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Chordoma: an update on the pathophysiology and molecular mechanisms

  • Orthopedic Oncology: New Concepts and Techniques (JH Schwab, Section Editor)
  • Published:
Current Reviews in Musculoskeletal Medicine Aims and scope Submit manuscript

Abstract

Chordoma is a rare low-grade primary malignant skeletal tumor, which is presumed to derive from notochord remnants. The pathogenesis of chordoma has not been fully elucidated. However, recent advances in the molecular biology studies have identified brachyury underlying the initiation and progression of chordoma cells. More efforts have been made on accumulating evidence of the notochordal origin of chordoma, discovering signaling pathways and identifying crucial targets in chordomagenesis. In this review, we summarize the most recent research findings and focus on the pathophysiology and molecular mechanisms of chordoma.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Walcott BP, Nahed BV, Mohyeldin A, et al. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69–76.

    Article  PubMed  Google Scholar 

  2. Bjornsson J, Wold LE, Ebersold MJ, et al. Chordoma of the mobile spine. A clinicopathologic analysis of 40 patients. Cancer. 1993;71(3):735–40.

    Article  CAS  PubMed  Google Scholar 

  3. Yakkioui Y, van Overbeeke JJ, Santegoeds R, et al. Chordoma: the entity. Biochim Biophys Acta. 2014;1846(2):655–69.

    CAS  PubMed  Google Scholar 

  4. Ferraresi V, Nuzzo C, Zoccali C, et al. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer. 2010;10:22.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Casali PG, Stacchiotti S, Sangalli C, et al. Chordoma. Curr Opin Oncol. 2007;19(4):367–70.

    Article  PubMed  Google Scholar 

  6. Wiacek MP, Kaczmarek K, Sulewski A, et al. Unusual location of chordoma metastasis. Pol Orthop Traumatol. 2014;79:47–9.

    PubMed  Google Scholar 

  7. Lee SH, Ahn BK. Sacral chordoma: challenging for resection margin. Ann Coloproctol. 2014;30(3):104–5.

    Article  PubMed Central  PubMed  Google Scholar 

  8. M¨uller H, Ueber das Vorkommen von Resten der Chorda dorsalisbeiMenschennachderGeburtund ¨uber ihrVerh¨altniss zu den Gallertgeschw¨ulsten am Clivus. Zeitung F¨ur Rationelle Medizin. 1858; 2: 202.

  9. Ribbert H, Uber die Ecchondrosis Physalifora Sphenooccipitalis. Zentralblatt F¨ur Allgemeine Pathologie Und Pathologische Anatomie. 1894; 5: 457–61.

  10. Chauvel A, Taillat F, Gille O, et al. Giant vertebral notochordal rest: a new entity distinct from chordoma. Histopathology. 2005;47(6):646–9.

    Article  CAS  PubMed  Google Scholar 

  11. Choi KS, Cohn MJ, Harfe BD. Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation. Dev Dyn. 2008;237(12):3953–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Yamaguchi T, Suzuki S, Ishiiwa H, et al. Benign notochordal cell tumors: a comparative histological study of benign notochordal cell tumors, classic chordomas, and notochordal vestiges of fetal intervertebral discs. Am J Surg Pathol. 2004;28(6):756–61.

    Article  PubMed  Google Scholar 

  13. Kreshak J, Larousserie F, Picci P, et al. Difficulty distinguishing benign notochordal cell tumor from chordoma further suggests a link between them. Cancer Imaging. 2014;14:4.

    PubMed Central  PubMed  Google Scholar 

  14. Aydemir E, Bayrak OF, Sahin F, et al. Characterization of cancer stem-like cells in chordoma. J Neurosurg. 2012;116(4):810–20.

    Article  CAS  PubMed  Google Scholar 

  15. Hsu ea W. Identification of cancer stem cells in human chordoma, 27th annual meeting of th AANS/CNS section on disorders of the spine and peripheral nerves. J Neurosurg. 2011;30(3):A1–25.

    Article  Google Scholar 

  16. Feng Y, Shen JK, Hornicek FJ, et al. Genomic and epigenetic instability in chordoma: current insights. Clin Cosmet Investig Dent. 2014;6:45–56.

    Google Scholar 

  17. Le LP, Nielsen GP, Rosenberg AE, et al. Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Scheil-Bertram S, Kappler R, von Baer A, et al. Molecular profiling of chordoma. Int J Oncol. 2014;44(4):1041–55.

