Skip to main content

Advertisement

SpringerLink
Log in

Osteosarcoma metastasis: prospective role of ezrin

  • Review
  • Published:
Tumor Biology

Abstract

Osteosarcoma is the most commonly diagnosed primary malignant bone tumor, with similar global incidence rate across childhood and adolescence. Patients with localized disease have a 5-year survival period of 80 %; however, the prognosis is poor in those with metastatic osteosarcoma. The origin of the primary tumor is most frequently the metaphyseal (actively growing) regions of the distal femur, proximal tibia, and proximal humerus, although the tumor can develop in any bone, and the most likely sites for metastasis are the lungs and bone. Ezrin is a member of the ezrin-radixin-moesin (ERM) family of proteins that functions as a cross-linker between the actin cytoskeleton and the plasma membrane, and ezrin also plays a positive role in maintaining cell shape and polarity and facilitates membrane-trafficking pathways, cell migration, cell signaling, growth regulation, and differentiation. There is strong evidence to suggest that ezrin is necessary for osteosarcoma metastasis. The objective of the current review is to summarize the know-how about metastatic progression in osteosarcoma, with a focus on ezrin. Despite the promise that preliminary studies on ezrin have shown, there is a great need to further analyze the role of ezrin in osteosarcoma metastasis and to determine its usefulness as a biomarker for the disease.

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

Similar content being viewed by others

References

  1. Damron TA, Ward WG, Stewart A. Osteosarcoma, chrondrosarcoma, and Ewing’s sarcoma. National Cancer Data Base Report. Clin Orthop Relat Res. 2007;459:40–7.

    Article  PubMed  Google Scholar 

  2. Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries LA, Smith MA, Gurney JG, et al., editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995 (Pub #99-4649). Bethesda, MD: SEER program, National Cancer Institute; 1999. p. 99–110.

    Google Scholar 

  3. Marcove RC, Mike V, Hajack JV, Levin AG, Hutter RV. Osteogenic sarcoma under the age of twenty-one. A review of one hundred and forty-five operative cases. J Bone Joint Surg. 1970;52:411–23.

    CAS  PubMed  Google Scholar 

  4. McKenna RJ, Schwinn CP, Soonh KY, Higinbotham N. Sarcomata of osteogenic series (osteosarcoma, fibrosarcoma, chondrosarcoma, parosteal osteosarcoma, and sarcomata arising in abnormal bone): an analysis of 552 cases. J Bone Joint Surg. 1966;48-A:1–26.

    Google Scholar 

  5. Wittig JC, Bickels J, Priebat D, Jelinek J, Kellar-Graney K, Shmookler B, et al. Osteosarcoma: a multidisciplinary approach to diagnosis and treatment. Am Fam Physician. 2002;65(1123–1132):1135–6.

    Google Scholar 

  6. Bianco P, Riminucci M, Gronthos S, Robey P. Bone marrow stromal cells: nature, biology and potential applications. Stem Cells. 2001;19:180–92.

    Article  CAS  PubMed  Google Scholar 

  7. Bickels J, Jelinek BM, Shmookler BM, Neff RS, Malawar MM. Biopsy of musculoskeletal tumors. Current concepts. Clin Orthop Relat Res. 1999;368:212–9.

    PubMed  Google Scholar 

  8. Huth JF, Eilber FR. Patterns of recurrence after resection of osteosarcoma of the extremity. Strategies for treatment of metastases. Arch Surg. 1989;124:122–6.

    Article  CAS  PubMed  Google Scholar 

  9. Meyers PA, Heller G, Healey JH, Huvos A, Applewhite A, Sun M, et al. Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol. 1993;11:449–53.

    CAS  PubMed  Google Scholar 

  10. Rubert CK, Malawer MM, Kellar KL. Modular endoprosthetic replacement of the proximal humerus: indications, surgical technique, and results. Semin Arthroplast. 1999;10:142–53.

    Google Scholar 

  11. Malawer MM, Chou LB. Prosthetic survival and clinical results with use of large segment replacements in the treatment of high-grade bone sarcomas. J Bone Joint Surg. 1995;77:1154–65.

    CAS  PubMed  Google Scholar 

  12. Bacci G, Picci P, Briccoli A, Avella M, Ferrari S, Femino FP, et al. Osteosarcoma of the extremity metastatic at presentation: results achieved in 26 patients treated with combined therapy (primary chemotherapy followed by simultaneous resection of the primary and metastatic lesions). Tumori. 1992;78:200–6.

    CAS  PubMed  Google Scholar 

  13. Bohndorf K, Reiser M, Lochner B, Feaux de Lacroix W, Steinbrich W. Magnetic resonance imaging of primary tumours and tumour-like lesions of bone. Skelet Radiol. 1986;15:511–7.

    Article  CAS  Google Scholar 

  14. Sundaram M, McGuire MH, Herbold DR. Magnetic resonance imaging of osteosarcoma. Skelet Radiol. 1987;16:23–9.

    Article  CAS  Google Scholar 

  15. Belli L, Scholl S, Livartowski A, Ashby M, Palangie T, Levasseur P, et al. Resection of pulmonary metastases in osteosarcoma. A retrospective analysis of 44 patients. Cancer. 1989;63:2546–50.

    Article  CAS  PubMed  Google Scholar 

  16. Enneking W, Spanier S, Goodman M. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop. 1980;153:106–20.

    PubMed  Google Scholar 

  17. Mialou V, Philip T, Kalifa C, Perol D, Gentet JC, Marec-Berard P, et al. Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome—the French pediatric experience. Cancer. 2005;104:1100–9.

