Serum S100B Levels in Melanoma

  • Anna Lisa Frauchiger
  • Reinhard Dummer
  • Joanna ManganaEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1929)


Malignant melanoma is a cancer with increasing incidence worldwide with relevant socioeconomic impact. Despite progress in prevention and early detection, it is one of the most lethal forms of skin cancer. Therefore it is urgent need to identify suitable biomarkers in order to improve early diagnosis, precise staging, and prognosis, as well as for therapy selection and monitoring. In this book chapter, we are focusing on S100B and discuss its clinical relevance in melanoma.

Key words

S100B Calcium EF hand Melanoma Staging Follow-up Therapy monitoring 


  1. 1.
    MacKie RM, Hauschild A, Eggermont AMM (2009) Epidemiology of invasive cutaneous melanoma. Ann Oncol 20:1–7. Scholar
  2. 2.
    Karimkhani C, Green AC, Nijsten T, Weinstock MA, Dellavalle RP, Naghavi M, Fitzmaurice C (2017) The global burden of melanoma: results from the Global Burden of Disease Study 2015. Br J Dermatol 177:134–140. Scholar
  3. 3.
    Kosary CL, Altekruse SF, Ruhl J, Lee R, Dickie L (2014) Clinical and prognostic factors for melanoma of the skin using SEER registries: collaborative stage data collection system, version 1 and version 2. Cancer 120(Suppl. 23):3807–3814. Scholar
  4. 4.
    Guy GP Jr et al (2015) Vital signs: melanoma incidence and mortality trends and projections – United States, 1982–2030 MMWR. Morb Mortal Wkly Rep 64:591–596Google Scholar
  5. 5.
    Whiteman DC, Green AC, Olsen CM (2016) The growing burden of invasive melanoma: projections of incidence rates and numbers of new cases in six susceptible populations through 2031. J Invest Dermatol 136:1161–1171. Scholar
  6. 6.
    Sneyd MJ, Cox B (2013) A comparison of trends in melanoma mortality in New Zealand and Australia: the two countries with the highest melanoma incidence and mortality in the world. BMC Cancer 13:372. Scholar
  7. 7.
    Azoury SC, Lange JR (2014) Epidemiology, risk factors, prevention, and early detection of melanoma. Surg Clin North Am 94:945–962, vii. Scholar
  8. 8.
    Linos E, Swetter SM, Cockburn MG, Colditz GA, Clarke CA (2009) Increasing burden of melanoma in the United States. J Invest Dermatol 129:1666–1674. Scholar
  9. 9.
    Nikolaou V, Stratigos AJ (2014) Emerging trends in the epidemiology of melanoma. Br J Dermatol 170:11–19. Scholar
  10. 10.
    Gaynor R, Irie R, Morton D, Herschman HR (1980) S100 protein is present in cultured human malignant melanomas. Nature 286:400–401CrossRefGoogle Scholar
  11. 11.
    Moore BW (1965) A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 19:739–744CrossRefGoogle Scholar
  12. 12.
    Donato R (2001) S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33:637–668CrossRefGoogle Scholar
  13. 13.
    Heizmann CW, Fritz G, Schafer BW (2002) S100 proteins: structure, functions and pathology. Front Biosci 7:d1356–d1368PubMedGoogle Scholar
  14. 14.
    Marenholz I, Heizmann CW, Fritz G (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 322:1111–1122. Scholar
  15. 15.
    Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL (2013) Functions of S100 proteins. Curr Mol Med 13:24–57. Scholar
  16. 16.
    Donato R et al (2009) S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 1793:1008–1022. Scholar
  17. 17.
    Hachem S, Laurenson AS, Hugnot JP, Legraverend C (2007) Expression of S100B during embryonic development of the mouse cerebellum. BMC Dev Biol 7:17. Scholar
  18. 18.
    Saito T, Ikeda T, Nakamura K, Chung UI, Kawaguchi H (2007) S100A1 and S100B, transcriptional targets of SOX trio, inhibit terminal differentiation of chondrocytes. EMBO Rep 8:504–509. Scholar
  19. 19.
    Mocellin S, Zavagno G, Nitti D (2008) The prognostic value of serum S100B in patients with cutaneous melanoma: a meta-analysis. Int J Cancer 123:2370–2376. Scholar
  20. 20.
    Brozzi F, Arcuri C, Giambanco I, Donato R (2009) S100B protein regulates astrocyte shape and migration via interaction with Src kinase: implications for astrocyte development, activation, and tumor growth. J Biol Chem 284:8797–8811. Scholar
  21. 21.
    Lin J, Yang Q, Wilder PT, Carrier F, Weber DJ (2010) The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma. J Biol Chem 285:27487–27498. Scholar
  22. 22.
    Tubaro C, Arcuri C, Giambanco I, Donato R (2010) S100B protein in myoblasts modulates myogenic differentiation via NF-kappaB-dependent inhibition of MyoD expression. J Cell Physiol 223:270–282. Scholar
