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Translational biology of osteosarcoma

Key Points

  • Osteosarcomas are rare malignancies of bone, affecting primarily children and adolescents. Patients are typically treated with surgery and intensive adjuvant chemotherapy. The 5-year survival rate for recurrent or metastatic osteosarcoma is less than 25%.

  • Bone has a highly specialized microenvironment. Crosstalk between osteoblasts, the cell lineage from which osteosarcoma arises, and monocyte-derived osteoclasts, occurs via signalling molecules that, in many cases, are linked to immune biology.

  • Osteosarcomas are characterized by high levels of genomic instability. Recently, novel mutation patterns have been observed, including chromothripsis and kataegis. Few recurrent, therapeutically targetable mutations have been found.

  • Therapeutic strategies targeting oncogenic kinases have been disappointing, while strategies targeting the osteoclast using denosumab and bisphosphonates are being evaluated.

  • Immune strategies show promise. The immune adjuvant, mifamurtide is the most substantial therapeutic advance in osteosarcoma in the past 10 years.

  • Evidence from preclinical studies suggests that immune checkpoint blockade inhibitors may be useful in the treatment of this disease.

Abstract

For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.

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Figure 1: Osteoclast, osteoblast and immune cell crosstalk.
Figure 2: Pathways for targeted therapies in osteosarcoma.
Figure 3: Targeting immune modulators in osteosarcoma.

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References

  1. WHO. WHO Classification of Tumours of Soft Tissue and Bone. 4th Edn, 281–295 (International Agency for Research on Cancer, 2013).

  2. Bernthal, N. M. et al. Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer 118, 5888–5893 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Link, M. P. et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N. Engl. J. Med. 314, 1600–1606 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Jaffe, N. et al. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N. Engl. J. Med. 291, 994–997 (1974).

    Article  CAS  PubMed  Google Scholar 

  5. Collins, M. et al. Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J. Clin. Oncol. 31, 2303–2312 (2013).

    Article  PubMed  Google Scholar 

  6. Meyers, P. A. et al. Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer 117, 1736–1744 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Grabowski, P. Physiology of bone. Endocr. Dev. 16, 32–48 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Wang, D. et al. Isolation and characterization of MC3T3-E1 preosteoblast subclones with distinct in vitro and in vivo differentiation/mineralization potential. J. Bone Miner. Res. 14, 893–903 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Gronthos, S. et al. Differential cell surface expression of the STRO-1 and alkaline phosphatase antigens on discrete developmental stages in primary cultures of human bone cells. J. Bone Miner. Res. 14, 47–56 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Mutsaers, A. J. & Walkley, C. R. Cells of origin in osteosarcoma: mesenchymal stem cells or osteoblast committed cells? Bone 62, 56–63 (2014).

    Article  PubMed  Google Scholar 

  11. Roodman, G. D. Cell biology of the osteoclast. Exp. Hematol. 27, 1229–1241 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Kaji, H. et al. Insulin-like growth factor-I mediates osteoclast-like cell formation stimulated by parathyroid hormone. J. Cell. Physiol. 172, 55–62 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Varghese, J. S. & Easton, D. F. Genome-wide association studies in common cancers—what have we learnt? Curr. Opin. Genet. Dev. 20, 201–209 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Savage, S. A. et al. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nature Genet. 45, 799–803 (2013). This paper reports the first multi-genome-wide study in humans investigating the genetic aetiology of osteosarcoma; it identified two susceptibility loci.

    Article  CAS  PubMed  Google Scholar 

  15. Skerry, T. M. The response of bone to mechanical loading and disuse: fundamental principles and influences on osteoblast/osteocyte homeostasis. Arch. Biochem. Biophys. 473, 117–123 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Chang, H. J. et al. Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance. Clin. Cancer Res. 11, 3288–3295 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Karlsson, E. K. et al. Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome Biol. 14, R132 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Molyneux, S. D. et al. Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. J. Clin. Invest. 120, 3310–3325 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vahle, J. L. et al. Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicol. Pathol. 32, 426–438 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Szymanska, J. et al. Ring chromosomes in parosteal osteosarcoma contain sequences from 12q13-15: a combined cytogenetic and comparative genomic hybridization study. Genes Chromosomes Cancer 16, 31–34 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Lau, C. C. et al. Frequent amplification and rearrangement of chromosomal bands 6p12-p21 and 17p11.2 in osteosarcoma. Genes Chromosomes Cancer 39, 11–21 (2004).

