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British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Mar 21;82(8):1453–1458. doi: 10.1054/bjoc.1999.1076

Expression of SCF splice variants in human melanocytes and melanoma cell lines: potential prognostic implications

P Welker 1, D Schadendorf 3, M Artuc 1, J Grabbe 2, B M Henz 1
PMCID: PMC2363371  PMID: 10780526

Abstract

Stem cell factor (SCF), the ligand for c-Kit, is known to regulate developmental and functional processes of haematopoietic stem cells, mast cells and melanocytes. Two different splice variants form predominantly soluble (sSCF or SCF-1) and in addition some membrane-bound SCF (mSCF or SCF-2). In order to explore the prognostic significance of these molecules in melanoma, total SCF, SCF splice variants and c-Kit expression were studied in normal skin melanocytes and in 11 different melanoma cell lines, using reverse transcription polymerase chain reaction, immunocytochemistry and enzyme-linked immunosorbent assay. Nine of the 11 melanoma cell lines expressed SCF-1 mRNA, only two of them SCF-2, and these two also SCF-1. Coexpression of both SCF-1 and c-Kit was noted in five cell lines, and only one cell line as well as normal melanocytes expressed both SCF-1 and SCF-2 as well as c-Kit. Corresponding results were obtained on immunocytochemical staining. Of three exemplary melanoma cell lines studied, two expressing SCF mRNA also released SCF spontaneously and on stimulation, whereas the line lacking SCF and c-kit mRNA (SK-Mel-23) failed to do so. These data demonstrate thus that melanoma cell lines, particularly those known to metastasize in vivo, lose the ability to express SCF-2 mRNA, suggesting that this molecule may serve, next to c-Kit, as a prognostic marker for malignant melanoma. © 2000 Cancer Research Campaign

