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Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy

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Abstract

For the majority of patients with metastatic malignant melanoma the prognosis is poor. Immunotherapy and biochemotherapy have shown promise with a subset of durable responses, but there is still a great need for a better understanding of the mechanisms of action during treatment to optimize future treatment schedules. In the present study Bcl-2 expression was studied in biopsies from ten patients with metastatic malignant melanoma (five with regional disease and five with systemic disease) treated with biochemotherapy (cisplatinum 30 mg/m2 days 1–3, DTIC 250 mg/m2 days 1–3 i.v. and Interferon-α2b 10 MIU s.c. 3 days a week, on a 28-day cycle). The expression of Bcl-2 by the tumour cells was separately recorded in areas of histopathological regressive changes and in areas of unaffected tumour growth. Comparisons were made with biopsies from 14 untreated patients. In 10 of 10 treated patients a high expression of Bcl-2 by the tumour cells was found in areas of unaffected tumour growth. In contrast, only in 5 of 13 untreated patients was a high expression of Bcl-2 by the tumour cells found in these areas (P=0.008). A significant difference was also found in the expression of Bcl-2 by the tumour cells between areas of unaffected tumour growth and areas of histopathological regressive changes (P=0.03). The significantly higher expression of Bcl-2 by the tumour cells in areas of unaffected tumour growth in treated patients compared to untreated patients indicates that clones with a high expression of Bcl-2 may be present after therapy, preventing apoptosis and eventually in many patients resulting in progressive disease. Supporting this concept, a difference was also found between the expression of Bcl-2 in areas of unaffected tumour growth, i.e. in areas of treatment failure, and the expression in areas of histopathological regressive changes. Thus immunohistochemical analysis of tumour biopsies shortly after therapy seems to be a good surrogate endpoint that allows a detailed analysis of Bcl-2 expression. The high expression of Bcl-2 shown in unaffected tumour areas after therapy suggests the need for additional treatment, e.g. Bcl-2 antisense therapy.

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References

  1. Boise LH, Minn AJ, Noel P, June CH, Accavitti MA, Lindsten T, Thompson CB (1995) CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 3:87

    CAS  PubMed  Google Scholar 

  2. Del Bello B, Valentini MA, Zunino F, Comporti M, Maellaro E (2001) Cleavage of Bcl-2 in oxidant- and cisplatin-induced apoptosis of human melanoma cells. Oncogene 20:4591

    Article  PubMed  Google Scholar 

  3. Demir G, Ozguroglu M, Sayhan N, Molinas-Mandel N, Demirelli F, Buyukunal E, Tuzuner N, Serdengecti S, Berkarda B (1999) Immunomodulating therapy with rIL-2 and interferon alpha indices in vivo expression of Bcl-2, Fas (APO-1/CD95), and Fas ligand on peripheral lymphocytes (a pilot study). Anticancer Res 19 (4C):3517

    CAS  PubMed  Google Scholar 

  4. Demke W, Rie C, Grothey A, Schmoll H-J (2001) Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clinical Oncol 127:411

    Article  Google Scholar 

  5. Esche C, Shurin GV, Kirkwood JM, Wang G-Q, Rabinowich H, Pirtskhalaishvili, Shurin MR (2001) Tumour necrosis factor-α-promoted expression of Bcl-2 and inhibition of mitochondrial cytochrome c release mediate resistance of mature dendritic cells to melanoma-induced apoptosis. Clin Cancer Res 7:974s

    CAS  PubMed  Google Scholar 

  6. Flaherty KT, Stevenson JP, O´Dwyer PJ (2001) Antisense therapeutics: lessons from early clinical trials. Curr Opin Oncol 13:499

    Article  CAS  PubMed  Google Scholar 

  7. Gautschi O, Tschopp S, Olie RA, Leech SH, Simones-Wüst AP, Ziegler A, Baumann B, Odermatt B, Hall J, Stahel RA, Zangemeister-Wittke U (2001) Activity of a novel bcl-2/bcl-xL-bispecific antisense oligonucleotide against tumors of diverse histologic origins. J Natl Cancer Inst 93:463

    CAS  Google Scholar 

  8. Grover R, Wilson GD (1996) Bcl-2 expression in malignant melanoma and its prognostic significance. Eur J Surg Oncol 22:347