    Article  PubMed  Google Scholar 

  22. Bayani, J. et al. Genomic mechanisms and measurement of structural and numerical instability in cancer cells. Semin. Cancer Biol. 17, 5–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014). This study uses WGS to investigate the genetic landscape of osteosarcoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Atiye, J. et al. Gene amplifications in osteosarcoma-CGH microarray analysis. Genes Chromosomes Cancer 42, 158–163 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Sadikovic, B. et al. Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling. Hum. Mol. Genet. 18, 1962–1975 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Kuijjer, M. L. et al. Genome-wide analyses on high-grade osteosarcoma: making sense of a genomically most unstable tumor. Int. J. Cancer 133, 2512–2521 (2013).

    CAS  PubMed  Google Scholar 

  27. Wunder, J. S. et al. TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study. J. Clin. Oncol. 23, 1483–1490 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Toguchida, J. et al. Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma. Nature 338, 156–158 (1989).

    Article  CAS  PubMed  Google Scholar 

  29. Cesare, A. J. & Reddel, R. R. Alternative lengthening of telomeres: models, mechanisms and implications. Nature Rev. Genet. 11, 319–330 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Scheel, C. et al. Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene 20, 3835–3844 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). This paper shows that bone cancers are highly genomically unstable and are more likely than most other tumour types to have undergone chromothripsis.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sowa, Y. et al. Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites. Biochem. Biophys. Res. Commun. 241, 142–150 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Watanabe, K. et al. Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP. Cell Death Differ. 12, 10–18 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Capobianco, E. et al. Separate and Combined Effects of DNMT and HDAC Inhibitors in Treating Human Multi-Drug Resistant Osteosarcoma HosDXR150 Cell Line. PLoS ONE 9, e95596 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li, Y. et al. Enhancement of radiosensitivity by 5-Aza-CdR through activation of G2/M checkpoint response and apoptosis in osteosarcoma cells. Tumour Biol. 35, 4831–4839 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Quinn, J. M. et al. Transforming growth factor β affects osteoclast differentiation via direct and indirect actions. J. Bone Miner. Res. 16, 1787–1794 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Dougall, W. C. et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412–2424 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee, J. A. et al. RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma. Pediatr. Blood Cancer 56, 738–743 (2011).

    Article  PubMed  Google Scholar 

  39. Rousseau, J. et al. Formulated siRNAs targeting Rankl prevent osteolysis and enhance chemotherapeutic response in osteosarcoma models. J. Bone Miner. Res. 26, 2452–2462 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Ory, B. et al. Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice. Cancer 104, 2522–2529 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Heymann, D. et al. Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma. Bone 37, 74–86 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Ohba, T. et al. Pleiotropic effects of bisphosphonates on osteosarcoma. Bone 63, 110–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Berger, M. et al. 153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients. Ann. Oncol. 23, 1899–1905 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Kelleher, F. C. et al. Prevailing importance of the hedgehog signaling pathway and the potential for treatment advancement in sarcoma. Pharmacol. Ther. 136, 153–168 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Yang, W. et al. Targeting hedgehog-GLI-2 pathway in osteosarcoma. J. Orthop. Res. 31, 502–509 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Lo, W. W. et al. Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma. Cancer 120, 537–547 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Mu, X. et al. Notch signaling is associated with ALDH activity and an aggressive metastatic phenotype in murine osteosarcoma cells. Front. Oncol. 3, 143 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kolb, E. A. et al. Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling. Pediatr. Blood Cancer 58, 815–818 (2012).

    Article  PubMed  Google Scholar 

  49. Vijayakumar, S. et al. High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/β-catenin target gene, CDC25A. Cancer Cell 19, 601–612 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cai, Y. et al. Wnt pathway in osteosarcoma, from oncogenic to therapeutic. J. Cell Biochem. 115, 625–631 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Lin, C. H. et al. Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma. Sarcoma 2013, 147541 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kansara, M. et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J. Clin. Invest. 119, 837–851 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rubin, E. M. et al. Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma. Mol. Cancer Ther. 9, 731–741 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu, X. W. et al. Prognostic significance of VEGF expression in osteosarcoma: a meta-analysis. Tumour Biol. 35, 155–160 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Grignani, G. et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann. Oncol. 23, 508–516 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Sulzbacher, I. et al. Expression of platelet-derived growth factor-AA is associated with tumor progression in osteosarcoma. Mod. Pathol. 16, 66–71 (2003).

