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Expression and distribution of MUC18 in human uveal melanoma

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Abstract

The immunoglobulin superfamily protein MUC18 is involved in transendothelial migration and signal transduction, and is expressed in malignancies including cutaneous melanoma. Recent in vitro studies showed evidence of increased MUC18 protein in some uveal melanoma cell lines with an increased potential for invasion. We assessed seven uveal and three metastasis-derived melanoma cell lines for the expression of MUC18 mRNA and protein by RT-PCR, and immunoblotting and immunocytochemistry, respectively. We also examined the expression and distribution of MUC18 in paraffin sections of primary uveal melanomas (n = 23; 5/23 spindle; 18/23 mixed and epithelioid) and normal eyes (n = 3) using a polyclonal goat anti-human antibody to MUC18 visualized with peroxidase and Vector NovaRED. Distribution and intensity of immunostaining was graded semi-quantitatively (grade 0 to 3) by 2 independent observers. All cell lines expressed MUC18 mRNA and protein (∼130 kDa), and showed punctate cell membrane MUC18 immunostaining. Primary melanomas displayed heterogeneous cell membrane and cytoplasmic MUC18, with moderate to strong immunolabelling (≥grade 2) in ∼70% of tumours. Vasculature in tumours and in retina and choroid of all melanoma-affected and normal eyes showed intense MUC18 immunostaining. These observations further suggest a role for MUC18 in uveal melanoma growth; moreover, interactions between MUC18-positive melanoma cells and vasculature may be important for the hematogenous spread of cells during metastases.

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References

  1. Aldovini D, Demichelis F, Doglioni C, Di Vizio D, Galligioni E, Brugnara S, Zeni B, Griso C, Pegoraro C, Zannoni M, Gariboldi M, Balladore E, Mezzanzanica D, Canevari S, Barbareschi M (2006) M-CAM expression as marker of poor prognosis in epithelial ovarian cancer. Int J Cancer 119:1920–1926

    Article  PubMed  CAS  Google Scholar 

  2. Anfosso F, Bardin N, Frances V, Vivier E, Camoin-Jau L, Sampol J, Dignat-George F (1998) Activation of human endothelial cells via S-endo-1 antigen (CD146) stimulates the tyrosine phosphorylation of focal adhesion kinase p125(FAK). J Biol Chem 273:26852–26856

    Article  PubMed  CAS  Google Scholar 

  3. Anfosso F, Bardin N, Vivier E, Sabatier F, Sampol J, Dignat-George F (2001) Outside-in signaling pathway linked to CD146 engagement in human endothelial cells. J Biol Chem 276:1564–1569

    Article  PubMed  CAS  Google Scholar 

  4. Bar-Eli M (1999) Role of AP-2 in tumor growth and metastasis of human melanoma. Cancer Metastasis Rev 18:377–385

    Article  PubMed  CAS  Google Scholar 

  5. Bardin N, Anfosso F, Masse JM, Cramer E, Sabatier F, Le Bivic A, Sampol J, Dignat-George F (2001) Identification of CD146 as a component of the endothelial junction involved in the control of cell–cell cohesion. Blood 98:3677–3684

    Article  PubMed  CAS  Google Scholar 

  6. Bardin N, Frances V, Lesaule G, Horschowski N, George F, Sampol J (1996) Identification of the S-Endo 1 endothelial-associated antigen. Biochem Biophys Res Commun 218:210–216

    Article  PubMed  CAS  Google Scholar 

  7. Bardin N, George F, Mutin M, Brisson C, Horschowski N, Frances V, Lesaule G, Sampol J (1996) S-Endo 1, a pan-endothelial monoclonal antibody recognizing a novel human endothelial antigen. Tissue Antigens 48:531–539

    Article  PubMed  CAS  Google Scholar 

  8. Bosher JM, Williams T, Hurst HC (1995) The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. Proc Natl Acad Sci USA 92:744–747

    Article  PubMed  CAS  Google Scholar 

  9. Denton KJ, Stretch JR, Gatter KC, Harris AL (1992) A study of adhesion molecules as markers of progression in malignant melanoma. J Pathol 167:187–191

    Article  PubMed  CAS  Google Scholar 

  10. Elshal MF, Khan SS, Takahashi Y, Solomon MA, McCoy JP Jr (2005) CD146 (Mel–CAM), an adhesion marker of endothelial cells, is a novel marker of lymphocyte subset activation in normal peripheral blood. Blood 106:2923–2924

    Article  PubMed  CAS  Google Scholar 

  11. Folberg R, Hendrix MJ, Maniotis AJ (2000) Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156:361–381

    PubMed  CAS  Google Scholar 

  12. Folberg R, Maniotis AJ (2004) Vasculogenic mimicry. APMIS 112:508–525

    Article  PubMed  Google Scholar 

  13. Folberg R, Pe’er J, Gruman LM, Woolson RF, Jeng G, Montague PR, Moninger TO, Yi H, Moore KC (1992) The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal melanoma: a matched case-control study. Hum Pathol 23:1298–1305

