Skip to main content

Advertisement

SpringerLink
Log in

High expression of CXCR3 is an independent prognostic factor in glioblastoma patients that promotes an invasive phenotype

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Chemokines are a superfamily of small heparin-binding cytokines that induce leukocytes to migrate to sites of inflammation or injury through interacting with specific transmembrane G protein-coupled receptors. Currently, attention is focused on chemokine/chemokine receptor pairs and their ability to promote tumor cell migration and angiogenesis. The chemokine receptor CXCR3 is involved in tumor metastasis and is used as a prognostic biomarker. However, its relationship with the clinicopathological features of primary glioblastoma multiforme (pGBM) and its potential prognostic value have yet to be investigated. Here, we report that high CXCR3 expression conferred poor survival in pGBM patients. Further analysis showed that CXCR3 served as an independent prognostic biomarker for pGBM patients. In addition, functional assays indicated that CXCR3 induced glioma cell invasion. Therefore, this evidence indicates CXCR3 is an independent prognostic factor for pGBM patients and promotes an invasive phenotype, which suggests a new potential biotarget for glioblastoma multiforme therapy.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Okumus NO, Gursel B, Meydan D, Ozdemir O, Odabas E, Gonullu G (2012) Prognostic significance of concomitant radiotherapy in newly diagnosed glioblastoma multiforme: a multivariate analysis of 116 patients. Ann Saudi Med 32(3):250–255. doi:10.5144/0256-4947.2012.250

    PubMed  Google Scholar 

  2. Drappatz J, Norden AD, Wen PY (2009) Therapeutic strategies for inhibiting invasion in glioblastoma. Expert Rev Neurother 9(4):519–534. doi:10.1586/ern.09.10

    Article  PubMed  Google Scholar 

  3. Demuth T, Berens ME (2004) Molecular mechanisms of glioma cell migration and invasion. J Neurooncol 70(2):217–228. doi:10.1007/s11060-004-2751-6

    Article  PubMed  Google Scholar 

  4. Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64(4):458–478. doi:10.1007/s00018-007-6342-5

    Article  CAS  PubMed  Google Scholar 

  5. Mikheeva SA, Mikheev AM, Petit A, Beyer R, Oxford RG, Khorasani L, Maxwell JP, Glackin CA, Wakimoto H, Gonzalez-Herrero I, Sanchez-Garcia I, Silber JR, Horner PJ, Rostomily RC (2010) TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Mol Cancer 9:194. doi:10.1186/1476-4598-9-194

    Article  PubMed Central  PubMed  Google Scholar 

  6. Thomas SL, Alam R, Lemke N, Schultz LR, Gutierrez JA, Rempel SA (2010) PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling. Neuro Oncology 12(9):941–955. doi:10.1093/neuonc/noq048

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Fulton AM (2009) The chemokine receptors CXCR4 and CXCR3 in cancer. Curr Oncol Rep 11(2):125–131

    Article  CAS  PubMed  Google Scholar 

  8. Asadi-Moghaddam K, Chiocca EA, Lawler SE (2010) Potential role of miRNAs and their inhibitors in glioma treatment. Expert Rev Anticancer Ther 10(11):1753–1762. doi:10.1586/era.10.168

    Article  CAS  PubMed  Google Scholar 

  9. Yan W, Zhang W, Sun L, Liu Y, You G, Wang Y, Kang C, You Y, Jiang T (2011) Identification of MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiforme. Brain Res 1411:108–115. doi:10.1016/j.brainres.2011.07.002

    CAS  PubMed  Google Scholar 

  10. Tanaka T, Bai Z, Srinoulprasert Y, Yang BG, Hayasaka H, Miyasaka M (2005) Chemokines in tumor progression and metastasis. Cancer Sci 96(6):317–322. doi:10.1111/j.1349-7006.2005.00059.x

