Aktuelle Dermatologie 2002; 28(8/9): 302-309
DOI: 10.1055/s-2002-33965
Tumormarker
© Georg Thieme Verlag Stuttgart · New York

Lösliche Serumfaktoren als prognostische Marker des Melanoms: sHLA, sFas und IL-8

Soluble Factors as Prognostic Serological Markers in Malignant Melanoma: sHLA, sFas and IL-8S.  Ugurel 1 , W.  Tilgen 2 , U.  Reinhold 2
  • 1 Klinische Kooperationseinheit Dermato-Onkologie (Leiter: Prof. D. Schadendorf), Deutsches Krebsforschungszentrum Heidelberg/Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Mannheim
  • 2 Universitäts-Hautklinik und Poliklinik (Direktor: Prof. W. Tilgen), Universitätskliniken des Saarlandes, Homburg/Saar
Further Information

Publication History

Publication Date:
10 September 2002 (online)

Zusammenfassung

Eine größere Anzahl serologischer Faktoren konnte in den letzten Jahren als Tumormarker des malignen Melanoms identifiziert werden. Für einen Großteil dieser Markerproteine konnte eine Korrelation mit der Prognose der Patienten gezeigt werden. Trotzdem gibt es aktuell keine internationalen Empfehlungen hinsichtlich eines routinemäßigen Einsatzes eines dieser Markerproteine. Der aktuell am häufigsten eingesetzte Marker ist das S100-β Protein, das ursprünglich als saures, Kalzium-bindendes Protein aus Rinderhirnextrakt dargestellt wurde. S100-β zeigte sich als nützlicher prognostischer Serummarker bei Patienten mit Melanom im metastasierten Stadium und stellt einen guten Verlaufsparameter für das Monitoring metastasierter Melanompatienten unter Chemotherapie dar. Andere Serumproteine, wie z. B. Melanoma Inhibiting Activity (MIA), wurden ebenfalls in zahlreichen Studien als serologische Prognoseindikatoren des Melanoms evaluiert, konnten jedoch die Aussagekraft des S100-β nicht übertreffen. Ein bedeutender Nachteil des S100-β ist dessen geringer prädiktiver Wert hinsichtlich der Prognose bei Patienten in frühen Erkrankungsstadien, vor Nachweis einer Metastasierung. Diese Patienten werden nach Exzision des Primärtumors aufwändigen Nachsorge-Untersuchungsprogrammen unterzogen, um eine eventuell auftretende Metastasierung möglichst frühzeitig zu erkennen und zu behandeln. Hierzu müssen diese Patienten aktuell invasive und kostenintensive Maßnahmen, wie beispielsweise die Exstirpation des Sentinel Lymphknotens, in Kauf nehmen. Insbesondere diese Patientengruppe würde von der Entwicklung neuer sensitiver und hinreichend genauer prognostischer Marker, die wenig aufwändig aus dem Serum des Patienten bestimmt werden könnten, profitieren.

Abstract

A variety of serological markers have been identified in malignant melanoma, most of them associated with disease progression. Nevertheless, none of them is currently recommended for routine diagnostic use by international guidelines. S100-β, originally described as an acidic, calcium-binding protein derived from a bovine brain extract, has been demonstrated as an appropriate serum marker in metastatic melanoma patients with high serum levels indicating disease progression or recurrence. Moreover, S100-β has been proved as a useful serum parameter in the monitoring of metastatic melanoma patients during ongoing chemotherapy. Other serological marker proteins like e. g. melanoma inhibiting activity (MIA) have been evaluated in several studies, but could not be approved to exceed the predictive value of S100-β. A major disadvantage of S100-β is the poor predictive value of this marker in early-stage non-metastasized melanoma patients. After surgical removal of their primary tumors, these patients are enrolled into elaborated follow-up examination programs aiming at a detection of recurrence of the disease as early as possible. To estimate their risk of recurrence, these patients currently have to undergo invasive and costly procedures like e. g. sentinel lymph node dissection. Therefore, the identification of sensitive and reliable serological markers with strong predictive impact for the patients' prognosis would be of high beneficial value for this group of patients.