Keywords: SCF splice variants, c-Kit, melanocytes, melanoma

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Selected References

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  1. Artuc M., Nürnberg W., Czarnetzki B. M., Schadendorf D. Characterization of gene regulatory elements for selective gene expression in human melanoma cells. Biochem Biophys Res Commun. 1995 Aug 15;213(2):699–705. doi: 10.1006/bbrc.1995.2187. [DOI] [PubMed] [Google Scholar]
  2. Bosenberg M. W., Massagué J. Juxtacrine cell signaling molecules. Curr Opin Cell Biol. 1993 Oct;5(5):832–838. doi: 10.1016/0955-0674(93)90032-l. [DOI] [PubMed] [Google Scholar]
  3. Cohen P. S., Chan J. P., Lipkunskaya M., Biedler J. L., Seeger R. C. Expression of stem cell factor and c-kit in human neuroblastoma. The Children's Cancer Group. Blood. 1994 Nov 15;84(10):3465–3472. [PubMed] [Google Scholar]
  4. Costa J. J., Demetri G. D., Harrist T. J., Dvorak A. M., Hayes D. F., Merica E. A., Menchaca D. M., Gringeri A. J., Schwartz L. B., Galli S. J. Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med. 1996 Jun 1;183(6):2681–2686. doi: 10.1084/jem.183.6.2681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dippel E., Haas N., Grabbe J., Schadendorf D., Hamann K., Czarnetzki B. M. Expression of the c-kit receptor in hypomelanosis: a comparative study between piebaldism, naevus depigmentosus and vitiligo. Br J Dermatol. 1995 Feb;132(2):182–189. doi: 10.1111/j.1365-2133.1995.tb05011.x. [DOI] [PubMed] [Google Scholar]
  6. Flanagan J. G., Chan D. C., Leder P. Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell. 1991 Mar 8;64(5):1025–1035. doi: 10.1016/0092-8674(91)90326-t. [DOI] [PubMed] [Google Scholar]
  7. Grabbe J., Welker P., Dippel E., Czarnetzki B. M. Stem cell factor, a novel cutaneous growth factor for mast cells and melanocytes. Arch Dermatol Res. 1994;287(1):78–84. doi: 10.1007/BF00370723. [DOI] [PubMed] [Google Scholar]
  8. Grabbe J., Welker P., Rosenbach T., Nürnberg W., Krüger-Krasagakes S., Artuc M., Fiebiger E., Henz B. M. Release of stem cell factor from a human keratinocyte line, HaCaT, is increased in differentiating versus proliferating cells. J Invest Dermatol. 1996 Aug;107(2):219–224. doi: 10.1111/1523-1747.ep12329664. [DOI] [PubMed] [Google Scholar]
  9. Grichnik J. M., Crawford J., Jimenez F., Kurtzberg J., Buchanan M., Blackwell S., Clark R. E., Hitchcock M. G. Human recombinant stem-cell factor induces melanocytic hyperplasia in susceptible patients. J Am Acad Dermatol. 1995 Oct;33(4):577–583. doi: 10.1016/0190-9622(95)91274-6. [DOI] [PubMed] [Google Scholar]
  10. Guo C. S., Wehrle-Haller B., Rossi J., Ciment G. Autocrine regulation of neural crest cell development by steel factor. Dev Biol. 1997 Apr 1;184(1):61–69. doi: 10.1006/dbio.1997.8520. [DOI] [PubMed] [Google Scholar]
  11. Hamann K., Grabbe J., Welker P., Haas N., Algermissen B., Czarnetzki B. M. Phenotypic evaluation of cultured human mast and basophilic cells and of normal human skin mast cells. Arch Dermatol Res. 1994;286(7):380–385. doi: 10.1007/BF00371797. [DOI] [PubMed] [Google Scholar]
  12. Hamann K., Haas N., Grabbe J., Czarnetzki B. M. Expression of stem cell factor in cutaneous mastocytosis. Br J Dermatol. 1995 Aug;133(2):203–208. doi: 10.1111/j.1365-2133.1995.tb02616.x. [DOI] [PubMed] [Google Scholar]
  13. Hartmann K., Henz B. M., Krüger-Krasagakes S., Köhl J., Burger R., Guhl S., Haase I., Lippert U., Zuberbier T. C3a and C5a stimulate chemotaxis of human mast cells. Blood. 1997 Apr 15;89(8):2863–2870. [PubMed] [Google Scholar]
  14. Herlyn M. Human melanoma: development and progression. Cancer Metastasis Rev. 1990 Sep;9(2):101–112. doi: 10.1007/BF00046337. [DOI] [PubMed] [Google Scholar]
