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Insights on PRAME and osteosarcoma by means of gene expression profiling

  • Original Article
  • Published:
Journal of Orthopaedic Science

Abstract

Background

Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers.

Objectives

The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology.

Methods

We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles.

Results

PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis.

Conclusions

The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.

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References

  1. Kirkin AF, Dzhandzhugazyan K, Zeuthen J. Melanoma-associated antigens recognized by cytotoxic T lymphocytes. Apmis. 1998;106:665–79.

    Article  PubMed  CAS  Google Scholar 

  2. Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen Y-T. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev. 2002;188:22–32.

    Article  PubMed  CAS  Google Scholar 

  3. Ikeda H, Lethé B, Lehmannn F, van Baren N, Baurain JF, De Smet C. Caracterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6:199–208.

    Article  PubMed  CAS  Google Scholar 

  4. van Baren N, Chambost H, Ferrant A, Michalex L, Ikeda II, Millard I, Olive D, Boon T, Collie PG. PRAME, a gene encoding an antigen recognized on a human melanoma by cytolytic T cells, is expressed in acute leukemia cells. Br J Haematol. 1998;102:1376–9.

    Article  PubMed  Google Scholar 

  5. Wang MG, Zakut R, Yi H, Rosenberg S, McBride OW. Localization of the MAGE1 gene encoding a human melanoma antigen to chromosome Xq28. Cytogenet Cell Genet. 1994;67(2):116–9.

    Google Scholar 

  6. Simpson AJG, Caballero OL, Jungbluth A, Chen Y-T, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005;5(8):615–25.

    Google Scholar 

  7. Epping MT, Wang L, Edel MJ, Carlee L, Hernandez M, Bernards R. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005;122:835–47.

    Article  PubMed  CAS  Google Scholar 

  8. Epping MT, Bernards R. A causal role for the human tumor antigen preferentially expressed antigen of melanoma in cancer. Cancer Res. 2006;66(22):10639–42.

    Article  PubMed  CAS  Google Scholar 

  9. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001;1:181–93.

    Article  PubMed  CAS  Google Scholar 

  10. Jacobs JFM, Brasseur F, Hulsbergen-van de Kaa C, van de Rakt MWMM, Figdor CG, Adema GJ, Hoogerbrugge PM, Coulie PG, de Vries IJM, et al. Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR. Int J Cancer. 2006;120:67–74.

    Article  Google Scholar 

  11. Jacobs JF, Grauer OM, Brasseur F, Hoogerbrugge PM, Wesseling P, Gidding CE, van de Rakt MW, Figdor CG, Coulie PG, de Vries IJ, Adema GJ. Selective cancer-germline gene expression in pediatric brain tumors. J Neurooncol. 2008;88:273–80.

    Google Scholar 

  12. Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am. 1997;44:973–89.

    Article  PubMed  CAS  Google Scholar 

  13. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jürgens H, Winkler K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of patients treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols. J Clin Oncol. 1702;2002(20):776–90.

    Google Scholar 

  14. Bacci G, Bertoni F, Longhi A, Ferrari S, Forni C, Biagini R, Bacchini P, Donati D, Manfrini M, Bernini G, Lari S. Neoadjvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer. 2003;97:3068–75.

    Article  PubMed  CAS  Google Scholar 

  15. Petrilli AS, de Camargo B, Filho VO, Bruniera P, Brunetto AL, Jesus-Garcia R, Camargo OP, Pena W, Péricles P, Davi A, Prospero JD, Alves MT, Oliveira CR, Macedo CR, Mendes WL, Almeida MT, Borsato ML, dos Santos TM, Ortega J, Consentino E, Brazilian Osteosarcoma Treatment Group Studies III and IV. Results of the Brazilian Osteosarcoma Treatment Group Studies III and IV: prognostic factors and impact on survival. J Clin Oncol. 2006;24:1161–8.

    Google Scholar 

  16. Gorlick R. Osteosarcoma: clinical practice and the expanding role of biology. J Musculoskel Neuron Interact. 2002;2:549–51.