    Article  PubMed  Google Scholar 

  57. Tanaka, T. et al. Dynamic analysis of lung metastasis by mouse osteosarcoma LM8: VEGF is a candidate for anti-metastasis therapy. Clin. Exp. Metastasis 30, 369–379 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Liu, Y. et al. Effect of c-erbB2 overexpression on prognosis in osteosarcoma: evidence from eight studies. Tumour Biol. http://dx.doi.org/10.1007/s13277-014-2165-9 (2014).

  59. Gorlick, R. et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J. Clin. Oncol. 17, 2781–2788 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Kilpatrick, S. E. et al. Clinicopathologic analysis of HER-2/neu immunoexpression among various histologic subtypes and grades of osteosarcoma. Mod. Pathol. 14, 1277–1283 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Ebb, D. et al. Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the children's oncology group. J. Clin. Oncol. 30, 2545–2551 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pollak, M. N. et al. Insulinlike growth factor I: a potent mitogen for human osteogenic sarcoma. J. Natl Cancer Inst. 82, 301–305 (1990).

    Article  CAS  PubMed  Google Scholar 

  63. Kuijjer, M. L. et al. IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma. BMC Cancer 13, 245 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Houghton, P. J. et al. Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program. Pediatr. Blood Cancer 54, 921–926 (2010).

    PubMed  PubMed Central  Google Scholar 

  65. Weigel, B. et al. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children's Oncology Group. Pediatr. Blood Cancer 61, 452–456 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. MacEwen, E. G. et al. c-Met tyrosine kinase receptor expression and function in human and canine osteosarcoma cells. Clin. Exp. Metastasis 20, 421–430 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Sampson, E. R. et al. The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model. J. Bone Miner. Res. 26, 1283–1294 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Hingorani, P. et al. Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo. Clin. Cancer Res. 15, 3416–3422 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Spreafico, A. et al. Antiproliferative and proapoptotic activities of new pyrazolo[3,4-d]pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells. FASEB J. 22, 1560–1571 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Liu, P. Y. et al. Inhibitory effect and significance of rapamycin on the mammalian target of rapamycin signaling pathway in osteosarcoma stem cells and osteosarcoma cells. Zhonghua Zhong Liu Za Zhi 35, 175–180 (2013).

    CAS  PubMed  Google Scholar 

  71. Chawla, S. P. et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J. Clin. Oncol. 30, 78–84 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Demetri, G. D. et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J. Clin. Oncol. 31, 2485–2492 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Pignochino, Y. et al. The combination of sorafenib and everolimus abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models. Clin. Cancer Res. 19, 2117–2131 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Saeki, T. et al. Physiological and oncogenic Aurora-A pathway. Int. J. Biol. Sci. 5, 758–762 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tavanti, E. et al. Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma. Br. J. Cancer 109, 2607–2618 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhu, X. P. et al. Inhibition of Aurora-B suppresses osteosarcoma cell migration and invasion. Exp. Ther. Med. 7, 560–564 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Schreiber, R. D. et al. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  79. Zitvogel, L. et al. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nature Rev. Immunol. 6, 715–727 (2006).

    Article  CAS  Google Scholar 

  80. Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Takayanagi, H. et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β. Nature 416, 744–749 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Franzoso, G. et al. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 11, 3482–3496 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408, 600–605 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Lorenzo, J. et al. Osteoimmunology. Immunol. Rev. 208, 5–6 (2005).

    Article  PubMed  Google Scholar 

  85. Lorenzo, J. et al. Osteoimmunology: interactions of the bone and immune system. Endocr. Rev. 29, 403–440 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Coley, W. B. I.I. Contribution to the Knowledge of Sarcoma. Ann. Surg. 14, 199–220 (1891).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Coley, W. B. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 3, 1–48 (1910).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Eilber, F. R. et al. Osteosarcoma. Results of treatment employing adjuvant immunotherapy. Clin Orthop Relat Res, 94–100 (1975).

  89. Karbach, J. et al. Phase I clinical trial of mixed bacterial vaccine (Coley's toxins) in patients with NY-ESO-1 expressing cancers: immunological effects and clinical activity. Clin. Cancer Res. 18, 5449–5459 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Jeys, L. M. et al. Post operative infection and increased survival in osteosarcoma patients: are they associated? Ann. Surg. Oncol. 14, 2887–2895 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Zitvogel, L. et al. Immunological aspects of cancer chemotherapy. Nature Rev. Immunol. 8, 59–73 (2008).