    Article  CAS  PubMed  Google Scholar 

  11. Zlotnik A (2006) Chemokines and cancer. Int J Cancer 119(9):2026–2029. doi:10.1002/ijc.22024

    Article  CAS  PubMed  Google Scholar 

  12. Kawada K, Sonoshita M, Sakashita H, Takabayashi A, Yamaoka Y, Manabe T, Inaba K, Minato N, Oshima M, Taketo MM (2004) Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes. Cancer Res 64(11):4010–4017. doi:10.1158/0008-5472.CAN-03-1757

    Article  CAS  PubMed  Google Scholar 

  13. Kawada K, Hosogi H, Sonoshita M, Sakashita H, Manabe T, Shimahara Y, Sakai Y, Takabayashi A, Oshima M, Taketo MM (2007) Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Oncogene 26(32):4679–4688. doi:10.1038/sj.onc.1210267

    Article  CAS  PubMed  Google Scholar 

  14. Ma X, Norsworthy K, Kundu N, Rodgers WH, Gimotty PA, Goloubeva O, Lipsky M, Li Y, Holt D, Fulton A (2009) CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model. Mol Cancer Ther 8(3):490–498. doi:10.1158/1535-7163.MCT-08-0485

    Article  CAS  PubMed  Google Scholar 

  15. Walser TC, Rifat S, Ma X, Kundu N, Ward C, Goloubeva O, Johnson MG, Medina JC, Collins TL, Fulton AM (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res 66(15):7701–7707. doi:10.1158/0008-5472.CAN-06-0709

    Article  CAS  PubMed  Google Scholar 

  16. Pradelli E, Karimdjee-Soilihi B, Michiels JF, Ricci JE, Millet MA, Vandenbos F, Sullivan TJ, Collins TL, Johnson MG, Medina JC, Kleinerman ES, Schmid-Alliana A, Schmid-Antomarchi H (2009) Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs. Int J Cancer 125(11):2586–2594. doi:10.1002/ijc.24665

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Cambien B, Karimdjee BF, Richard-Fiardo P, Bziouech H, Barthel R, Millet MA, Martini V, Birnbaum D, Scoazec JY, Abello J, Al Saati T, Johnson MG, Sullivan TJ, Medina JC, Collins TL, Schmid-Alliana A, Schmid-Antomarchi H (2009) Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism. Br J Cancer 100(11):1755–1764. doi:10.1038/sj.bjc.6605078

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Wu Z, Han X, Yan J, Pan Y, Gong J, Di J, Cheng Z, Jin Z, Wang Z, Zheng Q, Wang Y (2012) The prognostic significance of chemokine receptor CXCR3 expression in colorectal carcinoma. Biomed Pharmacother 66(5):373–377. doi:10.1016/j.biopha.2011.12.003

    Article  CAS  PubMed  Google Scholar 

  19. Klatte T, Seligson DB, Leppert JT, Riggs SB, Yu H, Zomorodian N, Kabbinavar FF, Strieter RM, Belldegrun AS, Pantuck AJ (2008) The chemokine receptor CXCR3 is an independent prognostic factor in patients with localized clear cell renal cell carcinoma. J Urol 179(1):61–66. doi:10.1016/j.juro.2007.08.148

    Article  PubMed  Google Scholar 

  20. Maru SV, Holloway KA, Flynn G, Lancashire CL, Loughlin AJ, Male DK, Romero IA (2008) Chemokine production and chemokine receptor expression by human glioma cells: role of CXCL10 in tumour cell proliferation. J Neuroimmunol 199(1–2):35–45. doi:10.1016/j.jneuroim.2008.04.029

    Article  CAS  PubMed  Google Scholar 

  21. Liu C, Luo D, Reynolds BA, Meher G, Katritzky AR, Lu B, Gerard CJ, Bhadha CP, Harrison JK (2011) Chemokine receptor CXCR3 promotes growth of glioma. Carcinogenesis 32(2):129–137. doi:10.1093/carcin/bgq224