  23. 23.
    Beccafico S, Riuzzi F, Puglielli C, Mancinelli R, Fulle S, Sorci G, Donato R (2011) Human muscle satellite cells show age-related differential expression of S100B protein and RAGE. Age (Dordr) 33:523–541. Scholar
  24. 24.
    Baudier J, Delphin C, Grunwald D, Khochbin S, Lawrence JJ (1992) Characterization of the tumor suppressor protein p53 as a protein kinase C substrate and a S100b-binding protein. Proc Natl Acad Sci U S A 89:11627–11631CrossRefGoogle Scholar
  25. 25.
    Rustandi RR, Drohat AC, Baldisseri DM, Wilder PT, Weber DJ (1998) The Ca(2+)-dependent interaction of S100B(beta beta) with a peptide derived from p53. Biochemistry 37:1951–1960. Scholar
  26. 26.
    Delphin C et al (1999) Calcium-dependent interaction of S100B with the C-terminal domain of the tumor suppressor p53. J Biol Chem 274:10539–10544CrossRefGoogle Scholar
  27. 27.
    Lin J, Yang Q, Yan Z, Markowitz J, Wilder PT, Carrier F, Weber DJ (2004) Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells. J Biol Chem 279:34071–34077. Scholar
  28. 28.
    Lin J, Blake M, Tang C, Zimmer D, Rustandi RR, Weber DJ, Carrier F (2001) Inhibition of p53 transcriptional activity by the S100B calcium-binding protein. J Biol Chem 276:35037–35041. Scholar
  29. 29.
    Wilder PT et al (2006) Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B. Biochim Biophys Acta 1763:1284–1297. Scholar
  30. 30.
    Donato R (1991) Perspectives in S-100 protein biology. Cell Calcium 12:713–726CrossRefGoogle Scholar
  31. 31.
    Wilder PT, Rustandi RR, Drohat AC, Weber DJ (1998) S100B(betabeta) inhibits the protein kinase C-dependent phosphorylation of a peptide derived from p53 in a Ca2+-dependent manner. Protein Sci 7:794–798. Scholar
  32. 32.
    Zimmer DB, Cornwall EH, Landar A, Song W (1995) The S100 protein family: history, function, and expression. Brain Res Bull 37:417–429CrossRefGoogle Scholar
  33. 33.
    Molina R, Navarro J, Filella X, Castel T, Ballesta AM (2002) S-100 protein serum levels in patients with benign and malignant diseases: false-positive results related to liver and renal function. Tumour Biol 23:39–44. Scholar
  34. 34.
    Brochez L, Naeyaert JM (2000) Serological markers for melanoma. Br J Dermatol 143:256–268CrossRefGoogle Scholar
  35. 35.
    Stigbrand T, Nyberg L, Ullen A, Haglid K, Sandstrom E, Brundell J (2000) A new specific method for measuring S-100B in serum. Int J Biol Markers 15:33–40CrossRefGoogle Scholar
  36. 36.
    Heizmann CW (2004) S100B protein in clinical diagnostics: assay specificity. Clin Chem 50:249–251. Scholar
  37. 37.
    Smit LH, Korse CM, Bonfrer JM (2005) Comparison of four different assays for determination of serum S-100B. Int J Biol Markers 20:34–42CrossRefGoogle Scholar
  38. 38.
    Gershenwald JE et al (2017) Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67:472–492. Scholar
  39. 39.
    Balch CM et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206. Scholar
  40. 40.
    Fagnart OC, Sindic CJ, Laterre C (1988) Particle counting immunoassay of S100 protein in serum. Possible relevance in tumors and ischemic disorders of the central nervous system. Clin Chem 34:1387–1391PubMedGoogle Scholar
  41. 41.
    Henze G, Dummer R, Joller-Jemelka HI, Boni R, Burg G (1997) Serum S100 – a marker for disease monitoring in metastatic melanoma. Dermatology 194:208–212. Scholar
  42. 42.
    Hauschild A, Engel G, Brenner W, Glaser R, Monig H, Henze E, Christophers E (1999) S100B protein detection in serum is a significant prognostic factor in metastatic melanoma. Oncology 56:338–344. Scholar
  43. 43.
    Guo HB, Stoffel-Wagner B, Bierwirth T, Mezger J, Klingmuller D (1995) Clinical significance of serum S100 in metastatic malignant melanoma. Eur J Cancer 31A:1898–1902CrossRefGoogle Scholar
  44. 44.
    Schlagenhauff B et al (2000) Significance of serum protein S100 levels in screening for melanoma metastasis: does protein S100 enable early detection of melanoma recurrence? Melanoma Res 10:451–459CrossRefGoogle Scholar
  45. 45.
    Nikolin B, Djan I, Trifunovic J, Dugandzija T, Novkovic D, Djan V, Vucinic N (2016) MIA, S100 and LDH as important predictors of overall survival of patients with stage IIb and IIc melanoma. J BUON 21:691–697PubMedGoogle Scholar
  46. 46.
    Ghanem G et al (2001) On the release and half-life of S100B protein in the peripheral blood of melanoma patients. Int J Cancer 94:586–590CrossRefGoogle Scholar
  47. 47.
