proc Natl Acad Sci USA 85: 74–78, 1988Google Scholar
  23. 23.
    Lizonova A, Bizik J, Grofova M, Vaheri A: Coexpression of tumor-associated alpha 2-macroglobulin and growth factors in human melanoma cell lines. J Cell Biochem 43: 315–325, 1990Google Scholar
  24. 24.
    Halaban R, Kwon BS, Ghosh S, Delli BP, Baird A: bFGF as an autocrine growth factor for human melanomas. Oncogene Res 3: 177–186, 1988Google Scholar
  25. 25.
    Becker D, Meier CB, Herlyn M: Proliferation of human malignant melanomas is inhibited by antisense oligodeoxynucleotides targeted against basic fibroblast growth factor. EMBO J 8: 3685–3691, 1989Google Scholar
  26. 26.
    Becker D, Lee PL, Rodeck U, Herlyn M: Inhibition of the fibroblast growth factor receptor 1 (FGFR-1) gene in human melanocytes and malignant melanomas leads to inhibition of proliferation and signs indicative of differentiation. Oncogene 7: 2303–2313, 1992Google Scholar
  27. 27.
    Ramon Y, Cayal S, Suster S, Halaban R, Filvaroff E, Dotto GP: Induction of different morphologic features of malignant melanoma and pigmented lesions after transformation of murine melanocytes with bFGF-cDNA and H-ras, myc, neu, andEla oncogenes. Am J Pathol 138: 349–358, 1991Google Scholar
  28. 28.
    Scott G, Stoler M, Sarkar S, Halaban R: Localization of basic fibroblast growth factor mRNA in melanocytic lesions byin situ hybridization. J Invest Dermatol 96: 318–322, 1991Google Scholar
  29. 29.
    Schulze OK, Risau W, Vollmer E, Sorg C:In situ detection of basic fibroblast growth factor by highly specific antibodies. Am J Pathol 137: 85–92, 1990Google Scholar
  30. 30.
    Cornil I, Theodorescu D, Man S, Herlyn M, Jambrosic J, Kerbel RS: Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression. Proc Natl Acad Sci USA 88: 6028–6032, 1991Google Scholar
  31. 31.
    Lu C, Vickers MF, Kerbel RS: Interleukin 6: a fibroblastderived growth inhibitor of human melanoma cells from early but not advanced stages of tumor progression. Proc Natl Acad Sci USA 89: 9215–9219, 1992Google Scholar
  32. 32.
    Lu C, Kerbel RS: Interleukin 6: transition from paracrine growth inhibitor to intracellular autocrine stimulator during human melanoma progression. J Cell Biol 120: 1281–1288, 1992Google Scholar
  33. 33.
    Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF, Sporn MS: Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci USA 82: 119–123, 1985Google Scholar
  34. 34.
    MacDougall JR, Kobayashi H, Kerbel RS: Responsiveness of normal/dysplastic melanocytes and melanoma cells from different lesional stages of disease progression to the growth inhibitory effects of TGF-β. Mol Cell Dif. In press, 1993Google Scholar
  35. 35.
    Elder DE, Rodeck U, Thurin J, Cardillo F, Clark WH, Stewart R, Herlyn M: Antigenic profile of tumor progression stages in human melanocytic nevi and melanomas. Cancer Res 49: 5091–5096, 1989Google Scholar
  36. 36.
    De Witt PE, Moretti S, Koenders PG, Weterman MA, Van Muijen GN, Gianotti B, Ruiter DJ: Increasing epidermal growth factor receptor expression in human melanocytic tumor progression. J Invest Dermatol 99: 168–173, 1992Google Scholar
  37. 37.
    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, 1985Google Scholar
  38. 38.
    Husain Z, Fitz GG, Wick MM: Comparison of cellular protooncogene activation and transformation-related activity of human melanocytes and metastatic melanoma. J Invest Dermatol 95: 571–575, 1990Google Scholar
  39. 39.
    Albino AP, Nanus DM, Mentle IR, Cordon CC, McNutt NS, Bressler J, Andreff M: Analysis ofras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. Oncogene 4: 1363–1374, 1989Google Scholar
  40. 40.
    Albino AP, Nanus DM, Davis ML, McNutt NS: Lack of evidence of KI-ras codon 12 mutations in melanocytic lesions. J Cutan Pathol 18: 273–278, 1991Google Scholar
  41. 41.
    Dasgupta P, Linnenbach AJ, Giaccia AJ, Stamato TD, Reddy EP: Molecular cloning of the breakpoint region on chromosome 6 in cutaneous malignant melanoma: evidence for deletion in the c-myb locus and translocation of a segment of chromosome 12. Oncogene 4: 1201–1205, 1989Google Scholar
  42. 42.
    Meese E, Meltzer PS, Witkowski CM, Trent JM: Molecular mapping of the oncogene MYB and rearrangements in malignant melanoma. Genes Chromosom Cancer 1: 88–94, 1989Google Scholar
  43. 43.
    Albino AP: Transformingras genes from human melanoma: a manifestation of tumor heterogeneity? Nature 302: 69–72, 1984Google Scholar
  44. 44.
    Shenkla VK, Hughes DC, Hughes LE, McCormick F, Padu RA:ras mutations in human melanocytic lesions: K-ras activation is a frequent and early event in melanoma development. Oncogene Res 5: 121–127, 1989Google Scholar
  45. 45.
    Chenevix TG, Martin NG, Ellem KA: Gene expression in melanoma cell lines and cultured melanocytes: correlation between levels of c-src-1, c-myc and p53. Oncogene 5: 1187–1193, 1990Google Scholar
  46. 46.
    Stretch JR, Gatter KC, Ralfkiaer E, Lane DP, Harris AL: Expression of mutant p53 in melanoma. Cancer Res 51: 5976–5979, 1991Google Scholar
  47. 47.
    Volkenandt M, Schlegel U, Nanus DM, Albino AP: Mutational analysis of the human p53 gene in malignant melanoma. Pigment Cell Res 4: 35–40, 1991Google Scholar
  48. 48.
    Weiss J, Schwechheimer K, Cavenee W, Herlyn M, Arden KC: Mutation and expression of the p53 gene in malignant melanoma cell line. Submitted, 1993Google Scholar
  49. 49.
    Forsberg K, Valyi-Nagy I, Heldin C-H, Herlyn M, Westermark B: Novel role for platelet-derived growth factor in oncogenesis is suggested by the development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-B. Proc Natl Acad Sci USA 90: 393–397, 1993Google Scholar

Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • Ulrich Rodeck
    • 1
  1. 1.The Wistar Institute of Anatomy and BiologyPhiladelphiaUSA

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