    Article  CAS  Google Scholar 

  92. Moore, C. et al. Prognostic significance of early lymphocyte recovery in pediatric osteosarcoma. Pediatr. Blood Cancer 55, 1096–1102 (2010).

    Article  PubMed  Google Scholar 

  93. Schroit, A. J. & Fidler, I. J. Effects of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res. 42, 161–167 (1982).

    CAS  PubMed  Google Scholar 

  94. Kleinerman, E. S. et al. Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J. Clin. Oncol. 10, 1310–1316 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Sone, S. et al. Potentiating effect of muramyl dipeptide and its lipophilic analog encapsulated in liposomes on tumor cell killing by human monocytes. J. Immunol. 132, 2105–2110 (1984).

    CAS  PubMed  Google Scholar 

  96. Kansara, M. et al. Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation. J. Clin. Invest. 123, 5351–5360 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. MacEwen, E. G. et al. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J. Natl Cancer Inst. 81, 935–938 (1989).

    Article  CAS  PubMed  Google Scholar 

  98. Meyers, P. A. et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group. J. Clin. Oncol. 26, 633–638 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Chou, A. J. et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group. Cancer 115, 5339–5348 (2009). This report shows efficacy of mifamurtide in human osteosarcoma.

    Article  CAS  PubMed  Google Scholar 

  100. Johal, S. et al. Mifamurtide for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection: a cost-effectiveness analysis. Value Health 16, 1123–1132 (2013).

    Article  PubMed  Google Scholar 

  101. Kosmidis, P. A. et al. The prognostic significance of immune changes in patients with renal cell carcinoma treated with interferon alfa-2b. J. Clin. Oncol. 10, 1153–1157 (1992).

    Article  CAS  PubMed  Google Scholar 

  102. Beresford, J. N. et al. Interferons and bone. A comparison of the effects of interferon-α and interferon-γ in cultures of human bone-derived cells and an osteosarcoma cell line. Eur. J. Biochem. 193, 589–597 (1990).

    Article  CAS  PubMed  Google Scholar 

  103. Yuan, X. W. et al. Interferon-α enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis. Acta Pharmacol. Sin. 28, 1835–1841 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Masuda, S. et al. Antitumor effect of human leukocyte interferon on human osteosarcoma transplanted into nude mice. Eur. J. Cancer Clin. Oncol. 19, 1521–1528 (1983).

    Article  CAS  PubMed  Google Scholar 

  105. Strander, H. et al. Adjuvant interferon treatment in human osteosarcoma. Cancer Treat. Res. 62, 29–32 (1993).

    Article  CAS  PubMed  Google Scholar 

  106. Strander, H. Interferons and osteosarcoma. Cytokine Growth Factor Rev. 18, 373–380 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Bielack, S. S. et al. MAP plus maintenance pegylated interferon α-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 “good response” randomization. 2013 ASCO Annual Meeting, Abstract LBA10504 (2014).

  108. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012). This paper reports remarkable results with partial or complete response in advanced cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kroemer, G. et al. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Zitvogel, L. et al. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013). This paper shows that many of the conventional chemotherapeutic and targeted neoplastic agents are mediating therapeutic effects by eliciting de novo or reactivating pre-existing tumour-specific immune responses.

    Article  CAS  PubMed  Google Scholar 

  111. Champiat, S. et al. Exomics and immunogenics: Bridging mutational load and immune checkpoints efficacy. Oncoimmunology 3, e27817 (2014). This study correlates mutational load and response to immune checkpoint targeted therapies.

    Article  PubMed  PubMed Central  Google Scholar 

  112. van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–442 (2013).

    Article  PubMed  Google Scholar 

  113. He, J. et al. Association between CTLA-4 genetic polymorphisms and susceptibility to osteosarcoma in Chinese Han population. Endocrine. 45, 325–330 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Liu, Y. et al. Cytotoxic T-lymphocyte antigen-4 polymorphisms and susceptibility to osteosarcoma. DNA Cell Biol. 30, 1051–1055 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Nagamori, M. et al. Intrinsic and extrinsic manipulation of B7/CTLA-4 interaction for induction of anti-tumor immunity against osteosarcoma cells. Anticancer Res. 22, 3223–3227 (2002).

