Medical Oncology

, 32:194 | Cite as

SDF-1/CXCR4 promotes F5M2 osteosarcoma cell migration by activating the Wnt/β-catenin signaling pathway

  • Yao Lu
  • Bin Hu
  • Guo-Feng Guan
  • Jie Chen
  • Chun-qiu Wang
  • Qiong Ma
  • Yan-Hua Wen
  • Xiu-Chun Qiu
  • Xiao-ping ZhangEmail author
  • Yong ZhouEmail author
Original Paper


Osteosarcoma (OS), the most common primary malignant bone tumor in children and adolescents, lacks an effective therapy. Stromal cell-derived factor (SDF-1) and its receptor, CXCR4, play multiple roles in migration, proliferation, and survival of different tumor cells. This study aimed to investigate whether the functional SDF-1/CXCR4 signaling mediates chemotaxis in F5M2 OS cells as well as the underlying mechanisms. Immunohistochemistry and immunofluorescence microscopy were used. RNA expression was detected by real-time quantitative polymerase chain reaction, and protein expression was examined by Western blotting. Migration assays were carried out in F5M2 cells. The results showed that the expression of CXCR4 and β-catenin mRNA and protein was significantly higher in OS tissues compared to the surrounding non-neoplastic tissues. SDF-1 promoted F5M2 cell migration by activating the AKT and Wnt/β-catenin signaling pathway, which was abrogated by preincubation with AMD3100 and LY294002. In conclusion, SDF-1/CXCR4 axis-promoted F5M2 cell migration was regulated by the Wnt/β-catenin signaling pathway.


Osteosarcoma SDF-1 CXCR4 Wnt/β-catenin Metastasis 



This study was supported by the National Natural Science Foundation of China (Nos. 81272441, 81201633, 81372297).

Conflict of interest

The authors declare that there is no conflict of interest in this study.