  15. Herlyn M., Thurin J., Balaban G., Bennicelli J. L., Herlyn D., Elder D. E., Bondi E., Guerry D., Nowell P., Clark W. H. Characteristics of cultured human melanocytes isolated from different stages of tumor progression. Cancer Res. 1985 Nov;45(11 Pt 2):5670–5676. [PubMed] [Google Scholar]
  16. Huang E. J., Nocka K. H., Buck J., Besmer P. Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Mol Biol Cell. 1992 Mar;3(3):349–362. doi: 10.1091/mbc.3.3.349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Huang S., Luca M., Gutman M., McConkey D. J., Langley K. E., Lyman S. D., Bar-Eli M. Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene. 1996 Dec 5;13(11):2339–2347. [PubMed] [Google Scholar]
  18. Inoue M., Kyo S., Fujita M., Enomoto T., Kondoh G. Coexpression of the c-kit receptor and the stem cell factor in gynecological tumors. Cancer Res. 1994 Jun 1;54(11):3049–3053. [PubMed] [Google Scholar]
  19. Lahav R., Lecoin L., Ziller C., Nataf V., Carnahan J. F., Martin F. H., Le Douarin N. M. Effect of the Steel gene product on melanogenesis in avian neural crest cell cultures. Differentiation. 1994 Dec;58(2):133–139. doi: 10.1046/j.1432-0436.1995.5820133.x. [DOI] [PubMed] [Google Scholar]
  20. Longley B. J., Jr, Morganroth G. S., Tyrrell L., Ding T. G., Anderson D. M., Williams D. E., Halaban R. Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med. 1993 May 6;328(18):1302–1307. doi: 10.1056/NEJM199305063281803. [DOI] [PubMed] [Google Scholar]
  21. Longley B. J., Tyrrell L., Ma Y., Williams D. A., Halaban R., Langley K., Lu H. S., Schechter N. M. Chymase cleavage of stem cell factor yields a bioactive, soluble product. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9017–9021. doi: 10.1073/pnas.94.17.9017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lu C., Kerbel R. S. Interleukin-6 undergoes transition from paracrine growth inhibitor to autocrine stimulator during human melanoma progression. J Cell Biol. 1993 Mar;120(5):1281–1288. doi: 10.1083/jcb.120.5.1281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Luo D., Chen H., Searles G., Jimbow K. Coordinated mRNA expression of c-Kit with tyrosinase and TRP-1 in melanin pigmentation of normal and malignant human melanocytes and transient activation of tyrosinase by Kit/SCF-R. Melanoma Res. 1995 Oct;5(5):303–309. doi: 10.1097/00008390-199510000-00002. [DOI] [PubMed] [Google Scholar]
  24. Majumdar M. K., Feng L., Medlock E., Toksoz D., Williams D. A. Identification and mutation of primary and secondary proteolytic cleavage sites in murine stem cell factor cDNA yields biologically active, cell-associated protein. J Biol Chem. 1994 Jan 14;269(2):1237–1242. [PubMed] [Google Scholar]
  25. Miura N., Suda T. [Stem cell factor/c-kit interaction in primordial germ cell, melanoblast and hematopoietic progenitors]. Gan To Kagaku Ryoho. 1992 Sep;19(11):1777–1785. [PubMed] [Google Scholar]
  26. Natali P. G., Nicotra M. R., Winkler A. B., Cavaliere R., Bigotti A., Ullrich A. Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer. 1992 Sep 9;52(2):197–201. doi: 10.1002/ijc.2910520207. [DOI] [PubMed] [Google Scholar]
  27. Papadimitriou C. A., Topp M. S., Serve H., Oelmann E., Koenigsmann M., Maurer J., Oberberg D., Reufi B., Thiel E., Berdel W. E. Recombinant human stem cell factor does exert minor stimulation of growth in small cell lung cancer and melanoma cell lines. Eur J Cancer. 1995 Dec;31A(13-14):2371–2378. doi: 10.1016/0959-8049(95)00438-6. [DOI] [PubMed] [Google Scholar]
  28. Ramenghi U., Ruggieri L., Dianzani I., Rosso C., Brizzi M. F., Camaschella C., Pietsch T., Saglio G. Human peripheral blood granulocytes and myeloid leukemic cell lines express both transcripts encoding for stem cell factor. Stem Cells. 1994 Sep;12(5):521–526. doi: 10.1002/stem.5530120508. [DOI] [PubMed] [Google Scholar]