    CAS  PubMed  Google Scholar 

  116. Kawano, M. et al. Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma. Oncol. Rep. 29, 1001–1006 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Kozawa, E. et al. Suppression of tumour metastasis in a murine osteosarcoma model with anti-CD25 monoclonal antibody treatment. Anticancer Res. 30, 5019–5022 (2010).

    PubMed  Google Scholar 

  118. Zitvogel, L. & Kroemer, G. Targeting PD-1/PD-L1 interactions for cancer immunotherapy. Oncoimmunology 1, 1223–1225 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Lussier, D. M. et al. 28th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC) 162 (Society for Immunotherapy of Cancer, 2013).

    Google Scholar 

  120. Paget, C. et al. Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma. Oncoimmunology 1, 1313–1322 (2012). This paper reports the first preclinical study showing that checkpoint blockade can suppress osteosarcoma.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Melero, I. et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nature Med. 3, 682–685 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Gorlick, R. et al. Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary. Clin. Cancer Res. 9, 5442–5453 (2003).

    PubMed  Google Scholar 

  123. Bunnell, B. A. et al. New concepts on the immune modulation mediated by mesenchymal stem cells. Stem Cell Res. Ther. 1, 34 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ishida, H. et al. Expression of the SART1 tumor-rejection antigen in human osteosarcomas. Int. J. Oncol. 17, 29–32 (2000).

    CAS  PubMed  Google Scholar 

  125. Tsuda, N. et al. Expression of a newly defined tumor-rejection antigen SART3 in musculoskeletal tumors and induction of HLA class I-restricted cytotoxic T lymphocytes by SART3-derived peptides. J. Orthop. Res. 19, 346–351 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Tsukahara, T. et al. Prognostic impact and immunogenicity of a novel osteosarcoma antigen, papillomavirus binding factor, in patients with osteosarcoma. Cancer Sci. 99, 368–375 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Jacobs, J. F. et al. Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR. Int. J. Cancer 120, 67–74 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Rainusso, N. et al. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther. 19, 212–217 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Navid, F. et al. Anti-GD2 antibody therapy for GD2-expressing tumors. Curr. Cancer Drug Targets 10, 200–209 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Shibuya, H. et al. Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. Cancer Sci. 103, 1656–1664 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ahmed, M. & Cheung, N. K. Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy. FEBS Lett. 588, 288–297 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Tarek, N. et al. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J. Clin. Invest. 122, 3260–3270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gorlick, R. et al. Children's Oncology Group's 2013 blueprint for research: bone tumors. Pediatr. Blood Cancer 60, 1009–1015 (2013).

    Article  PubMed  Google Scholar 

  134. Yang, R. et al. The folate receptor α is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate. Clin. Cancer Res. 13, 2557–2567 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Schiano, C. et al. Different expression of CD146 in human normal and osteosarcoma cell lines. Med. Oncol. 29, 2998–3002 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Joyama, S. et al. Dendritic cell immunotherapy is effective for lung metastasis from murine osteosarcoma. Clin. Orthop. Relat. Res. 453, 318–327 (2006).

    Article  PubMed  Google Scholar 

  137. Chauvin, C. et al. Killer dendritic cells link innate and adaptive immunity against established osteosarcoma in rats. Cancer Res. 68, 9433–9440 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Himoudi, N. et al. Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma. Clin. Transl. Oncol. 14, 271–279 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Schwinger, W. et al. Feasibility of high-dose interleukin-2 in heavily pretreated pediatric cancer patients. Ann. Oncol. 16, 1199–1206 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Worth, L. L. et al. Intranasal therapy with an adenoviral vector containing the murine interleukin-12 gene eradicates osteosarcoma lung metastases. Clin. Cancer Res. 6, 3713–3718 (2000).

    CAS  PubMed  Google Scholar 

  141. Zhou, Z. et al. Interleukin-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma cells by enhancing its promoter activity. Mol. Cancer Res. 3, 685–691 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Lafleur, E. A. et al. Interleukin (IL)-12 and IL-12 gene transfer up-regulate Fas expression in human osteosarcoma and breast cancer cells. Cancer Res. 61, 4066–4071 (2001).

    CAS  PubMed  Google Scholar 

  143. Igney, F. H. & Krammer, P. H. Immune escape of tumors: apoptosis resistance and tumor counterattack. J. Leukoc. Biol. 71, 907–920 (2002).