  1. 1.
    Link MP. Osteosarcoma in adolescents and young adults: new developments and controversies. Commentary on the use of presurgical chemotherapy. Cancer Treat Res. 1993;62:383–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer. 2009;115:1531–43.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.PubMedCrossRefGoogle Scholar
  4. 4.
    Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000;18:4016–27.PubMedGoogle Scholar
  5. 5.
    Arndt CA, Rose PS, Folpe AL, Laack NN. Common musculoskeletal tumors of childhood and adolescence. Mayo Clin Proc. 2012;87:475–87.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Ferguson WS, Goorin AM. Current treatment of osteosarcoma. Cancer Invest. 2001;19:292–315.PubMedCrossRefGoogle Scholar
  7. 7.
    Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010;16:2927–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Muller A, Homey B, Soto H, Ge N, Catron D, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000;18:217–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Douglass S, Meeson AP, Overbeck-Zubrzycka D, Brain JG, Bennett MR, et al. Breast cancer metastasis: demonstration that FOXP3 regulates CXCR4 expression and the response to CXCL12. J Pathol. 2014;234:74–85.PubMedCrossRefGoogle Scholar
  11. 11.
    Kim SY, Lee CH, Midura BV, Yeung C, Mendoza A, et al. Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis. 2008;25:201–11.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Portella L, Vitale R, De Luca S, D’Alterio C, Ierano C, et al. Preclinical development of a novel class of CXCR4 antagonist impairing solid tumors growth and metastases. PLoS ONE. 2013;8:e74548.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Baumhoer D, Smida J, Zillmer S, Rosemann M, Atkinson MJ, et al. Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. Mod Pathol. 2012;25:522–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Huang CY, Lee CY, Chen MY, Yang WH, Chen YH, et al. Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-kappaB-dependent pathways. J Cell Physiol. 2009;221:204–12.PubMedCrossRefGoogle Scholar
  15. 15.
    McQueen P, Ghaffar S, Guo Y, Rubin EM, Zi X, Hoang BH. The Wnt signaling pathway: implications for therapy in osteosarcoma. Expert Rev Anticancer Ther. 2011;11:1223–32.PubMedCrossRefGoogle Scholar
  16. 16.
    Zi X, Guo Y, Simoneau AR, Hope C, Xie J, et al. Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness. Cancer Res. 2005;65:9762–70.PubMedCrossRefGoogle Scholar
  17. 17.
    Mohinta S, Wu H, Chaurasia P, Watabe K. Wnt pathway and breast cancer. Front Biosci. 2007;12:4020–33.PubMedCrossRefGoogle Scholar
  18. 18.
    Najdi R, Holcombe RF, Waterman ML. Wnt signaling and colon carcinogenesis: beyond APC. J Carcinog. 2011;10:5.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Ma Y, Ren Y, Han EQ, Li H, Chen D, et al. Inhibition of the Wnt-beta-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochem Biophys Res Commun. 2013;431:274–9.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Hu TH, Yao Y, Yu S, Han LL, Wang WJ, et al. SDF-1/CXCR4 promotes epithelial–mesenchymal transition and progression of colorectal cancer by activation of the Wnt/beta-catenin signaling pathway. Cancer Lett. 2014;354:417–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Holland JD, Gyorffy B, Vogel R, Eckert K, Valenti G, et al. Combined Wnt/beta-catenin, Met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome. Cell Rep. 2013;5:1214–27.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen X, Yang TT, Wang W, Sun HH, Ma BA, et al. Establishment and characterization of human osteosarcoma cell lines with different pulmonary metastatic potentials. Cytotechnology. 2009;61:37–44.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Osaki M, Takeshita F, Sugimoto Y, Kosaka N, Yamamoto Y, et al. MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Mol Ther. 2011;19:1123–30.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kong W, He L, Coppola M, Guo J, Esposito NN, et al. MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. J Biol Chem. 2010;285:17869–79.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Han K, Zhao T, Chen X, Bian N, Yang T, et al. microRNA-194 suppresses osteosarcoma cell proliferation and metastasis in vitro and in vivo by targeting CDH2 and IGF1R. Int J Oncol. 2014;45:1437–49.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Carloni V, Pinzani M, Giusti S, Romanelli RG, Parola M, et al. Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in human hepatic stellate cells. Hepatology. 2000;31:131–40.PubMedCrossRefGoogle Scholar
  27. 27.
    Li X, Ma Q, Xu Q, Liu H, Lei J, et al. SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial–mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett. 2012;322:169–76.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Guo M, Cai C, Zhao G, Qiu X, Zhao H, et al. Hypoxia promotes migration and induces CXCR4 expression via HIF-1alpha activation in human osteosarcoma. PLoS ONE. 2014;9:e90518.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Cai Y, Mohseny AB, Karperien M, Hogendoorn PC, Zhou G, Cleton-Jansen AM. Inactive Wnt/beta-catenin pathway in conventional high-grade osteosarcoma. J Pathol. 2010;220:24–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–205.PubMedCrossRefGoogle Scholar
  31. 31.
    Shen X, Artinyan A, Jackson D, Thomas RM, Lowy AM, Kim J. Chemokine receptor CXCR4 enhances proliferation in pancreatic cancer cells through AKT and ERK dependent pathways. Pancreas. 2010;39:81–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Wang L, Li CL, Wang L, Yu WB, Yin HP, et al. Influence of CXCR4/SDF-1 axis on E-cadherin/beta-catenin complex expression in HT29 colon cancer cells. World J Gastroenterol. 2011;17:625–32.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Gentilini A, Rombouts K, Galastri S, Caligiuri A, Mingarelli E, et al. Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma. J Hepatol. 2012;57:813–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood. 2009;113:4341–51.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yao Lu
    • 1
  • Bin Hu
    • 2
  • Guo-Feng Guan
    • 1
  • Jie Chen
    • 1
  • Chun-qiu Wang
    • 3
  • Qiong Ma
    • 1
  • Yan-Hua Wen
    • 1
  • Xiu-Chun Qiu
    • 1
  • Xiao-ping Zhang
    • 1
    Email author
  • Yong Zhou
    • 1
    Email author
  1. 1.Department of Orthopaedic Surgery, Tangdu HospitalThe Fourth Military Medical UniversityXi’anChina
  2. 2.Department of Haematology, Tangdu HospitalThe Fourth Military Medical UniversityXi’anChina
  3. 3.Department of Orthopedic Surgery359 Hospital of Chinese PLAZhenjiangChina

Personalised recommendations