    PubMed Central  PubMed  Google Scholar 

  19. Kitamura Y, Sasaki H, Kimura T, et al. Molecular and clinical risk factors for recurrence of skull base chordomas: gain on chromosome 2p, expression of brachyury, and lack of irradiation negatively correlate with patient prognosis. J Neuropathol Exp Neurol. 2013;72(9):816–23.

    Article  CAS  PubMed  Google Scholar 

  20. Bayrakli F, Guney I, Kilic T, et al. New candidate chromosomal regions for chordoma development. Surg Neurol. 2007;68(4):425–30. discussion 430.

    Article  PubMed  Google Scholar 

  21. Walter BA, Begnami M, Valera VA, et al. Gain of chromosome 7 by chromogenic in situ hybridization (CISH) in chordomas is correlated to c-MET expression. J Neurooncol. 2011;101(2):199–206.

    Article  CAS  PubMed  Google Scholar 

  22. Longoni M, Orzan F, Stroppi M, et al. Evaluation of 1p36 markers and clinical outcome in a skull base chordoma study. Neuro Oncol. 2008;10(1):52–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Rinner B, Weinhaeusel A, Lohberger B, et al. Genomic instability and characteristic DNA methylation pattern in chordoma. In VIRCHOWS ARCHIV. 2013. Springer, New York.

  24. Choy E, MacConaill LE, Cote GM, et al. Genotyping cancer-associated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1. PLoS One. 2014;9(7):e101283.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Kaloostian PE, Gokaslan ZL. Understanding the cell cycle in the pathophysiology of chordomas: a molecular look. World Neurosurg. 2014;82(1–2):e135–7.

    Article  PubMed  Google Scholar 

  26. Barresi V, Ieni A, Branca G, et al. Brachyury: a diagnostic marker for the differential diagnosis of chordoma and hemangioblastoma versus neoplastic histological mimickers. Dis Markers. 2014;2014:514753.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Vujovic S, Henderson S, Presneau N, et al. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol. 2006;209(2):157–65.

    Article  CAS  PubMed  Google Scholar 

  28. Nibu Y, Jose-Edwards DS, Di Gregorio A. From notochord formation to hereditary chordoma: the many roles of brachyury. Biomed Res Int. 2013;2013:826435.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Cates JM, Itani DM, Coffin CM, et al. The sonic hedgehog pathway in chordoid tumours. Histopathology. 2010;56(7):978–9.

    Article  PubMed  Google Scholar 

  30. Kozmikova I, Candiani S, Fabian P, et al. Essential role of Bmp signaling and its positive feedback loop in the early cell fate evolution of chordates. Dev Biol. 2013;382(2):538–54.

    Article  CAS  PubMed  Google Scholar 

  31. Satoh N, Tagawa K, Takahashi H. How was the notochord born? Evol Dev. 2012;14(1):56–75.

    Article  CAS  PubMed  Google Scholar 

  32. Naka T, Boltze C, Kuester D, et al. Alterations of G1-S checkpoint in chordoma: the prognostic impact of p53 overexpression. Cancer. 2005;104(6):1255–63.

    Article  CAS  PubMed  Google Scholar 

  33. Yakkioui Y, Temel Y, Creytens D, et al. A comparison of cell-cycle markers in skull base and sacral chordomas. World Neurosurg. 2014;82(1–2):e311–8.

    Article  PubMed  Google Scholar 

  34. Wynford-Thomas D. P53 in tumour pathology: can we trust immunocytochemistry? J Pathol. 1992;166(4):329–30.

    Article  CAS  PubMed  Google Scholar 

  35. Hu Y, Mintz A, Shah SR, et al. The FGFR/MEK/ERK/brachyury pathway is critical for chordoma cell growth and survival. Carcinogenesis. 2014;35(7):1491–9.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Alholle A, Brini AT, Bauer J, et al. Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas. Epigenetics. 2015;10(3):213–20.

    Article  CAS  PubMed  Google Scholar 

  37. Kulis M, Queiros AC, Beekman R, et al. Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer. Biochim Biophys Acta. 2013;1829(11):1161–74.

    Article  CAS  PubMed  Google Scholar 

  38. Marucci G, Morandi L, Mazzatenta D, et al. MGMT promoter methylation status in clival chordoma. J Neurooncol. 2014;118(2):271–6.

    Article  CAS  PubMed  Google Scholar 

  39. Long C, Jiang L, Wei F, et al. Integrated miRNA-mRNA analysis revealing the potential roles of miRNAs in chordomas. PLoS One. 2013;8(6):e66676.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Duan Z, Shen J, Yang X, et al. Prognostic significance of miRNA-1 (miR-1) expression in patients with chordoma. J Orthop Res. 2014;32(5):695–701.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Duan Z, Choy E, Nielsen GP, et al. Differential expression of microRNA (miRNA) in chordoma reveals a role for miRNA-1 in Met expression. J Orthop Res. 2010;28(6):746–52.