    Article  PubMed  CAS  Google Scholar 

  14. Folberg R, Rummelt V, Parys-Van Ginderdeuren R, Hwang T, Woolson RF, Pe’er J, Gruman LM (1993) The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 100:1389–1398

    PubMed  CAS  Google Scholar 

  15. Gambrelle J, Grange JD, Devouassoux Shisheboran M, Rivoire M, Baggetto LG, Jean-Louis B, Fleury J, Kodjikian L (2006) Survival after primary enucleation for choroidal melanoma: changes induced by the introduction of conservative therapies. Graefes Arch Clin Exp Ophthalmol 245:657–663

    Article  PubMed  Google Scholar 

  16. Gragoudas ES, Egan KM, Seddon JM, Glynn RJ, Walsh SM, Finn SM, Munzenrider JE, Spar MD (1991) Survival of patients with metastases from uveal melanoma. Ophthalmology 98:383–389 (discussion 390)

    PubMed  CAS  Google Scholar 

  17. Haass NK, Smalley KS, Li L, Herlyn M (2005) Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res 18:150–159

    Article  PubMed  CAS  Google Scholar 

  18. Heimberger AB, McGary EC, Suki D, Ruiz M, Wang H, Fuller GN, Bar-Eli M (2005) Loss of the AP-2alpha transcription factor is associated with the grade of human gliomas. Clin Cancer Res 11:267–272

    Article  PubMed  CAS  Google Scholar 

  19. Hendrix MJ, Seftor EA, Kirschmann DA, Quaranta V, Seftor RE (2003) Remodeling of the microenvironment by aggressive melanoma tumor cells. Ann N Y Acad Sci 995:151–161

    Article  PubMed  CAS  Google Scholar 

  20. Jean D, Gershenwald JE, Huang S, Luca M, Hudson MJ, Tainsky MA, Bar-Eli M (1998) Loss of AP-2 results in up-regulation of MCAM/MUC18 and an increase in tumor growth and metastasis of human melanoma cells. J Biol Chem 273:16501–16508

    Article  PubMed  CAS  Google Scholar 

  21. Johnson JP (1994) Identification of molecules associated with the development of metastasis in human malignant melanoma. Invasion Metastasis 14:123–130

    PubMed  Google Scholar 

  22. Karlen S, Braathen LR (1999) Regulation of the melanoma cell adhesion molecule gene in melanoma: modulation of mRNA synthesis by cyclic adenosine monophosphate, phorbol ester, and stem cell fFactor/c-kKit signaling. J Invest Dermatol 113:711–719

    Article  PubMed  CAS  Google Scholar 

  23. Karlen S, Braathen LR (2000) Role of the initiator element in the regulation of the melanoma cell adhesion molecule gene. J Invest Dermatol 115:668–673

    Article  PubMed  CAS  Google Scholar 

  24. Kodjikian L, Grange JD, Baldo S, Baillif S, Garweg JG, Rivoire M (2005) Prognostic factors of liver metastases from uveal melanoma. Graefes Arch Clin Exp Ophthalmol 243:985–993

    Article  PubMed  Google Scholar 

  25. Kraus A, Masat L, Johnson JP (1997) Analysis of the expression of intercellular adhesion molecule-1 and MUC18 on benign and malignant melanocytic lesions using monoclonal antibodies directed against distinct epitopes and recognizing denatured, non-glycosylated antigen. Melanoma Res 7(Suppl 2):S75–S81

    PubMed  CAS  Google Scholar 

  26. Lai K, Di Girolamo N, Conway RM, Jager MJ, Madigan MC (2007) The effect of ultraviolet radiation on choroidal melanocytes and melanoma cell lines: cell survival and matrix metalloproteinase production. Graefes Arch Clin Exp Ophthalmol 245:715–724

    Article  PubMed  CAS  Google Scholar 

  27. Lehmann JM, Holzmann B, Breitbart EW, Schmiegelow P, Riethmuller G, Johnson JP (1987) Discrimination between benign and malignant cells of melanocytic lineage by two novel antigens, a glycoprotein with a molecular weight of 113,000 and a protein with a molecular weight of 76,000. Cancer Res 47:841–845

    PubMed  CAS  Google Scholar 

  28. Lehmann JM, Riethmuller G, Johnson JP (1989) MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci USA 86:9891–9895

    Article  PubMed  CAS  Google Scholar 

  29. Leslie MC, Bar-Eli M (2005) Regulation of gene expression in melanoma: new approaches for treatment. J Cell Biochem 94:25–38