    CAS  PubMed  Google Scholar 

  144. Gordon, N. & Kleinerman, E. S. The role of Fas/FasL in the metastatic potential of osteosarcoma and targeting this pathway for the treatment of osteosarcoma lung metastases. Cancer Treat. Res. 152, 497–508 (2009).

    Article  PubMed  Google Scholar 

  145. Koshkina, N. V. et al. Fas-negative osteosarcoma tumor cells are selected during metastasis to the lungs: the role of the Fas pathway in the metastatic process of osteosarcoma. Mol. Cancer Res. 5, 991–999 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Postiglione, L. et al. Effect of human granulocyte macrophage-colony stimulating factor on differentiation and apoptosis of the human osteosarcoma cell line SaOS-2. Eur. J. Histochem. 47, 309–316 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. Arndt, C. A. et al. Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free survival and immunomodulation. a report from the Children's Oncology Group. Clin. Cancer Res. 16, 4024–4030 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Huang, M. et al. Molecularly targeted cancer therapy: some lessons from the past decade. Trends Pharmacol. Sci. 35, 41–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014). This paper discusses the recent advances in DNA sequencing and its broader clinical applications.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Brown, S. D. et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 24, 743–750 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nature Med. 19, 747–752 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Hacohen, N. et al. Getting personal with neoantigen-based therapeutic cancer vaccines. Cancer Immunol. Res. 1, 11–15 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Pritchard-Jones, K. et al. Cancer in children and adolescents in Europe: developments over 20 years and future challenges. Eur. J. Cancer 42, 2183–2190 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Cotterill, S. J. et al. Stature of young people with malignant bone tumors. Pediatr. Blood Cancer 42, 59–63 (2004).

    Article  PubMed  Google Scholar 

  155. Logue, J. P. & Cairnduff, F. Radiation induced extraskeletal osteosarcoma. Br. J. Radiol. 64, 171–172 (1991).

    Article  CAS  PubMed  Google Scholar 

  156. Le Vu, B. et al. Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. Int. J. Cancer 77, 370–377 (1998).

    Article  CAS  PubMed  Google Scholar 

  157. Seton, M. Paget disease of bone: diagnosis and drug therapy. Cleve Clin. J. Med. 80, 452–462 (2013).

    Article  PubMed  Google Scholar 

  158. Smith, J. et al. Bone sarcomas in Paget disease: a study of 85 patients. Radiology 152, 583–590 (1984).

    Article  CAS  PubMed  Google Scholar 

  159. Laurin, N. et al. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70, 1582–1588 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Srivastava, S. et al. Several mutant p53 proteins detected in cancer-prone families with Li-Fraumeni syndrome exhibit transdominant effects on the biochemical properties of the wild-type p53. Oncogene 8, 2449–2456 (1993).

    CAS  PubMed  Google Scholar 

  161. Gokgoz, N. et al. Comparison of p53 mutations in patients with localized osteosarcoma and metastatic osteosarcoma. Cancer 92, 2181–2189 (2001).

    Article  CAS  PubMed  Google Scholar 

  162. Hansen, M. F. et al. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Proc. Natl Acad. Sci. USA 82, 6216–6220 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Larsen, N. B. & Hickson, I. D. RecQ Helicases: Conserved Guardians of Genomic Integrity. Adv. Exp. Med. Biol. 767, 161–184 (2013).

    Article  CAS  PubMed  Google Scholar 

  164. Wang, L. L. et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J. Natl Cancer Inst. 95, 669–674 (2003).

    Article  CAS  PubMed  Google Scholar 

  165. Wang, L. L. et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am. J. Med. Genet. 102, 11–17 (2001).

    Article  CAS  PubMed  Google Scholar 

  166. Rosen, R. S. et al. Werner's syndrome. Br. J. Radiol. 43, 193–198 (1970).

    Article  CAS  PubMed  Google Scholar 

  167. Lauper, J. M. et al. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS ONE 8, e59709 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. German, J. Bloom's syndrome. XX. The first 100 cancers. Cancer Genet. Cytogenet. 93, 100–106 (1997).

    Article  CAS  PubMed  Google Scholar 

  169. Siitonen, H. A. et al. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Hum. Mol. Genet. 12, 2837–2844 (2003).

    Article  CAS  PubMed  Google Scholar 

  170. Lonardo, F. et al. p53 and MDM2 alterations in osteosarcomas: correlation with clinicopathologic features and proliferative rate. Cancer 79, 1541–1547 (1997).