    Kruijff S, Bastiaannet E, Kobold AC, van Ginkel RJ, Suurmeijer AJ, Hoekstra HJ (2009) S-100B concentrations predict disease-free survival in stage III melanoma patients. Ann Surg Oncol 16:3455–3462. Scholar
  48. 48.
    Balch CM et al (2010) Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol 28:2452–2459. Scholar
  49. 49.
    Damude S, Hoekstra HJ, Bastiaannet E, Muller Kobold AC, Kruijff S, Wevers KP (2016) The predictive power of serum S-100B for non-sentinel node positivity in melanoma patients. Eur J Surg Oncol 42:545–551. Scholar
  50. 50.
    Wevers KP, Kruijff S, Speijers MJ, Bastiaannet E, Muller Kobold AC, Hoekstra HJ (2013) S-100B: a stronger prognostic biomarker than LDH in stage IIIB-C melanoma. Ann Surg Oncol 20:2772–2779. Scholar
  51. 51.
    Banfalvi T, Gilde K, Gergye M, Boldizsar M, Kremmer T, Otto S (2003) Use of serum 5-S-CD and S-100B protein levels to monitor the clinical course of malignant melanoma. Eur J Cancer 39:164–169CrossRefGoogle Scholar
  52. 52.
    Weide B et al (2012) Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis. Br J Cancer 107:422–428. Scholar
  53. 53.
    Smit LH et al (2005) Normal values of serum S-100B predict prolonged survival for stage IV melanoma patients. Eur J Cancer 41:386–392. Scholar
  54. 54.
    Alegre E, Sammamed M, Fernandez-Landazuri S, Zubiri L, Gonzalez A (2015) Circulating biomarkers in malignant melanoma. Adv Clin Chem 69:47–89. Scholar
  55. 55.
    Wollina U, Karte K, Hipler UC, Knoll B, Kirsch K, Herold C (2000) Serum protein s100beta in patients with malignant melanoma detected by an immunoluminometric assay. J Cancer Res Clin Oncol 126:107–110CrossRefGoogle Scholar
  56. 56.
    Montagut C, Settleman J (2009) Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett 283:125–134. Scholar
  57. 57.
    Chapman PB et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516. Scholar
  58. 58.
    Frauchiger AL et al (2016) Prognostic relevance of lactate dehydrogenase and serum S100 levels in stage IV melanoma with known BRAF mutation status. Br J Dermatol 174:823–830. Scholar
  59. 59.
    Hauschild A, Engel G, Brenner W, Glaser R, Monig H, Henze E, Christophers E (1999) Predictive value of serum S100B for monitoring patients with metastatic melanoma during chemotherapy and/or immunotherapy. Br J Dermatol 140:1065–1071CrossRefGoogle Scholar
  60. 60.
    Felix J et al (2016) Relevance of serum biomarkers associated with melanoma during follow-up of anti-CTLA-4 immunotherapy. Int Immunopharmacol 40:466–473. Scholar
  61. 61.
    Abusaif S et al (2013) S100B and lactate dehydrogenase as response and progression markers during treatment with vemurafenib in patients with advanced melanoma. Melanoma Res 23:396–401. Scholar
  62. 62.
    Sanmamed MF et al (2014) Relevance of MIA and S100 serum tumor markers to monitor BRAF inhibitor therapy in metastatic melanoma patients. Clin Chim Acta 429:168–174. Scholar
  63. 63.
    Bosserhoff AK et al (1997) Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res 57:3149–3153PubMedGoogle Scholar
  64. 64.
    Dummer R et al (2016) The updated Swiss guidelines 2016 for the treatment and follow-up of cutaneous melanoma. Swiss Med Wkly 146:w14279. Scholar
  65. 65.
    Garbe C et al (2016) Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – update 2016. Eur J Cancer 63:201–217. Scholar
  66. 66.
    Garbe C, Leiter U, Ellwanger U, Blaheta HJ, Meier F, Rassner G, Schittek B (2003) Diagnostic value and prognostic significance of protein S-100beta, melanoma-inhibitory activity, and tyrosinase/MART-1 reverse transcription-polymerase chain reaction in the follow-up of high-risk melanoma patients. Cancer 97:1737–1745. Scholar
  67. 67.
    Krahn G, Kaskel P, Sander S, Waizenhofer PJ, Wortmann S, Leiter U, Peter RU (2001) S100 beta is a more reliable tumor marker in peripheral blood for patients with newly occurred melanoma metastases compared with MIA, albumin and lactate-dehydrogenase. Anticancer Res 21:1311–1316PubMedGoogle Scholar
  68. 68.
    Beyeler M, Waldispuhl S, Strobel K, Joller-Jemelka HI, Burg G, Dummer R (2006) Detection of melanoma relapse: first comparative analysis on imaging techniques versus S100 protein. Dermatology 213:187–191. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Anna Lisa Frauchiger
    • 1
  • Reinhard Dummer
    • 1
  • Joanna Mangana
    • 1
    Email author
  1. 1.Department of DermatologyUniversity Hospital ZurichZurichSwitzerland

Personalised recommendations