    CAS  Google Scholar 

  17. Vêncio RZ, Patrão DF, Baptista CS, Pereira CA, Zingales B. BayBoots: a model-free Bayesian tool to identify class markers from gene expression data. Genet Mol Res. 2006;5(1):138–42.

    PubMed  Google Scholar 

  18. Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001;411:380–4.

    Article  PubMed  CAS  Google Scholar 

  19. De Smet C, Lurquin C, Lethe B, Martelange V, Boon T. DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol. 1999;19:7327–35.

    PubMed  Google Scholar 

  20. De Smet C, De Backer O, Faraoni I, Lurquin C, Brasser F, Boon T. The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci USA. 1996;93:7149–53.

    Article  PubMed  Google Scholar 

  21. Sudo T, Kuramoto T, Komiya S, Inoune A, Itoh K. Expression of MAGE genes in osteosarcoma. J Orthop Res. 1997;15(1):128–32.

    Article  PubMed  CAS  Google Scholar 

  22. Sigalotti L, Coral S, Altomonte M, Natali L, Gaudino G, Cacciotti P, Libener R, Colizzi F, Vianale G, Martini F, Tognon M, Jungbluth A, Cebon J, Maraskovsky E, Mutti L, Maio M. Cancer testis antigens expression in mesothelioma: role of DNA methylation and bioimmunotherapeutic implications. Br J Cancer. 2002;18;86(6):979–82.

    Google Scholar 

  23. Hosomi Y, Gemma A, Hosoya Y, Nara M, Okano T, Takenaka K, Yoshimura A, Koizumi K, Shimizu K, Kudoh S. Somatic mutation of the Caspase-5 gene in human lung cancer. Int J Mol Med. 2003;12(4):443–6.

    PubMed  CAS  Google Scholar 

  24. Maaser K, Borlak J, et al. A genome-wide expression analysis identifies a network of EpCAM-induced cell cycle regulators. Br J Cancer. 2008;99(10):1635–43.

    Article  PubMed  CAS  Google Scholar 

  25. Elia L, Mennuni C, Storto M, Podda S, Calvaruso F, Salucci V, Aurisicchio L, Scarito A, Ciliberto G, La Monica N, Palombo F. Genetic vaccines against Ep-CAM break tolerance to self in a limited subset of subjects: initial identification of predictive biomarkers. Eur J Immunol. 2006;36(5):1337–49.

    Article  PubMed  CAS  Google Scholar 

  26. Bauerle PA, Giris O. EpCAM (CD326) finding its role in cancer. Br J Cancer. 2007;96:417–23.

    Article  Google Scholar 

  27. Mariani E, Meneghetti A, Tarozzi A, Cattini L, Facchini A. Interleukin-12 induces efficient lysis of natural killer-sensitive and natural killer-resistant human osteosarcoma cells: the synergistic effect of interleukin-2. Scand J Immunol. 2000;51(6):618–25.

    Article  PubMed  CAS  Google Scholar 

  28. Zhang P, Yang Y, Zweidler-McKay PA, Hughes DP. Critical role of notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res. 2008;14(10):2962–9.

    Article  PubMed  CAS  Google Scholar 

  29. Tanaka M, Setoguchi T, Hirotsu M, Gao H, Sasaki H, Matsunoshita Y, Komiya S. Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer. 2009;100(12):1957–65.

    Article  PubMed  CAS  Google Scholar 

  30. Meredith JE Jr, Fazeli B, Schwartz MA. The extracellular matrix as a cell survival factor. Mol Biol Cell. 1993;(9):953–61.

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Acknowledgments

This work was supported by awards from the FAPESP (The State of São Paulo Research Foundation: 04/12150-8, 07/53869-3) and GRAACC (Grupo de Apoio ao Adolescente e Criança com Câncer).

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of this paper.

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Correspondence to Sílvia Regina Caminada Toledo.

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Toledo, S.R.C., Zago, M.A., Oliveira, I.D. et al. Insights on PRAME and osteosarcoma by means of gene expression profiling. J Orthop Sci 16, 458–466 (2011). https://doi.org/10.1007/s00776-011-0106-7

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  • DOI: https://doi.org/10.1007/s00776-011-0106-7

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