    Article  PubMed Central  PubMed  Google Scholar 

  22. Honeth G, Staflin K, Kalliomaki S, Lindvall M, Kjellman C (2006) Chemokine-directed migration of tumor-inhibitory neural progenitor cells towards an intracranially growing glioma. Exp Cell Res 312(8):1265–1276. doi:10.1016/j.yexcr.2005.12.018

    Article  CAS  PubMed  Google Scholar 

  23. Sun L, Yan W, Wang Y, Sun G, Luo H, Zhang J, Wang X, You Y, Yang Z, Liu N (2011) MicroRNA-10b induces glioma cell invasion by modulating MMP-14 and uPAR expression via HOXD10. Brain Res 1389:9–18. doi:10.1016/j.brainres.2011.03.013

    Article  CAS  PubMed  Google Scholar 

  24. Zhang JP, Lu WG, Ye F, Chen HZ, Zhou CY, Xie X (2007) Study on CXCR4/SDF-1alpha axis in lymph node metastasis of cervical squamous cell carcinoma. Int J Gynecol Cancer 17(2):478–483. doi:10.1111/j.1525-1438.2007.00786.x

    Article  PubMed  Google Scholar 

  25. Koizumi K, Hojo S, Akashi T, Yasumoto K, Saiki I (2007) Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Sci 98(11):1652–1658. doi:10.1111/j.1349-7006.2007.00606.x

    Article  CAS  PubMed  Google Scholar 

  26. Vandercappellen J, Van Damme J, Struyf S (2008) The role of CXC chemokines and their receptors in cancer. Cancer Lett 267(2):226–244. doi:10.1016/j.canlet.2008.04.050

    Article  CAS  PubMed  Google Scholar 

  27. Robledo MM, Bartolome RA, Longo N, Rodriguez-Frade JM, Mellado M, Longo I, van Muijen GN, Sanchez-Mateos P, Teixido J (2001) Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. J Biol Chem 276(48):45098–45105. doi:10.1074/jbc.M106912200

    Article  CAS  PubMed  Google Scholar 

  28. Monteagudo C, Martin JM, Jorda E, Llombart-Bosch A (2007) CXCR3 chemokine receptor immunoreactivity in primary cutaneous malignant melanoma: correlation with clinicopathological prognostic factors. J Clin Pathol 60(6):596–599. doi:10.1136/jcp.2005.032144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Wu Q, Dhir R, Wells A (2012) Altered CXCR3 isoform expression regulates prostate cancer cell migration and invasion. Mol Cancer 11:3. doi:10.1186/1476-4598-11-3

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Jones D, Benjamin RJ, Shahsafaei A, Dorfman DM (2000) The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. Blood 95(2):627–632

    CAS  PubMed  Google Scholar 

  31. Flynn G, Maru S, Loughlin J, Romero IA, Male D (2003) Regulation of chemokine receptor expression in human microglia and astrocytes. J Neuroimmunol 136(1–2):84–93

    Article  CAS  PubMed  Google Scholar 

  32. Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, Porcile C, Ravetti JL, Zona G, Spaziante R, Corte G, Schettini G, Florio T (2006) Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int 49(5):423–432. doi:10.1016/j.neuint.2006.03.003

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by National Natural Science Foundation of China (Grant Nos. 81302183, 81302200). Natural Science Foundation of Jiangsu Province (Grant No. BK20141099).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China

    Yi Pu, Zhengxiang Yang & Lihua Sun

  2. Department of Neurosurgery, Beijing San Bo Brain Hospital, Capital Medical University, Beijing, China

    Shouwei Li

  3. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Chuanbao Zhang & Zhaoshi Bao

Authors
  1. Yi Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shouwei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chuanbao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhaoshi Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhengxiang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lihua Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lihua Sun.

Additional information

Yi Pu and Shouwei Li have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pu, Y., Li, S., Zhang, C. et al. High expression of CXCR3 is an independent prognostic factor in glioblastoma patients that promotes an invasive phenotype. J Neurooncol 122, 43–51 (2015). https://doi.org/10.1007/s11060-014-1692-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1692-y

Keywords

Search

Navigation