    Article  CAS  PubMed  Google Scholar 

  171. Colombo, E. A. et al. Novel physiological RECQL4 alternative transcript disclosed by molecular characterisation of Rothmund-Thomson Syndrome sibs with mild phenotype. Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2014.18 (2014).

  172. Maire, G. et al. Recurrent RECQL4 imbalance and increased gene expression levels are associated with structural chromosomal instability in sporadic osteosarcoma. Neoplasia 11, 260–268, (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Oh, J. H. et al. Aberrant methylation of p14ARF gene correlates with poor survival in osteosarcoma. Clin. Orthop. Relat. Res. 442, 216–222 (2006).

    Article  PubMed  Google Scholar 

  174. Sonaglio, V. et al. Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma. Onco Targets Ther. 6, 713–723 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Tsuchiya, T. et al. Analysis of the p16INK4, 14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma. Cancer Genet. Cytogenet. 120, 91–98 (2000).

    Article  CAS  PubMed  Google Scholar 

  176. Hou, P. et al. Quantitative analysis of promoter hypermethylation in multiple genes in osteosarcoma. Cancer 106, 1602–1609 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Entz-Werle, N. et al. Involvement of MET/TWIST/APC combination or the potential role of ossification factors in pediatric high-grade osteosarcoma oncogenesis. Neoplasia 9, 678–688 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mendoza, S. et al. Allelic loss at 10q26 in osteosarcoma in the region of the BUB3 and FGFR2 genes. Cancer Genet. Cytogenet. 158, 142–147 (2005).

    Article  CAS  PubMed  Google Scholar 

  179. Kresse, S. H. et al. LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization. Genes Chromosomes Cancer 48, 679–693 (2009).

    Article  CAS  PubMed  Google Scholar 

  180. Yen, C. C. et al. Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma. Int. J. Oncol. 35, 775–788 (2009).

    CAS  PubMed  Google Scholar 

  181. Yang, J. et al. Deletion of the WWOX gene and frequent loss of its protein expression in human osteosarcoma. Cancer Lett. 291, 31–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Freeman, S. S. et al. Copy number gains in EGFR and copy number losses in PTEN are common events in osteosarcoma tumors. Cancer 113, 1453–1461 (2008).

    Article  CAS  PubMed  Google Scholar 

  183. Chen, W. et al. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell 6, 387–398 (2004).

    Article  CAS  PubMed  Google Scholar 

  184. Rathi, A. et al. Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clin. Cancer Res. 9, 3674–3678 (2003).

    CAS  PubMed  Google Scholar 

  185. Li, Y. et al. Epigenetic regulation of the pro-apoptosis gene TSSC3 in human osteosarcoma cells. Biomed. Pharmacother. 68, 45–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  186. Lim, S. et al. Inactivation of the RASSF1A in osteosarcoma. Oncol. Rep. 10, 897–901 (2003).

    CAS  PubMed  Google Scholar 

  187. Al-Romaih, K. et al. Decitabine-induced demethylation of 5′ CpG island in GADD45A leads to apoptosis in osteosarcoma cells. Neoplasia 10, 471–480 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Kresse, S. H. et al. Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma. PLoS ONE 7, e48262 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Wei, G. et al. CDK4 gene amplification in osteosarcoma: reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons. Int. J. Cancer 80, 199–204 (1999).

    Article  CAS  PubMed  Google Scholar 

  190. Yotov, W. V. et al. Amplifications of DNA primase 1 (PRIM1) in human osteosarcoma. Genes Chromosomes Cancer 26, 62–69 (1999).

    Article  CAS  PubMed  Google Scholar 

  191. Entz-Werle, N. et al. Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas. Int. J. Cancer 117, 349–355 (2005).

    Article  CAS  PubMed  Google Scholar 

  192. van Dartel, M. et al. Amplification of 17p11.2 approximately p12, including PMP22, TOP3A, and MAPK7, in high-grade osteosarcoma. Cancer Genet. Cytogenet. 139, 91–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  193. Yang, J. et al. Correlation of WWOX, RUNX2 and VEGFA protein expression in human osteosarcoma. BMC Med. Genom. 6, 56 (2013).