    CAS  PubMed  Google Scholar 

  42. Bayrak OF, Gulluoglu S, Aydemir E, et al. MicroRNA expression profiling reveals the potential function of microRNA-31 in chordomas. J Neurooncol. 2013;115(2):143–51.

    Article  CAS  PubMed  Google Scholar 

  43. Zou MX, Huang W, Wang XB, et al. Identification of miR-140-3p as a marker associated with poor prognosis in spinal chordoma. Int J Clin Exp Pathol. 2014;7(8):4877–85.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Zhang Y, Schiff D, Park D, et al. MicroRNA-608 and microRNA-34a regulate chordoma malignancy by targeting EGFR, Bcl-xL and MET. PLoS One. 2014;9(3):e91546.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Osaka E, Kelly AD, Spentzos D, et al. MicroRNA-155 expression is independently predictive of outcome in chordoma. Oncotarget. 2015;6(11):9125–39.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Zou MX, Huang W, Wang XB, et al., Reduced expression of miRNA-1237-3p associated with poor survival of spinal chordoma patients. Eur Spine J. 2015.

  47. Heymann D, Redini F. Targeted therapies for bone sarcomas. Bonekey Rep. 2013;2:378.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Tamborini E, Miselli F, Negri T, et al. Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas. Clin Cancer Res. 2006;12(23):6920–8.

    Article  CAS  PubMed  Google Scholar 

  49. Tamborini E, Virdis E, Negri T, et al. Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. Neuro-Oncol. 2010;12(8):776–89.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. de Castro CV, Guimaraes G, Aguiar Jr S, et al. Tyrosine kinase receptor expression in chordomas: phosphorylated AKT correlates inversely with outcome. Hum Pathol. 2013;44(9):1747–55.

    Article  PubMed  Google Scholar 

  51. Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res. 2011;1(1):4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Siu IM, Ruzevick J, Zhao Q, et al. Erlotinib inhibits growth of a patient-derived chordoma xenograft. PLoS One. 2013;8(11):e78895.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Schwab J, Antonescu C, Boland P, et al. Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma. Anticancer Res. 2009;29(6):1867–71.

    CAS  PubMed  Google Scholar 

  54. Chen K, Mo J, Zhou M, et al. Expression of PTEN and mTOR in sacral chordoma and association with poor prognosis. Med Oncol. 2014;31(4):886.

    Article  PubMed  Google Scholar 

  55. Burger A, Vasilyev A, Tomar R, et al. A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12. Dis Model Mech. 2014;7(7):907–13.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Davies JM, Robinson AE, Cowdrey C, et al. Generation of a patient-derived chordoma xenograft and characterization of the phosphoproteome in a recurrent chordoma. J Neurosurg. 2014;120(2):331–6.

    Article  PubMed  Google Scholar 

  57. Karikari IO, Gilchrist CL, Jing L, et al. Molecular characterization of chordoma xenografts generated from a novel primary chordoma cell source and two chordoma cell lines. J Neurosurg Spine. 2014;21(3):386–93.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Siu IM, Salmasi V, Orr BA, et al. Establishment and characterization of a primary human chordoma xenograft model. J Neurosurg. 2012;116(4):801–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Trucco MM, Awad O, Wilky BA, et al. A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-kappaB signaling in chordoma biology. PLoS One. 2013;8(11):e79950.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Section of Orthopedic Oncology, Department of Orthopedic Surgery, Harvard Medical School, Massachusetts General Hospital, Yawkey 355 Fruit Street, Boston, MA, 02114, USA

    Xin Sun, Francis Hornicek & Joseph H. Schwab

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  1. Xin Sun
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  2. Francis Hornicek
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  3. Joseph H. Schwab
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Correspondence to Joseph H. Schwab.

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Conflict of interest

Dr. Schwab has been a consultant for Stryker, Biom’up, and Synthes, plus a speaker for Synthes. Dr. Sun and Dr. Hornicek have nothing to disclose.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Orthopedic Oncology: New Concepts and Techniques

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Sun, X., Hornicek, F. & Schwab, J.H. Chordoma: an update on the pathophysiology and molecular mechanisms. Curr Rev Musculoskelet Med 8, 344–352 (2015). https://doi.org/10.1007/s12178-015-9311-x

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