    Article  PubMed  CAS  Google Scholar 

  30. Leslie MC, Zhao YJ, Lachman LB, Hwu P, Bar-Eli M (2006) Immunization against MUC18/MCAM, a novel antigen that drives melanoma invasion and metastasis. Gene Ther 14:316–323

    Article  PubMed  CAS  Google Scholar 

  31. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155:739–752

    PubMed  CAS  Google Scholar 

  32. McGary EC, Heimberger A, Mills L, Weber K, Thomas GW, Shtivelband M, Lev DC, Bar-Eli M (2003) A fully human antimelanoma cellular adhesion molecule/MUC18 antibody inhibits spontaneous pulmonary metastasis of osteosarcoma cells in vivo. Clin Cancer Res 9:6560–6566

    PubMed  CAS  Google Scholar 

  33. Meier F, Schittek B, Busch S, Garbe C, Smalley K, Satyamoorthy K, Li G, Herlyn M (2005) The RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma. Front Biosci 10:2986–3001

    Article  PubMed  CAS  Google Scholar 

  34. Melnikova VO, Bar-Eli M (2006) Bioimmunotherapy for melanoma using fully human antibodies targeting MCAM/MUC18 and IL-8. Pigment Cell Res 19:395–405

    Article  PubMed  CAS  Google Scholar 

  35. Mintz-Weber CS, Johnson JP (2000) Identification of the elements regulating the expression of the cell adhesion molecule MCAM/MUC18. Loss of AP-2 is not required for MCAM expression in melanoma cell lines. J Biol Chem 275:34672–34680

    Article  PubMed  CAS  Google Scholar 

  36. Onken MD, Lin AY, Worley LA, Folberg R, Harbour JW (2005) Association between microarray gene expression signature and extravascular matrix patterns in primary uveal melanomas. Am J Ophthalmol 140:748–749

    Article  PubMed  CAS  Google Scholar 

  37. Pacifico MD, Grover R, Richman PI, Daley FM, Buffa F, Wilson GD (2005) Development of a tissue array for primary melanoma with long-term follow-up: discovering melanoma cell adhesion molecule as an important prognostic marker. Plast Reconstr Surg 115:367–375

    Article  PubMed  CAS  Google Scholar 

  38. Pardo M, Garcia A, Thomas B, Pineiro A, Akoulitchev A, Dwek RA, Zitzmann N (2005) Proteome analysis of a human uveal melanoma primary cell culture by 2-DE and MS. Proteomics 5:4980–4993

    Article  PubMed  CAS  Google Scholar 

  39. Pardo M, Garcia A, Thomas B, Pineiro A, Akoulitchev A, Dwek RA, Zitzmann N (2006) The characterization of the invasion phenotype of uveal melanoma tumour cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker. Int J Cancer 119:1014–1022

    Article  PubMed  CAS  Google Scholar 

  40. Pickl WF, Majdic O, Fischer GF, Petzelbauer P, Fae I, Waclavicek M, Stockl J, Scheinecker C, Vidicki T, Aschauer H, Johnson JP, Knapp W (1997) MUC18/MCAM (CD146), an activation antigen of human T lymphocytes. J Immunol 158:2107–2115

    PubMed  CAS  Google Scholar 

  41. Rivoire M, Kodjikian L, Baldo S, Kaemmerlen P, Negrier S, Grange JD (2005) Treatment of liver metastases from uveal melanoma. Ann Surg Oncol 12:422–428

    Article  PubMed  Google Scholar 

  42. Ruiz M, Troncoso P, Bruns C, Bar-Eli M (2001) Activator protein 2alpha transcription factor expression is associated with luminal differentiation and is lost in prostate cancer. Clin Cancer Res 7:4086–4095

    PubMed  CAS  Google Scholar 

  43. Seddon J, Egan K, Gragoudas E (1994) Epidemiology of Uveal Melanoma. Retina 1:717–723

    Google Scholar 

  44. Seftalioglu A, Karakoc L (2000) Expression of CD146 adhesion molecules (MUC18 or MCAM) in the thymic microenvironment. Acta Histochem 102:69–83

    Article  PubMed  CAS  Google Scholar 

  45. Seftor EA, Meltzer PS, Kirschmann DA, Margaryan NV, Seftor RE, Hendrix MJ (2006) The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment. J Cell Mol Med 10:174–196

    Article  PubMed  CAS  Google Scholar 

  46. Seftor EA, Meltzer PS, Kirschmann DA, Pe’er J, Maniotis AJ, Trent JM, Folberg R, Hendrix MJ (2002) Molecular determinants of human uveal melanoma invasion and metastasis. Clin Exp Metastasis 19:233–246