    CAS  PubMed  Google Scholar 

  9. Heere-Ress E, Thallinger C, Lucas T, Schlagbauer-Wadl H, Wachek V, Monia BP, Wolff K, Pehamberger H, Jansen B (2002) Bcl-XL is a chemoresistance factor in human melanoma cell that can be inhibited by antisense therapy. Int J Cancer 99:29

    Article  CAS  PubMed  Google Scholar 

  10. Hernberg M, Turunen JP, von Boguslawsky K, Muhonen T, Pyrhonen S (1998) Prognostic value of biomarkers in malignant melanoma. Melanoma Res 8:283

    CAS  PubMed  Google Scholar 

  11. Håkansson A, Gustafsson, B Krysander, Håkansson L (1996) Tumour-infiltrating lymphocytes in metastatic malignant melanoma and response to interferon-alpha treatment. Br J Cancer 74:670

    PubMed  Google Scholar 

  12. Håkansson A, Gustafsson B, Krysander L, Bergenwald C, Sander B, Håkansson L (1997) Effect of interferon-α on the expression of tumour necrosis factor-α by metastatic malignant melanoma in vivo. Melanoma Res 7:139

    PubMed  Google Scholar 

  13. Håkansson A, Gustafsson B, Krysander L, Håkansson L (1998) Effect of interferon-α on tumour-infiltrating mononuclear cells and regressive changes in metastatic malignant melanoma. J Interferon Cytokine Res 18:33

    PubMed  Google Scholar 

  14. Håkansson A, Gustafsson B, Krysander L, Hjelmqvist B, Rettrup B, Håkansson L (1999) On down-regulation of the immune response to metastatic malignant melanoma. Cancer Immunol Immunother 48:253

    PubMed  Google Scholar 

  15. Håkansson A, Gustafsson B, Krysander L, Hjelmqvist B, Rettrup B, Håkansson L (2001) Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes. Br J Cancer 85:1871

    PubMed  Google Scholar 

  16. Håkansson A, Håkansson L, Gustafsson B, Krysander L, Rettrup B, Ruiter D, Bernsen M (2002) Biochemotherapy of metastatic malignant melanoma. On down-regulation of CD28. Cancer Immunol Immunother 51:499

    Article  PubMed  Google Scholar 

  17. Imam H, Gobl A, Eriksson B, Oberg K (1997) Interferon-alpha induces bcl-2 proto-oncogene in patients with neuroendocrine gut tumour responding to its antitumour action. Anticancer Res 17(6D):4659

    CAS  PubMed  Google Scholar 

  18. Jansen B, Schlagbauer-Wadl H, Brown BD, Bryan RN, van Elasa A, Muller M, Wolff K, Eichler HG, Pehamberger H (1998) Bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med 4:232

    CAS  PubMed  Google Scholar 

  19. Jewell AP, Worman CP, Lydyard PM, Giles FJ, Goldstone AH (1994) Interferon-alpha up-regulates bcl-2 expression and protects B CLL cells from apoptosis in vitro and in vivo. Br J Haematol 88:268

    CAS  PubMed  Google Scholar 

  20. Kang S, Barnhill RL, Mihm MC, Sober AJ (1993) Histologic regression in malignant melanoma: an interobserver concordance study. J Cutan Pathol 20:126

    CAS  PubMed  Google Scholar 

  21. Kikuyama S, Inada T, Shimizu K, Miyakita M, Ogata Y (2001) P53, bcl-2 and thymidine phosphorylase as predictive markers of chemotherapy in patients with advanced and recurrent gastric cancer. Anticancer Res 21:2149

    CAS  PubMed  Google Scholar 

  22. Legha SS (1997) Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alfa and chemotherapy. Semin Oncol 24 [Suppl 4]:S39

  23. Leiter U, Schmid RM, Kaskel P, Peter RU, Krähn G (2000) Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. Arch Dermatol Res 292:225

    Article  CAS  PubMed  Google Scholar 

  24. Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hla T (2001) Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563

    Article  CAS  PubMed  Google Scholar 

  25. Loggini B, Rinaldi I, Pingitore R, Cristofani R, Castagna M, Barachini P (2001) Immunohistochemical study of 49 cutaneous melanomas: p53, PCNA, Bcl-2 expression and multidrug resistance. Tumori 87:179

    CAS  PubMed  Google Scholar 

  26. Mandic A, Viktorsson K, Molin M, Akusjärvi G, Eguchi H, Hayashi S-I, Toi M, Hansson J, Linder S, Shoshan MC (2001) Cisplatin induces the proapoptotic conformation of Bak in a deltaMEKK1-dependent manner. Mol Cell Biol 11:3684

