Cancer Immunology, Immunotherapy

, Volume 64, Issue 6, pp 769–776 | Cite as

Evaluation of serum osteopontin level and gene polymorphism as biomarkers: analyses from the Nordic Adjuvant Interferon alpha Melanoma trial

  • Lina PrasmickaiteEmail author
  • Gisle Berge
  • Ingrid J. Bettum
  • Steinar Aamdal
  • Johan Hansson
  • Lars Bastholt
  • Miriam Øijordsbakken
  • Kjetil Boye
  • Gunhild M. Mælandsmo
Original Article


Malignant melanoma is highly aggressive cancer with poor prognosis and few therapeutic options. Interferon alpha (IFN-α) has been tested as adjuvant immunotherapy in high-risk melanoma patients in a number of studies, but its beneficial role is controversial. Although IFN-α treatment can prolong relapse-free survival, the effect on overall survival is not significant. However, a small subset of patients benefits from the treatment, signifying the need for biomarkers able to identify a responding subgroup. Here we evaluated whether serum osteopontin (OPN) could function as a biomarker identifying patients with poor prognosis that might benefit from IFN-α. The choice of osteopontin was based on the knowledge about the dual role of this protein in cancer and immune response, an apparent association between OPN and IFN signaling and a prognostic value of OPN in multiple other tumor types. Serum samples from 275 high-risk melanoma patients enrolled in the Nordic Adjuvant IFN Melanoma trial were analyzed for circulating OPN concentrations and OPN promoter polymorphisms in position −443. The potential relation between serum OPN levels, the genotypes and survival in non-treated patients and patients receiving adjuvant IFN-α was investigated. Although slightly better survival was observed in the treated patients that had high levels of OPN, the difference was not statistically significant. In conclusion, serum OPN (its level or the genotype) cannot distinguish melanoma patients with poor prognosis, or patients that might benefit from adjuvant treatment with IFN-α.


Melanoma Osteopontin Interferon Gene polymorphism Serum biomarker 



American Joint Committee on Cancer


Enzyme-linked immunosorbent assay


Interferon alpha


Matrix metalloproteinase




Overall survival


Relapse-free survival


Small integrin-binding ligand N-linked glycoprotein


Single-nucleotide polymorphism



The project was supported by the Norwegian Cancer Society, the Research Council of Norway and the South East Regional Health Authority. We thank Karen-Marie Heintz and Geir Frode Øy from the genotyping core facility for performing SNP analysis.

Conflict of interest

Johan Hansson and Lars Bastholt have been involved in advisory board activities for Merck MSD. Lars Bastholt has received congress-related travel support from Merck MSD. The other authors have no conflicts of interest to report.