Literatur

  • 1 Swerdlow A J. International trends in cutaneous melanoma.  Ann NY Acad Sci. 1990;  60 235-251
  • 2 McMasters K M, Reintgen D S, Ross M I. et al . Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement.  J Clin Oncol. 2001;  19 2851-2855
  • 3 Guo H B, Stoffel-Wagner B, Bierwirth T, Mezger J, Klingmuller D. Clinical significance of serum S100 in metastatic malignant melanoma.  Eur J Cancer. 1995;  31 924-928
  • 4 Hauschild A, Engel G, Brenner W. et al . S100B protein detection in serum is a significant prognostic factor in metastatic melanoma.  Oncology. 1999;  56 338-344
  • 5 Hauschild A, Engel G, Brenner W. et al . Predictive value of serum S100B for monitoring patients with metastatic melanoma during chemotherapy and/or immunotherapy.  Br J Dermatol. 1999;  140 1065-1071
  • 6 Bosserhoff A K, Kaufmann M, Kaluza B. et al . Melanoma-inhibitory activity, a novel serum marker for progression of malignant melanoma.  Cancer Res. 1997;  57 3149-3153
  • 7 Stahlecker J, Gauger A, Bosserhoff A, Buettner R, Ring J, Hein R. MIA as a reliable tumor marker in the serum of patients with malignant melanoma.  Anticancer Res. 2000;  20 5041-5044
  • 8 Deichmann M, Brenner A, Bock M. et al . S100-beta, melanoma-inhibiting activity and lactate dehydrogenase discriminate progressive from non-progressive American Joint Committee on Cancer stage IV melanoma.  J Clin Oncol. 1999;  17 1891-1896
  • 9 Ruiz-Cabello F, Garrido F. HLA and cancer: from research to clinical impact.  Immunol Today. 1998;  19 539-542
  • 10 van Rood J J, van Leeuwen A, van Santen M C. Anti HL-A2 inhibitor in normal human serum.  Nature. 1970;  226 366-367
  • 11 Reisfeld R A, Allison J P, Ferrone S, Pellegrino M A, Poulik M D. HL-A antigens in serum and urine: isolation, characterization, and immunogenic properties.  Transplant Proc. 1976;  8 173-178
  • 12 Zavazava N, Kronke M. Soluble HLA class I molecules induce apoptosis in alloreactive cytotoxic T lymphocytes.  Nat Med. 1996;  2 1005-1010
  • 13 Filaci G, Contini P, Brenci S. et al . Increased serum concentration of soluble HLA-DR antigens in HIV infection and following transplantation.  Tissue Antigens. 1995;  46 117-123
  • 14 Ditschkowski M, Kreuzfelder E, Rebmann V. et al . HLA-DR expression and soluble HLA-DR levels in septic patients after trauma.  Ann Surg. 1999;  229 246-254
  • 15 Rebmann V, Ugurel S, Tilgen W, Reinhold U, Grosse-Wilde H. Soluble HLA-DR is a potent predictive indicator of disease progression in serum from early-stage melanoma patients.  Int J Cancer. 2002;  (in press)
  • 16 Ferrone S, Marincola F M. Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance.  Immunol Today. 1995;  16 487-494
  • 17 Westhoff U, Fox C, Otto F J. Soluble HLA class I antigens in plasma of patients with malignant melanoma.  Anticancer Res. 1998;  18 3789-3792
  • 18 Le Bouteiller P, Blaschitz A. The functionality of HLA-G is emerging.  Immunol Rev. 1999;  167 233-244
  • 19 Carosella E D, Rouas-Freiss N, Paul P, Dausset J. HLA-G: a tolerance molecule from the major histocompatibility complex.  Immunol Today. 1999;  20 60-62