    Article  Google Scholar 

  27. McGovern VJ (1975) Spontaneous regression of melanoma. Pathology 7:91

    PubMed  Google Scholar 

  28. Osanto S, Schiphorst PP, Weijl NI, Dilkstra N, van Wees A, Brouwenstein N, Vaessen N, van Krieken JHJM, Hermans J, Cleton FJ, Schrier PI (2000) Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line. Hum Gene Ther 11:739

    Article  CAS  PubMed  Google Scholar 

  29. Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos EO, Geilen CC (2001) The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol 117:333

    Article  CAS  PubMed  Google Scholar 

  30. Ronan SG, Eng AM, Briele HA, Shioura NN, Das Gupta TK (1987) Thin malignant melanomas with regression and metastases. Arch Dermatol 123:1326

    CAS  PubMed  Google Scholar 

  31. Selzer E, Schlagbauer-Wadl H, Okamoto I, Pehamberger H, Potter R, Jansen B (1998) Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines. Melanoma Res 8:197

    CAS  PubMed  Google Scholar 

  32. Sondergaard K, Hou-Jensen K (1985) Partial regression in thin primary cutaneous malignant melanomas clinical stage I. Virchows Arch A Pathol Anat Histopathol 408:241

    Google Scholar 

  33. Su L, David M (1999) Inhibition of B cell receptor mediated apoptosis by IFN. J Immunol 162:6317

    CAS  PubMed  Google Scholar 

  34. Subbarayan V, Sabichi AL, Llansa N, Lippman SM, Menter DG (2001) Differential expression of cyclooxygenase-2 and its regulation by tumour necrosis factor-alpha in normal and malignant prostate cells. Cancer Res 61:2720

    CAS  PubMed  Google Scholar 

  35. Tang L, Tron VA, Reed JC, Mah KJ, Krajewska M, Li G, Zhou X, Ho VC, Trotter MJ (1998) Expression of apoptosis regulators in cutaneous malignant melanoma. Clin Cancer Res 4:1865

    CAS  PubMed  Google Scholar 

  36. Ugurel S, Seiter S, Rappl G, Stark A, Tilgen W, Reinhold U (1999) Heterogeneous 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 82:727

    Article  CAS  PubMed  Google Scholar 

  37. Vlaykova T, Talve L, Hahka-Kemppinen M, Hernberg M, Muhonen T, Collan Y, Pyrhonen S (2002) Immunohistochemically detectable bcl-2 expression in metastatic melanoma: association with survival and treatment response. Oncology 62:259

    Article  CAS  PubMed  Google Scholar 

  38. Whiteside T (1998) Immune cells in the tumour microenvironment. Mechanisms responsible for functional and signaling defects. In: Walden P (ed) Gene therapy of cancer. Plenum Press, New York, p 167

  39. Xie K, Huang S, Wang Y, Beltran PJ, Juang S-H, Dong Z, Reed JC, McDonnell TJ, McConkey DJ, Fidler IJ (1996) Bcl-2 protects cells from cytokine-induced nitric-oxide-dependent apoptosis. Cancer Immunol Immunother 43:109

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Professor John Carstensen, Department of Health and Society, Tema Research Institute, for his assistance in the statistical analysis, and Karin Hellander and Catharina Tranaeus Röckert for excellent technical help in performing the immunohistochemistry stainings.

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Authors and Affiliations

  1. Department of Oncology, Division of Clinical Tumour Immunology, University Hospital of Linköping, SE-581 85, Linköping, Sweden

    Annika Håkansson & Leif Håkansson

  2. Department of Pathology and Cytology, University Hospital of Linköping, Linköping, Sweden

    Bertil Gustafsson

  3. Department of Plastic Surgery, Hand Surgery and Burns, University Hospital of Linköping, Linköping, Sweden

    Avni Abdiu & Lennart Krysander

Authors
  1. Annika Håkansson
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  2. Bertil Gustafsson
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  3. Avni Abdiu
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  4. Lennart Krysander
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  5. Leif Håkansson
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Correspondence to Annika Håkansson.

Additional information

This work was supported by the County Council of Östergötland, Sweden.

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Håkansson, A., Gustafsson, B., Abdiu, A. et al. Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy. Cancer Immunol Immunother 52, 249–254 (2003). https://doi.org/10.1007/s00262-003-0373-z

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  • DOI: https://doi.org/10.1007/s00262-003-0373-z

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