  1. 1.
    Forsea AM, del Marmol V, de Vries E, Bailey EE, Geller AC (2012) Melanoma incidence and mortality in Europe: new estimates, persistent disparities. Br J Dermatol 167:1124–1130PubMedCrossRefGoogle Scholar
  2. 2.
    Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ascierto PA, Chiarion-Sileni V, Muggiano A, Mandala M, Pimpinelli N, Del Vecchio M, Rinaldi G, Simeone E, Queirolo P (2014) Interferon alpha for the adjuvant treatment of melanoma: review of international literature and practical recommendations from an expert panel on the use of interferon. J Chemother 26:193–201PubMedCrossRefGoogle Scholar
  4. 4.
    Hansson J, Aamdal S, Bastholt L, Brandberg Y, Hernberg M, Nilsson B, Stierner U, von der Maase H (2011) Two different durations of adjuvant therapy with intermediate-dose interferon alpha-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. Lancet Oncol 12:144–152PubMedCrossRefGoogle Scholar
  5. 5.
    Eggermont AM, Suciu S, Santinami M et al (2008) Adjuvant therapy with pegylated interferon alpha-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372:117–126PubMedCrossRefGoogle Scholar
  6. 6.
    Mocellin S, Pasquali S, Rossi CR, Nitti D (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 102:493–501PubMedCrossRefGoogle Scholar
  7. 7.
    Asmana Ningrum R (2014) Human interferon alpha-2b: a therapeutic protein for cancer treatment. Scientifica (Cairo) 2014:1–8CrossRefGoogle Scholar
  8. 8.
    Ashkar S, Weber GF, Panoutsakopoulou V et al (2000) Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287:860–864PubMedCrossRefGoogle Scholar
  9. 9.
    Shinohara ML, Lu L, Bu J, Werneck MB, Kobayashi KS, Glimcher LH, Cantor H (2006) Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat Immunol 7:498–506PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Bandopadhyay M, Bulbule A, Butti R et al (2014) Osteopontin as a therapeutic target for cancer. Expert Opin Ther Targets 18:883–895PubMedCrossRefGoogle Scholar
  11. 11.
    Shevde LA, Samant RS (2014) Role of osteopontin in the pathophysiology of cancer. Matrix Biol 37:131–141PubMedCrossRefGoogle Scholar
  12. 12.
    Naito M, Matsui A, Inao M et al (2005) SNPs in the promoter region of the osteopontin gene as a marker predicting the efficacy of interferon-based therapies in patients with chronic hepatitis C. J Gastroenterol 40:381–388PubMedCrossRefGoogle Scholar
  13. 13.
    Rittling SR, Chambers AF (2004) Role of osteopontin in tumour progression. Br J Cancer 90:1877–1881PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Maier T, Laubender RP, Sturm RA, Klingenstein A, Korting HC, Ruzicka T, Berking C (2012) Osteopontin expression in plasma of melanoma patients and in melanocytic tumours. J Eur Acad Dermatol Venereol 26:1084–1091PubMedCrossRefGoogle Scholar
  15. 15.
    Filia A, Elliott F, Wind T et al (2013) Plasma osteopontin concentrations in patients with cutaneous melanoma. Oncol Rep 30:1575–1580PubMedCentralPubMedGoogle Scholar
  16. 16.
    Rangel J, Nosrati M, Torabian S, Shaikh L, Leong SP, Haqq C, Miller JR 3rd, Sagebiel RW, Kashani-Sabet M (2008) Osteopontin as a molecular prognostic marker for melanoma. Cancer 112:144–150PubMedCrossRefGoogle Scholar
  17. 17.
    Weber GF, Lett GS, Haubein NC (2010) Osteopontin is a marker for cancer aggressiveness and patient survival. Br J Cancer 103:861–869PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Weber GF, Lett GS, Haubein NC (2011) Categorical meta-analysis of Osteopontin as a clinical cancer marker. Oncol Rep 25:433–441PubMedCrossRefGoogle Scholar
  19. 19.
    Clancy T, Pedicini M, Castiglione F, Santoni D, Nygaard V, Lavelle TJ, Benson M, Hovig E (2011) Immunological network signatures of cancer progression and survival. BMC Med Genomics 4:28PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Bjorheim J, Gaudernack G, Giercksky KE, Ekstrom PO (2003) Direct identification of all oncogenic mutants in KRAS exon 1 by cycling temperature capillary electrophoresis. Electrophoresis 24:63–69PubMedCrossRefGoogle Scholar
  21. 21.
    Lanteri P, Lombardi G, Colombini A, Grasso D, Banfi G (2012) Stability of osteopontin in plasma and serum. Clin Chem Lab Med 50:1979–1984PubMedCrossRefGoogle Scholar
  22. 22.
    Dong QZ, Zhang XF, Zhao Y et al (2013) Osteopontin promoter polymorphisms at locus −443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma. Hepatology 57:1024–1034PubMedCrossRefGoogle Scholar
  23. 23.
    Chen Y, Liu H, Wu W, Li Y, Li J (2013) Osteopontin genetic variants are associated with overall survival in advanced non-small-cell lung cancer patients and bone metastasis. J Exp Clin Cancer Res 32:45PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kluger HM, Hoyt K, Bacchiocchi A et al (2011) Plasma markers for identifying patients with metastatic melanoma. Clin Cancer Res 17:2417–2425PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Grigoriu BD, Scherpereel A, Devos P et al (2007) Utility of osteopontin and serum mesothelin in malignant pleural mesothelioma diagnosis and prognosis assessment. Clin Cancer Res 13:2928–2935PubMedCrossRefGoogle Scholar
  26. 26.
    Isa S, Kawaguchi T, Teramukai S et al (2009) Serum osteopontin levels are highly prognostic for survival in advanced non-small cell lung cancer: results from JMTO LC 0004. J Thorac Oncol 4:1104–1110PubMedCrossRefGoogle Scholar
  27. 27.
    Mack PC, Redman MW, Chansky K et al (2008) Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003. J Clin Oncol 26:4771–4776PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Weber GF (2011) The cancer biomarker osteopontin: combination with other markers. Cancer Genomics Proteomics 8:263–288PubMedGoogle Scholar
  29. 29.
    Rud AK, Boye K, Oijordsbakken M et al (2013) Osteopontin is a prognostic biomarker in non-small cell lung cancer. BMC Cancer 13:540PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Vihinen P, Tervahartiala T, Sorsa T et al (2014) Benefit of adjuvant interferon alpha-2b (IFN-alpha) therapy in melanoma patients with high serum MMP-8 levels. Cancer Immunol Immunother 64:173–180PubMedCrossRefGoogle Scholar
  31. 31.
    Sangaletti S, Tripodo C, Sandri S et al (2014) Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res 74:4706–4719PubMedCrossRefGoogle Scholar
  32. 32.
    Lund SA, Giachelli CM, Scatena M (2009) The role of osteopontin in inflammatory processes. J Cell Commun Signal 3:311–322PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Hao Y, Liu J, Wang P, Wang F, Yu Z, Li M, Chen S, Ning F (2014) OPN polymorphism is related to the chemotherapy response and prognosis in advanced NSCLC. Int J Genomics 2014:846142PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Lina Prasmickaite
    • 1
    Email author
  • Gisle Berge
    • 1
  • Ingrid J. Bettum
    • 1
  • Steinar Aamdal
    • 2
    • 3
  • Johan Hansson
    • 4
  • Lars Bastholt
    • 5
  • Miriam Øijordsbakken
    • 6
  • Kjetil Boye
    • 1
    • 7
  • Gunhild M. Mælandsmo
    • 1
    • 8
    • 9
  1. 1.Division of Cancer, Surgery and Transplantation, Department of Tumor Biology, Institute for Cancer ResearchOslo University HospitalMontebello, OsloNorway
  2. 2.Section for Clinical Cancer Research and Resource DevelopmentOslo University HospitalOsloNorway
  3. 3.Faculty of MedicineUniversity of OsloOsloNorway
  4. 4.Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
  5. 5.Department of OncologyOdense University HospitalOdenseDenmark
  6. 6.Department of Medical BiochemistryOslo University HospitalOsloNorway
  7. 7.Department of OncologyOslo University HospitalOsloNorway
  8. 8.Institute for Pharmacy, Faculty of Health ScienceUniversity of TromsøTromsøNorway
  9. 9.K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of MedicineUniversity of OsloOsloNorway

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