Skip to main content

Advertisement

SpringerLink
Log in

Clinicopathological and immunohistochemical analysis of autoimmune regulator expression in patients with osteosarcoma

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Autoimmune regulator (AIRE) is a transcription factor that is expressed in medullary thymic epithelial cells. It plays an essential role in central tolerance by eliminating self-reactive T cells. Recently, extrathymic AIRE-expressing cells have been revealed, which are associated with peripheral tolerance. Moreover, AIRE expression has been demonstrated in skin tumors and breast cancer. However, the expression of AIRE in osteosarcoma is unknown. We used immunohistochemistry to investigate AIRE expression in biopsy samples from 43 patients with conventional osteosarcoma and statistically analyzed the association between AIRE expression and clinicopathological characteristics. High AIRE expression was detected in 25 patients (58.1%), and significantly associated with the presence of lung metastasis (P = 0.014) and an increased number of forkhead box P3-positive tumor-infiltrating lymphocytes (regulatory T cells) (P = 0.014). The overall survival rate for all osteosarcoma patients with high AIRE expression was significantly shorter than that for those with low AIRE expression (P = 0.046). In a subgroup analysis of American Joint Committee on Cancer stage II patients who underwent complete surgical resection and conventional chemotherapy, the overall survival and metastasis-free survival rates were significantly shorter for patients with high AIRE expression than for those with low AIRE expression (P = 0.019 and P < 0.01, respectively). High AIRE expression was confirmed to be an independent poor prognostic factor for both overall survival (hazard ratio: 3.841, P = 0.038) and metastasis-free survival (hazard ratio: 4.348, P = 0.022) in the multivariate analysis. The evaluation of AIRE expression may be useful for stratifying osteosarcoma patients for more effective clinical follow-up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AIRE :

Autoimmune regulator

eTACs :

Extrathymic AIRE-expressing cells

TILs :

Tumor-infiltrating lymphocytes

References

  1. Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P (2006) Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 106:1154–1161

    Article  PubMed  Google Scholar 

  2. Allison DC, Carney SC, Ahlmann ER, Hendifar A, Chawla S, Fedenko A, Angeles C, Menendez LR (2012) A meta-analysis of osteosarcoma outcomes in the modern medical era. Sarcoma 2012:704872. https://doi.org/10.1155/2012/704872

    Article  PubMed  PubMed Central  Google Scholar 

  3. Urakawa H, Nishida Y, Nakashima H, Shimoyama Y, Nakamura S, Ishiguro N (2009) Prognostic value of indoleamine 2,3-dioxygenase expression in high grade osteosarcoma. Clin Exp Metastas 26:1005–1012. https://doi.org/10.1007/s10585-009-9290-7

    Article  CAS  Google Scholar 

  4. Isakoff MS, Bielack SS, Meltzer P, Gorlick R (2015) Osteosarcoma: current treatment and a collaborative pathway to success. J Clin Oncol 33:3029–3035. https://doi.org/10.1200/JCO.2014.59.4895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mathis D, Benoist C (2009) Aire. Annu Rev Immunol 27:287–312. https://doi.org/10.1146/annurev.immunol.25.022106.141532

    Article  CAS  PubMed  Google Scholar 

  6. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401

    Article  CAS  PubMed  Google Scholar 

  7. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17:393–398

    Article  CAS  PubMed  Google Scholar 

  8. Eldershaw SA, Sansom DM, Narendran P (2011) Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue. Clin Exp Immunol 163:296–308. https://doi.org/10.1111/j.1365-2249.2010.04316.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gardner JM, Metzger TC, McMahon EJ, Au-Yeung BB, Krawisz AK, Lu W, Price JD, Johannes KP, Satpathy AT, Murphy KM, Tarbell KV, Weiss A, Anderson MS (2013) Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4+ T cells. Immunity 39:560–572. https://doi.org/10.1016/j.immuni.2013.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hobbs RP, DePianto DJ, Jacob JT, Han MC, Chung BM, Batazzi AS, Poll BG, Guo Y, Han J, Ong S, Zheng W, Taube JM, Čiháková D, Wan F, Coulombe PA (2015) Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes. Nat Genet 47:933–938. https://doi.org/10.1038/ng.3355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bianchi F, Sommariva M, De Cecco L, Triulzi T, Romero-Cordoba S, Tagliabue E, Sfondrini L, Balsari A (2016) Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells. Cell Cycle 15:3220–3229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rosenberg AE, Cleton-Jansen AM, de Pinieux G, Deyrup AT, Hauben E, Squire J (2013) Conventional osteosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PC, Mertens F (eds) WHO Classification of Tumors of Soft Tissue and Bone, 4th edn. IARC, Lyon, pp 282–288

    Google Scholar 

  13. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  CAS  PubMed  Google Scholar 

  14. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, Amit AS, Kang C, Geddes JE, Allison JP, Socci ND, Savage PA (2013) Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339:1219–1224. https://doi.org/10.1126/science.1233913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T, Jeker LT, Bösl MR, Holländer GA, Hayashi Y, Malefyt Rde W, Nitta T, Takahama Y (2011) Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J Exp Med 208:383–394. https://doi.org/10.1084/jem.20102327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS (2008) Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321:843–847. https://doi.org/10.1126/science.1159407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, Peterson P, Facchetti F (2010) Human peripheral lymphoid tissues contain autoimmune regulator-expressing dendritic cells. Am J Pathol 176:1104–1112. https://doi.org/10.2353/ajpath.2010.090956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon KS, Auffinger B, Tobias AL, Han Y, Lesniak MS (2012) IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res 18:6110–6121. https://doi.org/10.1158/1078-0432.CCR-12-2130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Abramson J, Giraud M, Benoist C, Mathis D (2010) Aire’s partners in the molecular control of immunological tolerance. Cell 140:123–135. https://doi.org/10.1016/j.cell.2009.12.030

    Article  CAS  PubMed  Google Scholar 

  21. Guerau-de-Arellano M, Mathis D, Benoist C (2008) Transcriptional impact of Aire varies with cell type. Proc Natl Acad Sci USA 105:14011–14016. https://doi.org/10.1073/pnas.0806616105

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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 (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20:776–790

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank Mayumi Miura, Kanoko Miyazaki, Yuki Morotomi, Chie Kuroki, Kaoruko Nagatomo, Kensaku Sato, and Kazutaka Nakashima for their technical support.

Author information

Authors and Affiliations

  1. Departments of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan

    Kotaro Matsuda, Hiroaki Miyoshi, Mayuko Moritsubo & Koichi Ohshima

  2. Orthopedic Surgery, Kurume University School of Medicine, Fukuoka, Japan

    Kotaro Matsuda, Koji Hiraoka, Tetsuya Hamada & Naoto Shiba

Authors
  1. Kotaro Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroaki Miyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mayuko Moritsubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koji Hiraoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetsuya Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoto Shiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koichi Ohshima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroaki Miyoshi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsuda, K., Miyoshi, H., Moritsubo, M. et al. Clinicopathological and immunohistochemical analysis of autoimmune regulator expression in patients with osteosarcoma. Clin Exp Metastasis 35, 641–648 (2018). https://doi.org/10.1007/s10585-018-9928-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-018-9928-4

Keywords

Search

Navigation