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:

Gene therapy with CX3CL1/Fractalkine induces antitumor immunity to regress effectively mouse hepatocellular carcinoma

Gene Therapy volume 14, pages 1226–1234 (2007)Cite this article

Abstract

CX3CL1/Fractalkine(FK), a chemokine existing in both secreted and membrane anchored form, was reported to induce suppressive activities in tumor models. Here, we demonstrate for the first time the antitumor effects of FK in murine hepatocellular carcinoma (HCC) by constructing a FK eukaryotic expression vector (pIRES-FK) and transferring it into such tumor cells. Tumor rejection experiments were performed by injecting FK gene-modified murine HCC cell line (MM45T.Li) into immunocompetent mice, which significantly inhibited tumorigenicity or growth of MM45T.Li-FK cells. Immunohistochemistry examination and fluorescence-activated cell sorting analyses revealed both CD4+ and CD8+ T cells infiltration within the tumor together with a marked increase of these cells in the peripheral blood. Splenic lymphocyte from mice treated with MM45T.Li-FK were effective in the induction of tumor-specific cytotoxic T cells . We also observed an increased production of IL-2 and IFN-γ in MM45T.Li-FK tumor tissue. Our results suggest that transfer of the FK gene into tumor cells could elicit a specific antitumor immunity capable of inhibiting tumor growth which lead to increased survival of tumor-bearing hosts. FK should be considered as a chemokine suitable for cancer immunoprevention or gene therapy.

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

Access options

Buy this article

  • Purchase on Springer Link
  • 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

Similar content being viewed by others

References

  1. Sherman M . Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 2005; 25: 143–154.

    Article  Google Scholar 

  2. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J et al. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 1995; 270: 27348–27357.

    Article  CAS  Google Scholar 

  3. Baggiolini M, Dewald B, Moser B . Human chemokines: an update. Annu Rev Immunol 1997; 15: 675–705.

    Article  CAS  Google Scholar 

  4. Yoshie O, Imai T, Nomiyama H . Chemokines in immunity. Adv Immunol 2001; 78: 57–110.

    Article  CAS  Google Scholar 

  5. Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 1997; 385: 640–644.

    Article  CAS  Google Scholar 

  6. Homey B, Muller A, Zlotnik A . Chemokines: agents for the immunotherapy of cancer? Nat Rev Immunol 2002; 2: 175–184.

    Article  CAS  Google Scholar 

  7. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–56.

    Article  CAS  Google Scholar 

  8. Balkwill F, Mantovani A . Inflammation and cancer: back to Virchow? Lancet 2001; 357: 539–545.

    Article  CAS  Google Scholar 

  9. Menten P, Saccani A, Dillen C, Wuyts A, Struyf S, Proost P et al. Role of the autocrine chemokines MIP-1alpha and MIP-1beta in the metastatic behavior of murine T cell lymphoma. J Leukoc Biol 2002; 72: 780–789.

    CAS  PubMed  Google Scholar 

  10. Luster AD, Leder P . IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo. J Exp Med 1993; 178: 1057–1065.

    Article  CAS  Google Scholar 

  11. Sgadari C, Farber JM, Angiolillo AL, Liao F, Teruya-Feldstein J, Burd PR et al. Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo. Blood 1997; 89: 2635–2643.

    CAS  PubMed  Google Scholar 

  12. Sgadari C, Angiolillo AL, Cherney BW, Pike SE, Farber JM, Koniaris LG et al. Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo. Proc Natl Acad Sci USA 1996; 93: 13791–13796.

    Article  CAS  Google Scholar 

  13. Cairns CM, Gordon JR, Li F, Baca-Estrada ME, Moyana T, Xiang J . Lymphotactin expression by engineered myeloma cells drives tumor regression: mediation by CD4+ and CD8+ T cells and neutrophils expressing XCR1 receptor. J Immunol 2001; 167: 57–65.

    Article  CAS  Google Scholar 

  14. Yang SC, Batra RK, Hillinger S, Reckamp KL, Strieter RM, Dubinett SM et al. Intrapulmonary administration of CCL21 gene-modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell carcinoma. Cancer Res 2006; 66: 3205–3213.

    Article  CAS  Google Scholar 

  15. Fushimi T, O’Connor TP, Crystal RG . Adenoviral gene transfer of stromal cell-derived factor-1 to murine tumors induces the accumulation of dendritic cells and suppresses tumor growth. Cancer Res 2006; 66: 3513–3522.

    Article  CAS  Google Scholar 

  16. Nakazaki Y, Hase H, Inoue H, Beppu Y, Meng XK, Sakaguchi G et al. Serial analysis of gene expression in progressing and regressing mouse tumors implicates the involvement of RANTES and TARC in antitumor immune responses. Mol Ther 2006; 14: 599–606.