    Article  PubMed  Google Scholar 

  18. Khanna C, Khan J, Nguyen P, et al. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res. 2001;61:3750–9.

    CAS  PubMed  Google Scholar 

  19. Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002;3:586–99.

    Article  CAS  PubMed  Google Scholar 

  20. Khanna C, Wan X, Bose S, et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10:182–6.

    Article  CAS  PubMed  Google Scholar 

  21. Tsukita S, Yonemura S. ERM family: from cytoskeleton to signal transduction. Curr Opin Cell Biol. 1997;9:70–5.

    Article  CAS  PubMed  Google Scholar 

  22. Curto M, McClatchey AI. Ezrin a metastatic determinant? Cancer Cell. 2004;5:113–4.

    Article  CAS  PubMed  Google Scholar 

  23. McClatchey AI. Merlin and ERM proteins: unappreciated roles in cancer development? Nat Rev Cancer. 2003;3:877–82.

    Article  PubMed  Google Scholar 

  24. Yu Y, Khan J, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med. 2004;10:175–81.

    Article  CAS  PubMed  Google Scholar 

  25. Gautreau A, Poullet P, Louvard D, Arpin M. Ezrin, a plasma membrane microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96:7300–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ward Y, Wang W, Woodhouse E, Linnoila I, Liotta L, Kelly K. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Mol Cell Biol. 2001;21:5958–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Fukaya Y, Ishiguro N, Senga T, et al. A role for PI3K-Akt signaling in pulmonary metastatic nodule formation of the osteosarcoma cell line, LM8. Oncol Rep. 2005;14:847–52.

    CAS  PubMed  Google Scholar 

  28. Martin TA, Harrison G, Mansel RE, Jiang WG. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol. 2003;46:165–86.

    Article  PubMed  Google Scholar 

  29. Peng TS, Qiu JS, Wu HX, Liang HZ, Luo CQ. Expressions of CD44s, MMP-9, and Ki-67: possible association with invasion, metastasis, and recurrence of osteosarcoma. Ai Zheng. 2002;21:745–50.

    PubMed  Google Scholar 

  30. Crepaldi T, Gautreau A, Comoglio PM, Louvard D, Arpin M. Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells. J Cell Biol. 1997;138:423–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003;22:309–25.

    Article  CAS  PubMed  Google Scholar 

  32. Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev. 2002;16:3074–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Pujuguet P, Del Maestro L, Gautreau A, Louvard D, Arpin M. Ezrin regulates E-cadherin-dependent adherens junction assembly through Rac1 activation. Mol Biol Cell. 2003;14:2181–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Tsukita S, Oishi K, Sato N, Sagara J, Kawai A, Tsukita S. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol. 1994;126:391–401.

    Article  CAS  PubMed  Google Scholar 

  35. Xu Y, Yu Q. E-cadherin negatively regulates CD44-hyaluronan interaction and CD44-mediated tumor invasion and branching morphogenesis. J Biol Chem. 2003;278:8661–8.

    Article  CAS  PubMed  Google Scholar 

  36. Vo HP, Lee MK, Crowe DL. Α2β1 integrin signaling via the mitogen activated protein kinase pathway modulates retinoic acid-dependent tumor cell invasion and transcriptional downregulation of matrix metalloproteinase 9 activity. Int J Oncol. 1998;13:1127–34.

    CAS  PubMed  Google Scholar 

  37. Hunter KW. Ezrin, a key component in tumor metastasis. Trends Mol Med. 2004;10:201–4.

    Article  CAS  PubMed  Google Scholar 

  38. Park HR, Jung WW, Bacchini P, Bertoni F, Kim YW, Park YK. Ezrin in osteosarcoma: comparison between conventional high-grade and central low-grade osteosarcoma. Pathol Res Pract. 2006;202:509–15.

    Article  CAS  PubMed  Google Scholar 

  39. Weng WH, Ahlén J, Aström K, Lui WO, Larsson C. Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas. Clin Cancer Res. 2005;11:6198–204.

    Article  CAS  PubMed  Google Scholar 

  40. Wan X, Mendoza A, Khanna C, Helman L. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res. 2005;65:2406–11.

    Article  CAS  PubMed  Google Scholar 

  41. Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 1995;377:441–6.

    Article  CAS  PubMed  Google Scholar 

  42. Brown EJ, Schreiber SL. A signaling pathway to translational control. Cell. 1996;86:517–20.

    Article  CAS  PubMed  Google Scholar 

  43. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128–35.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

None.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Orthopedics, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, No. 141 Tianjin Road, Huangshi City, 435000, Hubei Province, China

    Yuanjin Zhang, Ling Zhang, Guofu Zhang, Songbai Li, Jun Duan, Jie Cheng, Guozhen Ding & Chibing Zhou

  2. Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Huangshi City, Hubei Province, China

    Jie Zhang, Pengcheng Luo, Dongbing Cai, Lianghong Kuang, Yichun Zhou, Liqun Tong, Xiangdong Yu, Lifang Zhang, Lijun Xu, Li Yu, Xiaomei Shi & Aihong Ke

Authors
  1. Yuanjin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guofu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Songbai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guozhen Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chibing Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pengcheng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dongbing Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lianghong Kuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yichun Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Liqun Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xiangdong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lifang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Lijun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Li Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Xiaomei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Aihong Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuanjin Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Zhang, L., Zhang, G. et al. Osteosarcoma metastasis: prospective role of ezrin. Tumor Biol. 35, 5055–5059 (2014). https://doi.org/10.1007/s13277-014-1799-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-1799-y

Keywords

Search

Navigation