Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Targeting the CXCR4/CXCL12 axis in treating epithelial ovarian cancer

Gene Therapy volume 24, pages 621–629 (2017)Cite this article

Subjects

Abstract

Ovarian carcinoma is the most crucial and difficult target for available therapeutic treatments among gynecological malignancies, and great efforts are required to find an effective solution. Molecular studies showed that the chemokine stromal cell-derived factor-1 (also known as CXCL12) and its receptor, CXCR4, are key determinants of tumor initiation, progression and metastasis in ovarian carcinomas. Hence, it is generally believed that blocking the CXCR4/CXCL12 pathway could serve as a potential therapy for patients with ovarian cancer. Herein, we investigated the role of the CXCR4/CXCL12 axis in regulating ovarian cancer progression. Using flow cytometry, a real-time PCR and western blot analyses, we showed that the chemokine receptor CXCR4 protein and mRNA were overexpressed in human epithelial ovarian cancer cell lines, and these were closely correlated with poor outcomes. Moreover, silencing CXCR4 by small hairpin RNA in HTB75 cells reduced cell proliferation, migration and invasion and significantly reduced RhoA and Rac-1/Cdc42 expressions, whereas overexpression of CXCR4 in SKOV3 cells significantly increased cell migration and markedly increased RhoA, Rac-1/Cdc42 levels. Silencing CXCR4 also led to decreased in vitro cytotoxicity of AMD3100, a specific antagonist of CXCR4, which exerts its effect upon CXCR4 expression. Remarkably, knockdown of CXCR4 in HTB75 cells led to a significantly decreased capability to form tumors in vivo, and the Ki67 proliferation index of xenograft tumors showed a dramatic reduction. Our results revealed that the CXCR4/CXCL12 pathway represents a promising therapeutic target for epithelial ovarian carcinoma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Fong MY, Kakar SS . Ovarian cancer mouse models: a summary of current models and their limitations. J Ovarian Res 2009; 2: 12.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Romero I, Bast RC Jr . Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology 2012; 153: 1593–1602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bast RC Jr, Hennessy B, Mills GB . The biology of ovarian cancer: new opportunities for translation. Nat rev Cancer 2009; 9: 415–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jiang YP, Wu XH, Shi B, Wu WX, Yin GR . Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression. Gynecol oncol 2006; 103: 226–233.

    Article  CAS  PubMed  Google Scholar 

  5. Foussat A, Balabanian K, Amara A, Bouchet-Delbos L, Durand-Gasselin I, Baleux F et al. Production of stromal cell-derived factor 1 by mesothelial cells and effects of this chemokine on peritoneal B lymphocytes. Eur j immunol 2001; 31: 350–359.

    Article  CAS  PubMed  Google Scholar 

  6. Salomonnson E, Stacer AC, Ehrlich A, Luker KE, Luker GD . Imaging CXCL12-CXCR4 signaling in ovarian cancer therapy. PloS one 2013; 8: e51500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Balkwill F . The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol 2004; 14: 171–179.

    Article  CAS  PubMed  Google Scholar 

  8. Ma M, Ye JY, Deng R, Dee CM, Chan GC . Mesenchymal stromal cells may enhance metastasis of neuroblastoma via SDF-1/CXCR4 and SDF-1/CXCR7 signaling. Cancer Lett 2011; 312: 1–10.

    Article  CAS  PubMed  Google Scholar 

  9. Li X, Ma Q, Xu Q, Liu H, Lei J, Duan W 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: 169–176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 2002; 62: 5930–5938.

    CAS  PubMed  Google Scholar 

  11. Lau BW, Kane AB . SDF1/CXCL12 is involved in recruitment of stem-like progenitor cells to orthotopic murine malignant mesothelioma spheroids. Anticancer res 2010; 30: 2153–2160.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, Cooper S et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 2003; 102: 2728–2730.

    Article  CAS  PubMed  Google Scholar 

  13. Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X 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: 4341–4351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 2007; 109: 2708–2717.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Tan XY, Chang S, Liu W, Tang HH . Silencing of CXCR4 inhibits tumor cell proliferation and neural invasion in human hilar cholangiocarcinoma. Gut Liver 2014; 8: 196–204.

    Article  CAS  PubMed  Google Scholar 

  16. Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 2012; 119: 3917–3924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. D'Alterio C, Barbieri A, Portella L, Palma G, Polimeno M, Riccio A et al. Inhibition of stromal CXCR4 impairs development of lung metastases. Cancer Immunol Immunother 2012; 61: 1713–1720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ramsey DM, McAlpine SR . Halting metastasis through CXCR4 inhibition. Bioorg Med Chem Lett 2013; 23: 20–25.

    Article  CAS  PubMed  Google Scholar 

  19. Liao YX, Fu ZZ, Zhou CH, Shan LC, Wang ZY, Yin F et al. AMD3100 reduces CXCR4-mediated survival and metastasis of osteosarcoma by inhibiting JNK and Akt, but not p38 or Erk1/2, pathways in in vitro and mouse experiments. Oncol Rep 2015; 34: 33–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Muralidharan R, Panneerselvam J, Chen A, Zhao YD, Munshi A, Ramesh R . HuR-targeted nanotherapy in combination with AMD3100 suppresses CXCR4 expression, cell growth, migration and invasion in lung cancer. Cancer Gene Ther 2015; 22: 581–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anglesio MS, Wiegand KC, Melnyk N, Chow C, Salamanca C, Prentice LM et al. Type-specific cell line models for type-specific ovarian cancer research. PloS one 2013; 8: e72162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Raman D, Baugher PJ, Thu YM, Richmond A . Role of chemokines in tumor growth. Cancer Lett 2007; 256: 137–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Akashi T, Koizumi K, Tsuneyama K, Saiki I, Takano Y, Fuse H . Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer. Cancer Sci 2008; 99: 539–542.