    Article  CAS  Google Scholar 

  194. Yang, J. et al. Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma. Cancer 117, 4925–4938 (2011).

    Article  CAS  PubMed  Google Scholar 

  195. Lu, X. Y. et al. Cell cycle regulator gene CDC5L, a potential target for 6p12-p21 amplicon in osteosarcoma. Mol. Cancer Res. 6, 937–946 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Lockwood, W. W. et al. Cyclin E1 is amplified and overexpressed in osteosarcoma. J. Mol. Diagn. 13, 289–296 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Yan, T. et al. COPS3 amplification and clinical outcome in osteosarcoma. Cancer 109, 1870–1876 (2007).

    Article  CAS  PubMed  Google Scholar 

  198. Li, Y. et al. Changes in genomic imprinting and gene expression associated with transformation in a model of human osteosarcoma. Exp. Mol. Pathol. 84, 234–239 (2008).

    Article  CAS  PubMed  Google Scholar 

  199. Ulaner, G. A. et al. Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Hum. Mol. Genet. 12, 535–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  200. Anderson, P. M. et al. Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments. Pediatr. Blood Cancer 61, 238–244 (2014).

    Article  PubMed  Google Scholar 

  201. Strander, H. et al. Long-term adjuvant interferon treatment of human osteosarcoma. A pilot study. Acta Oncol. 34, 877–880 (1995).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors apologize to those whose work on the biology and clinical aspects of osteosarcoma have advanced the field but could not be cited owing to space limitations. The work of the authors is funded by the National Health and Medical Research Council (NHMRC), Australia. D.M.T. is supported by an NHMRC Senior Research Fellowship (1003929).

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Glossary

Metaphyseal growth plate

The wide portion of the long bone between the narrow diaphysis and the epiphysis that grows during childhood.

Osteoid

This is the organic un-mineralized portion of the bone matrix composed primarily of type I collagen that is secreted by osteoblasts prior to maturation of bone tissue.

Conventional

Conventional osteosarcomas are primary intramedullary high-grade malignant tumours in which neoplastic cells produce osteoid.

Low-grade central

Low-grade central osteosarcomas arise from the medullary cavity of bone and are composed of hypo-cellular to moderately cellular fibroblastic stroma with variable amounts of osteoid.

Periosteal

Periosteal osteosarcoma is an intermediate-grade chondroblastic osteosarcoma that occurs on the surface of the metaphysis of long bone.

Parosteal

Parosteal osteosarcoma is a low-grade tumour that originates from the outer surface of the periosteum.

Telangiectatic

Telangiectatic osteosarcoma occurs in the metaphyseal portion of the long bones. It is characterized by dilated blood-filled vascular spaces lined by malignant osteoblasts.

Chondroblastic

In chondroblastic osteosarcoma, chondroid matrix is predominant, with minimal amounts of osseous matrix.

Small cell

Small cell osteosarcoma is composed of small cells with variable degrees of osteoid production.

Periosteal surfaces

Thick membranes composed of fibrous connective tissue that wraps around all bone except for the articulating surfaces in joints.

Alternative lengthening of telomeres

(ALT). A mechanism used by 10–15% of cancer cells to counteract telomere attrition that accompanies DNA replication and finite replicative potential. ALT uses homologous recombination to maintain telomere length throughout many cell doublings in the absence of telomerase activity.

Chromothripsis

A genomic phenomenon in which a single catastrophic event results in massive genomic rearrangements and remodelling of a chromosome.

Kataegis

Kataegis is defined by patterns of localized hypermutation colocalized with regions of somatic genome rearrangements.

Quality-adjusted life years

This measure takes into account both the quantity (life expectancy) and the quality of the remaining life years generated by health care interventions.

Chimeric antigen receptors

(CARs). These are engineered receptors that consist of an antibody-derived targeting domain fused with a T cell signalling domain that, when expressed by T cells, confers T cell antigen specificity governed by the targeting domain of the CAR.

Keyhole limpet haemocyanin

(KLH). This is a large, multi-subunit metalloprotein that is found in the haemolymph of the giant keyhole limpet (Megathura crenulata), which is a type of gastropod, and is used extensively as a carrier protein to generate a substantial immune response in the production of antibodies.

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Kansara, M., Teng, M., Smyth, M. et al. Translational biology of osteosarcoma. Nat Rev Cancer 14, 722–735 (2014). https://doi.org/10.1038/nrc3838

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