  29. Ratajczak M. Z., Luger S. M., DeRiel K., Abrahm J., Calabretta B., Gewirtz A. M. Role of the KIT protooncogene in normal and malignant human hematopoiesis. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1710–1714. doi: 10.1073/pnas.89.5.1710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schadendorf D., Fichtner I., Makki A., Alijagic S., Küpper M., Mrowietz U., Henz B. M. Metastatic potential of human melanoma cells in nude mice--characterisation of phenotype, cytokine secretion and tumour-associated antigens. Br J Cancer. 1996 Jul;74(2):194–199. doi: 10.1038/bjc.1996.337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schadendorf D., Gawlik C., Haney U., Ostmeier H., Suter L., Czarnetzki B. M. Tumour progression and metastatic behaviour in vivo correlates with integrin expression on melanocytic tumours. J Pathol. 1993 Aug;170(4):429–434. doi: 10.1002/path.1711700405. [DOI] [PubMed] [Google Scholar]
  32. Schadendorf D., Kohlmus C., Gawlik C., Suter L., Czarnetzki B. M. Mast cells in melanocytic tumours. Arch Dermatol Res. 1995;287(5):452–456. doi: 10.1007/BF00373428. [DOI] [PubMed] [Google Scholar]
  33. Schadendorf D., Möller A., Algermissen B., Worm M., Sticherling M., Czarnetzki B. M. IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol. 1993 Sep 1;151(5):2667–2675. [PubMed] [Google Scholar]
  34. Scott G., Ewing J., Ryan D., Abboud C. Stem cell factor regulates human melanocyte-matrix interactions. Pigment Cell Res. 1994 Feb;7(1):44–51. doi: 10.1111/j.1600-0749.1994.tb00017.x. [DOI] [PubMed] [Google Scholar]
  35. Sviderskaya E. V., Wakeling W. F., Bennett D. C. A cloned, immortal line of murine melanoblasts inducible to differentiate to melanocytes. Development. 1995 May;121(5):1547–1557. doi: 10.1242/dev.121.5.1547. [DOI] [PubMed] [Google Scholar]
  36. Takahashi H., Saitoh K., Kishi H., Parsons P. G. Immunohistochemical localisation of stem cell factor (SCF) with comparison of its receptor c-Kit proto-oncogene product (c-KIT) in melanocytic tumours. Virchows Arch. 1995;427(3):283–288. doi: 10.1007/BF00203396. [DOI] [PubMed] [Google Scholar]
  37. Tokunaga K., Nakamura Y., Sakata K., Fujimori K., Ohkubo M., Sawada K., Sakiyama S. Enhanced expression of a glyceraldehyde-3-phosphate dehydrogenase gene in human lung cancers. Cancer Res. 1987 Nov 1;47(21):5616–5619. [PubMed] [Google Scholar]
  38. Turner A. M., Zsebo K. M., Martin F., Jacobsen F. W., Bennett L. G., Broudy V. C. Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. Blood. 1992 Jul 15;80(2):374–381. [PubMed] [Google Scholar]
  39. Wehrle-Haller B., Weston J. A. Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. Development. 1995 Mar;121(3):731–742. doi: 10.1242/dev.121.3.731. [DOI] [PubMed] [Google Scholar]
  40. Welker P., Grabbe J., Gibbs B., Zuberbier T., Henz B. M. Human mast cells produce and differentially express both soluble and membrane-bound stem cell factor. Scand J Immunol. 1999 May;49(5):495–500. doi: 10.1046/j.1365-3083.1999.00519.x. [DOI] [PubMed] [Google Scholar]
  41. Worm M., Reichert U., Dippel E., Czarnetzki B. M., Schadendorf D. Expression of growth factor receptors on human melanoma cells: comparison of modulating effects of interferons and retinoids. Exp Dermatol. 1993 Oct;2(5):217–223. doi: 10.1111/j.1600-0625.1993.tb00036.x. [DOI] [PubMed] [Google Scholar]
  42. Zsebo K. M., Williams D. A., Geissler E. N., Broudy V. C., Martin F. H., Atkins H. L., Hsu R. Y., Birkett N. C., Okino K. H., Murdock D. C. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990 Oct 5;63(1):213–224. doi: 10.1016/0092-8674(90)90302-u. [DOI] [PubMed] [Google Scholar]
  43. van Muijen G. N., Jansen K. F., Cornelissen I. M., Smeets D. F., Beck J. L., Ruiter D. J. Establishment and characterization of a human melanoma cell line (MV3) which is highly metastatic in nude mice. Int J Cancer. 1991 Apr 22;48(1):85–91. doi: 10.1002/ijc.2910480116. [DOI] [PubMed] [Google Scholar]

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