  • 20 Paul P, Rouas-Freiss N, Khalil-Daher I. et al . HLA-G expression in melanoma: a way for tumor cells to escape from immunsurveillance.  Proc Natl Acad Sci U S A. 1998;  95 4510-4515
  • 21 Rebmann V, Pfeiffer K, Passler M. et al . Detection of soluble HLA-G molecules in plasma and amniotic fluid.  Tissue Antigens. 1999;  53 14-22
  • 22 Ugurel S, Rebmann V, Ferrone S, Tilgen W, Grosse-Wilde H, Reinhold U. Soluble human leukocyte antigen-G serum level is elevated in melanoma patients and is further increased by interferon-alpha immunotherapy.  Cancer. 2001;  92 369-376
  • 23 Nagata S. Fas and Fas ligand: a death factor and its receptor.  Adv Immunol. 1994;  57 129-144
  • 24 Chouaib S, Asselin-Paturel C, Mami-Chouaib F, Caignard A, Blay J Y. The host-tumor immune conflict: from immunosuppression to resistance and destruction.  Immunol Today. 1997;  18 493-497
  • 25 Owen-Schaub L B, Radinsky R, Kruzel E, Berry K, Yonehara S. Anti-Fas on nonhematopoietic tumors: levels of Fas/APO-1 and bcl-2 are not predictive of biological responsiveness.  Cancer Res. 1994;  54 1580-1586
  • 26 O'Connell J, Bennett M W, O'Sullivan G C, Collins J K, Shanahan F. The Fas counterattack: cancer as a site of immune privilege.  Immunol Today. 1999;  20 46-52
  • 27 Hahne M, Rimoldi D, Schroeter M. et al . Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape.  Science. 1996;  274 1363-1366
  • 28 Rivoltini L, Radrizzani M, Accornero P. et al . Human melanoma-reactive CD4+ and CD8+ CTL clones resist Fas ligand-induced apoptosis and use Fas/Fas ligand-independent mechanisms for tumor killing.  J Immunol. 1998;  161 1220-1230
  • 29 Thomas W D, Hersey P. CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95).  Int J Cancer. 1998;  75 384-390
  • 30 Ugurel S, Seiter S, Rappl G, Stark A, Tilgen W, Reinhold U. Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-gamma.  Int J Cancer. 1999;  82 727-736
  • 31 Raisova M, Bektas M, Wieder T. et al . Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release.  Febs Lett. 2000;  473 27-32
  • 32 Owen-Schaub L B, van Golen K L, Hill L L, Price J E. Fas and Fas ligand interactions suppress melanoma lung metastasis.  J Exp Med. 1998;  188 1717-1723
  • 33 Cheng J, Zhou T, Liu C. et al . Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule.  Science. 1994;  263 1759-1762
  • 34 Cascino I, Fiucci G, Papoff G, Ruberti G. Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing.  J Immunol. 1995;  154 2706-2713
  • 35 Jodo S, Kobayashi S, Kayagaki N. et al . Serum levels of soluble Fas/APO-1 (CD95) and its molecular structure in patients with systemic lupus erythematosus (SLE) and other autoimmune diseases.  Clin Exp Immunol. 1997;  107 89-95
  • 36 Midis G P, Shen Y, Owen-Schaub L B. Elevated soluble Fas (sFas) levels in nonhematopoietic human malignancy.  Cancer Res. 1996;  56 3870-3874
  • 37 Munker R, Midis G, Owen-Schaub L, Andreff M. Soluble FAS (CD95) is not elevated in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes.  Leukemia. 1996;  10 1531-1533
  • 38 Munker R, Younes A, Cabanillas F, Andreeff M. Soluble CD95 in the serum of patients with low and intermediate grade malignant lymphomas: absence of prognostic correlations.  Leuk Lymphoma. 1997;  27 517-521