    Article  CAS  Google Scholar 

  17. Luo X, Yu Y, Liang A, Xie Y, Liu S, Guo J et al. Intratumoral expression of MIP-1beta induces antitumor responses in a pre-established tumor model through chemoattracting T cells and NK cells. Cell Mol Immunol 2004; 1: 199–204.

    CAS  PubMed  Google Scholar 

  18. Kagaya T, Nakamoto Y, Sakai Y, Tsuchiyama T, Yagita H, Mukaida N et al. Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer. Cancer Gene Ther 2006; 13: 357–366.

    Article  CAS  Google Scholar 

  19. Ruehlmann JM, Xiang R, Niethammer AG, Ba Y, Pertl U, Dolman CS et al. MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma. Cancer Res 2001; 61: 8498–8503.

    CAS  PubMed  Google Scholar 

  20. Pan Y, Lloyd C, Zhou H, Dolich S, Deeds J, Gonzalo JA et al. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 1997; 387: 611–617. published erratum appears in Nature 1997; 389: 100.

    Article  CAS  Google Scholar 

  21. Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ et al. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 2001; 276: 37993–38001.

    CAS  PubMed  Google Scholar 

  22. Tsou CL, Haskell CA, Charo IF . Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine. J Biol Chem 2001; 276: 44622–44626.

    Article  CAS  Google Scholar 

  23. Dichmann S, Herouy Y, Purlis D, Rheinen H, Gebicke-Harter P, Norgauer J . Fractalkine induces chemotaxis and actin polymerization in human dendritic cells. Inflamm Res 2001; 50: 529–533.

    Article  CAS  Google Scholar 

  24. Umehara H, Goda S, Imai T, Nagano Y, Minami Y, Tanaka Y et al. Fractalkine, a CX3C-chemokine, functions predominantly as an adhesion molecule in monocytic cell line THP-1. Immunol Cell Biol 2001; 79: 298–302.

    Article  CAS  Google Scholar 

  25. Guo J, Wang B, Zhang M, Chen T, Yu Y, Regulier E et al. Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity. Gene Therapy 2002; 9: 793–803.

    Article  CAS  Google Scholar 

  26. Yang SC, Hillinger S, Riedl K, Zhang L, Zhu L, Huang M et al. Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity. Clin Cancer Res 2004; 10: 2891–2901.

    Article  CAS  Google Scholar 

  27. Braun SE, Chen K, Foster RG, Kim CH, Hromas R, Kaplan MH et al. The CC chemokine CK beta-11/MIP-3 beta/ELC/Exodus 3 mediates tumor rejection of murine breast cancer cells through NK cells. J Immunol 2000; 164: 4025–4031.

    Article  CAS  Google Scholar 

  28. Guo J, Zhang M, Wang B, Yuan Z, Guo Z, Chen T et al. Fractalkine transgene induces T-cell-dependent antitumor immunity through chemoattraction and activation of dendritic cells. Int J Cancer 2003; 103: 212–220.

    Article  CAS  Google Scholar 

  29. Guo J, Chen T, Wang B, Zhang M, An H, Guo Z et al. Chemoattraction, adhesion and activation of natural killer cells are involved in the antitumor immune response induced by fractalkine/CX3CL1. Immunol Lett 2003; 89: 1–7.

    Article  CAS  Google Scholar 

  30. Xin H, Kikuchi T, Andarini S, Ohkouchi S, Suzuki T, Nukiwa T et al. Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells. Eur J Immunol 2005; 35: 1371–1380.

    Article  CAS  Google Scholar 

  31. Lavergne E, Combadiere B, Bonduelle O, Iga M, Gao JL, Maho M et al. Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res 2003; 63: 7468–7474.

    CAS  PubMed  Google Scholar 

  32. Gao JQ, Tsuda Y, Katayama K, Nakayama T, Hatanaka Y, Tani Y et al. Antitumor effect by interleukin-11 receptor alpha-locus chemokine/CCL27, introduced into tumor cells through a recombinant adenovirus vector. Cancer Res 2003; 63: 4420–4425.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by funds from Doctoral Fund of Ministry of Education of China 20040631012.

Author information

Authors and Affiliations

  1. Institute of Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China

    L Tang, H-d Hu, P Hu, Y-h Lan, M-l Peng, M Chen & H Ren

Authors
  1. L Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H-d Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y-h Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M-l Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Ren.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tang, L., Hu, Hd., Hu, P. et al. Gene therapy with CX3CL1/Fractalkine induces antitumor immunity to regress effectively mouse hepatocellular carcinoma. Gene Ther 14, 1226–1234 (2007). https://doi.org/10.1038/sj.gt.3302959

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302959

Keywords

This article is cited by

Search

Advanced search

Quick links