    Article  CAS  PubMed  Google Scholar 

  24. Koishi K, Yoshikawa R, Tsujimura T, Hashimoto-Tamaoki T, Kojima S, Yanagi H et al. Persistent CXCR4 expression after preoperative chemoradiotherapy predicts early recurrence and poor prognosis in esophageal cancer. World J Gastroenterol 2006; 12: 7585–7590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Scala S, Ottaiano A, Ascierto PA, Cavalli M, Simeone E, Giuliano P et al. Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma. Clin Cancer Res 2005; 11: 1835–1841.

    Article  CAS  PubMed  Google Scholar 

  26. Circelli L, Sciammarella C, Guadagno E, Tafuto S, del Basso de Caro M, Botti G et al. CXCR4/CXCL12/CXCR7 axis is functional in neuroendocrine tumors and signals on mTOR. Oncotarget 2016; 7: 18865–18875.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Guo J, Yu X, Gu J, Lin Z, Zhao G, Xu F et al. Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer. Tumour Biol 2016; 37: 6371–6378.

    Article  CAS  PubMed  Google Scholar 

  28. Zhu X, Bai Q, Lu Y, Lu Y, Zhu L, Zhou X et al. Expression and function of CXCL12/CXCR4/CXCR7 in thyroid cancer. Int j oncol 2016; 48: 2321–2329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Porcile C, Bajetto A, Barbero S, Pirani P, Schettini G . CXCR4 activation induces epidermal growth factor receptor transactivation in an ovarian cancer cell line. Ann NY Acad Sci 2004; 1030: 162–169.

    Article  CAS  PubMed  Google Scholar 

  30. Shen X, Wang S, Wang H, Liang M, Xiao L, Wang Z . The role of SDF-1/CXCR4 axis in ovarian cancer metastasis. J Huazhong Univ Sci Technolog Med Sci 2009; 29: 363–367.

    Article  PubMed  Google Scholar 

  31. Li K, Zhou ZY, Ji PP, Luo HS . Knockdown of beta-catenin by siRNA influences proliferation, apoptosis and invasion of the colon cancer cell line SW480. Oncol Lett 2016; 11: 3896–3900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang J, Cai J, Han F, Yang C, Tong Q, Cao T et al. Silencing of CXCR4 blocks progression of ovarian cancer and depresses canonical Wnt signaling pathway. Int J Gynecol Cancer 2011; 21: 981–987.

    Article  CAS  PubMed  Google Scholar 

  33. Song ZY, Gao ZH, Chu JH, Han XZ, Qu XJ . Downregulation of the CXCR4/CXCL12 axis blocks the activation of the Wnt/beta-catenin pathway in human colon cancer cells. Biomed Pharmacother 2015; 71: 46–52.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang H, Nan W, Wang S, Zhang T, Si H, Yang F et al. Epidermal growth factor promotes proliferation and migration of follicular outer root sheath cells via Wnt/beta-catenin signaling. Cell Physiol Biochem 2016; 39: 360–370.

    Article  CAS  PubMed  Google Scholar 

  35. Monin MB, Krause P, Stelling R, Bocuk D, Niebert S, Klemm F et al. The anthelmintic niclosamide inhibits colorectal cancer cell lines via modulation of the canonical and noncanonical Wnt signaling pathway. J Surg Res 2016; 203: 193–205.

    Article  CAS  PubMed  Google Scholar 

  36. Jing He, Zhou M, Chen X, Yue D, Yang Li, Qin G et al. Inhibition of SALL4 reduces tumorigenicity involving epithelial-mesenchymal transition via Wnt/b-catenin pathway in esophageal squamous cell carcinoma. J Exp Clin Cancer Res 2016; 35: 98.

    Article  Google Scholar 

  37. Saeki T, Mhashilkar A, Chada S, Branch C, Roth JA, Ramesh R . Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Therapy 2000; 7: 2051–2057.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant (NSC1022314B038056) from the Ministry of Science and Technology and by a special grant (TMU102AE1B17) from Taipei Medical University to CLL. We would like to thank the National RNAi Core Facility Platform located at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica (Taipei, Taiwan) for providing shRNA clones for our experiments.

Author information

Authors and Affiliations

  1. Department of Pathology, National Taiwan University, Taipei, Taiwan

    T L Mao

  2. School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    K F Fan & C L Liu

Authors
  1. T L Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K F Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C L Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C L Liu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mao, T., Fan, K. & Liu, C. Targeting the CXCR4/CXCL12 axis in treating epithelial ovarian cancer. Gene Ther 24, 621–629 (2017). https://doi.org/10.1038/gt.2017.69

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2017.69

This article is cited by

Search

Advanced search

Quick links