  • 39 Mizutani Y, Yoshida O, Bonavida B. Prognostic significance of soluble Fas in the serum of patients with bladder cancer.  J Urol. 1998;  160 571-576
  • 40 Jodo S, Kobayashi S, Nakajima Y. et al . Elevated serum levels of soluble Fas/APO-1 (CD95) in patients with hepatocellular carcinoma.  Clin Exp Immunol. 1998;  112 166-171
  • 41 Streffer J R, Schuster M, Zipp F, Weller M. Soluble CD95 (Fas/APO-1) in malignant glioma: (no) implications for CD95-based immunotherapy?.  J Neurooncol. 1998;  40 233-235
  • 42 Ueno T, Toi M, Tominaga T. Circulating soluble Fas concentration in breast cancer patients.  Clin Cancer Res. 1999;  5 3529-3533
  • 43 Nonomura N, Nishimura K, Ono Y. et al . Soluble Fas in serum from patients with renal cell carcinoma.  Urology. 2000;  55 151-155
  • 44 Hefler L, Mayerhofer K, Nardi A, Reinthaller A, Kainz C, Tempfer C. Serum soluble Fas levels in ovarian cancer.  Obstet Gynecol. 2000;  96 65-69
  • 45 Mouawad R, Khayat D, Soubrane C. Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in advanced melanoma.  Melanoma Res. 2000;  10 461-467
  • 46 Ugurel S, Rappl G, Tilgen W, Reinhold U. Increased soluble CD95 (sFas/CD95) serum level correlates with poor prognosis in melanoma patients.  Clin Cancer Res. 2001;  7 1282-1286
  • 47 Walz A, Peveri P, Aschauer A O, Baggiolini M. Purification and amino acid sequencing of NAF, a novel neutrophil activating factor produced by monocytes.  Biochem Biophys Res Commun. 1987;  149 755-761
  • 48 Koch A E, Polverini P J, Kunkel S L. et al . Interleukin-8 as a macrophage derived mediator of angiogenesis.  Science. 1992;  258 1798-1801
  • 49 Schadendorf D, Möller A, Algemissen B, Worm M, Sticherling M, Czarnetzki B M. IL-8 produced by human malignant melanoma cells in vitro is an autocrine growth factor.  J Immunol. 1993;  151 2667-2675
  • 50 Wang J M, Taroboletti G, Matsushima K, Damme J V, Mantovani A. Induction of haptotactic migration of melanoma cells by neutrophil activating protein/IL-8.  Biochem Biophys Res Commun. 1990;  169 165-170
  • 51 Singh R K, Gutman M, Radinsky R, Bucana C D, Fiedler I J. Expression of interleukin-8 correlates with metastatic potential of human melanoma cells in nude mice.  Cancer Res. 1994;  54 3242-3247
  • 52 Singh R K, Gutman M, Reich R, Bar-Eli M. Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin-8.  Cancer Res. 1995;  55 3669-3674
  • 53 Luca M, Huang S, Gershenwald J E, Singh R K, Reich R, Bar-Eli M. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis.  Am J Pathol. 1997;  151 1105-1113
  • 54 Nürnberg W, Tobias D, Otto F, Henz B M, Schadendorf D. Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma.  J Pathol. 1999;  189 546-551
  • 55 Scheibenbogen C, Mohler T, Haefele J, Hunstein W, Keilholz U. Serum interleukin-8 (IL-8) is elevated in patients with metastatic melanoma and correlates with tumor load.  Melanoma Res. 1995;  5 179-181
  • 56 Ugurel S, Rappl G, Tilgen W, Reinhold U. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival.  J Clin Oncol. 2001;  19 577-583

Selma Ugurel

Klinische Kooperationseinheit für Dermato-Onkologie (DKFZ) · Universitätsklinikum Mannheim

Theodor-Kutzer-Ufer 1 · 68135 Mannheim

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