    Article  PubMed  CAS  Google Scholar 

  47. Sers C, Riethmuller G, Johnson JP (1994) MUC18, a melanoma-progression associated molecule, and its potential role in tumor vascularization and hematogenous spread. Cancer Res 54:5689–5694

    PubMed  CAS  Google Scholar 

  48. Shih IM (1999) The role of CD146 (Mel–CAM) in biology and pathology. J Pathol 189:4–11

    Article  PubMed  CAS  Google Scholar 

  49. Shih IM, Nesbit M, Herlyn M, Kurman RJ (1998) A new Mel–CAM (CD146)-specific monoclonal antibody, MN-4, on paraffin-embedded tissue. Mod Pathol 11:1098–1106

    PubMed  CAS  Google Scholar 

  50. Shih IM, Speicher D, Hsu MY, Levine E, Herlyn M (1997) Melanoma cell–cell interactions are mediated through heterophilic Mel–CAM/ligand adhesion. Cancer Res 57:3835–3840

    PubMed  CAS  Google Scholar 

  51. Shih IM, Wang TL, Westra WH (1996) Diagnostic and biological implications of mel–CAM expression in mesenchymal neoplasms. Clin Cancer Res 2:569–575

    PubMed  CAS  Google Scholar 

  52. Solovey AN, Gui L, Chang L, Enenstein J, Browne PV, Hebbel RP (2001) Identification and functional assessment of endothelial P1H12. J Lab Clin Med 138:322–331

    Article  PubMed  CAS  Google Scholar 

  53. Stang A, Schmidt-Pokrzywniak A, Lehnert M, Parkin DM, Ferlay J, Bornfeld N, Marr A, Jockel KH (2006) Population-based incidence estimates of uveal melanoma in Germany. Supplementing cancer registry data by case-control data. Eur J Cancer Prev 15:165–170

    Article  PubMed  Google Scholar 

  54. Tellez C, Bar-Eli M (2003) Role and regulation of the thrombin receptor (PAR-1) in human melanoma. Oncogene 22:3130–3137

    Article  PubMed  CAS  Google Scholar 

  55. Vajdic CM, Kricker A, Giblin M, McKenzie J, Aitken J, Giles GG, Armstrong BK (2003) Incidence of ocular melanoma in Australia from 1990 to 1998. Int J Can 105:117–122

    Article  CAS  Google Scholar 

  56. van der Velden PA, Zuidervaart W, Hurks MH, Pavey S, Ksander BR, Krijgsman E, Frants RR, Tensen CP, Willemze R, Jager MJ, Gruis NA (2003) Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development. Int J Cancer 106:472–479

    Article  PubMed  CAS  Google Scholar 

  57. Watson-Hurst K, Becker D (2006) The role of N-cadherin, MCAM and beta(3) integrin in melanoma progression, proliferation, migration and invasion. Cancer Biol Ther 5:1375–1382

    PubMed  CAS  Google Scholar 

  58. Wu GJ, Varma VA, Wu MW, Wang SW, Qu P, Yang H, Petros JA, Lim SD, Amin MB (2001) Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues. Prostate 48:305–315

    Article  PubMed  CAS  Google Scholar 

  59. Xie S, Luca M, Huang S, Gutman M, Reich R, Johnson JP, Bar-Eli M (1997) Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res 57:2295–2303

    PubMed  CAS  Google Scholar 

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Acknowledgement

Cell lines were kindly provided as follows: OCM-1, OCM-3 and OCM-8 (Dr J Kan-Mitchell, Karmanos Cancer Institute, Department of Pathology and Immunology, Wayne State University, Detroit); OMM-1 (Dr GP Luyten, Erasmus University, Rotterdam), 92-1 (Dr MJ Jager, Leiden University Medical Center, Leiden); Mel202 (Dr B. Ksander, Schepens Eye Research Institute, Boston) and OCM-1A, C918, MUM2B and MUM2C (Dr MJ Hendrix, Children’s Memorial Research Center, Northwestern University, Chicago).

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Authors and Affiliations

  1. Save Sight Institute, Discipline of Clinical Ophthalmology, University of Sydney, Sydney, NSW 2006, Australia

    Kenneth Lai, Vidushi Sharma, R. Max Conway & Michele C. Madigan

  2. Department of Ophthalmology, Leiden University Medical Center Leiden, Leiden, The Netherlands

    Martine J. Jager

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  1. Kenneth Lai
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  2. Vidushi Sharma
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  5. Michele C. Madigan
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Correspondence to Michele C. Madigan.

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Supported by Sydney Foundation for Medical Research (MCM) and the National Health & Medical Research Council #211190 (RMC).

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Lai, K., Sharma, V., Jager, M.J. et al. Expression and distribution of MUC18 in human uveal melanoma. Virchows Arch 451, 967–976 (2007). https://doi.org/10.1007/s00428-007-0498-0

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