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:

Interleukin-10 gene transfer to peritoneal mesothelial cells suppresses peritoneal dissemination of gastric cancer cells due to a persistently high concentration in the peritoneal cavity

Cancer Gene Therapy volume 15, pages 51–59 (2008)Cite this article

Abstract

Interleukin (IL)-10 has potent biological properties including an inhibitory action on the proliferation and metastasis of various cancer cells. However, it is difficult to maintain a high concentration of this cytokine as it has a short half life. In this study, we evaluated whether peritoneal mesothelial cells (PMCs) could be suitable for maintaining a high concentration of IL-10 using adenoviral gene transfer. We also evaluated the therapeutic effects of an intraperitoneal injection with adenoviral vector containing mouse IL-10 gene (Ad-mIL-10) using a mouse peritoneal dissemination model of MKN45 gastric cancer cells. We demonstrated that in vitro transfection efficiency of a recombinant adenovirus containing the bacterial β-galactosidase gene (Ad-LacZ) was approximately 10-fold higher for primarily isolated PMCs than MKN45. The entire peritoneum was transfected until 3 weeks after an intraperitoneal Ad-LacZ injection. Ad-mIL-10 treatment increased intraperitoneal IL-10 levels until 3 weeks after treatment, and then significantly inhibited peritoneal cancer growth by inhibiting angiogenesis. This treatment also improved cachexia and prolonged mice survival. We thus concluded that IL-10 gene transfer in PMCs could be a new strategy for the prevention of peritoneal dissemination of gastric cancer due to the resulting persistently high IL-10 concentration in the peritoneal cavity.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

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

Similar content being viewed by others

References

  1. Fiorentino DF, Bond MW, Mosmann TR . Two types of mouse helper T cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989; 170: 2081–2095.

    Article  CAS  PubMed  Google Scholar 

  2. de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 1991; 174: 915–924.

    Article  CAS  PubMed  Google Scholar 

  3. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A . IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991; 147: 3815–3822.

    CAS  PubMed  Google Scholar 

  4. Bogdan C, Vodovotz Y, Nathan C . Macrophage deactivation by interleukin 10. J Exp Med 1991; 174: 1549–1555.

    Article  CAS  PubMed  Google Scholar 

  5. Huang S, Ullrich SE, Bar-Eli M . Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. J Interferon Cytokine Res 1999; 19: 697–703.

    Article  CAS  PubMed  Google Scholar 

  6. Cervenak L, Morbidelli L, Donati D, Donnini S, Kambayashi T, Wilson JL et al. Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by interleukin-10. Blood 2000; 96: 2568–2573.

    CAS  PubMed  Google Scholar 

  7. Kohno T, Mizukami H, Suzuki M, Saga Y, Takei Y, Shimpo M et al. Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer. Cancer Res 2003; 63: 5091–5094.

    CAS  PubMed  Google Scholar 

  8. Stearns ME, Rhim J, Wang M . Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)-2/MMP-9 secretion. Clin Cancer Res 1999; 5: 189–196.

    CAS  PubMed  Google Scholar 

  9. Kundu N, Beaty TL, Jackson MJ, Fulton AM . Antimetastatic and antitumor activities of interleukin 10 in a murine model of breast cancer. J Natl Cancer Inst 1996; 88: 536–541.

    Article  CAS  PubMed  Google Scholar 

  10. Zheng LM, Ojclus DM, Garaud F, Roth C, Maxwell E, Li Z et al. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med 1996; 184: 579–584.

    Article  CAS  PubMed  Google Scholar 

  11. Berman RM, Susuki T, Tahara H, Robbins PD, Narula SK, Lotze MT . Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol 1996; 157: 231–238.

    CAS  PubMed  Google Scholar 

  12. Kundu N, Fulton AM . Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis. Cell Immunol 1997; 180: 55–61.

    Article  CAS  PubMed  Google Scholar 

  13. Di Carlo E, Coletti A, Modesti A, Giovarelli M, Forni G, Musiani P . Local release of interleukin-10 by transfected mouse adenocarcinoma cells exhibits pro- and anti-inflammatory activity and results in a delayed tumor rejection. Eur Cytokine Netw 1998; 9: 61–68.

    CAS  PubMed  Google Scholar 

  14. Kundu N, Dorsey R, Jackson MJ, Guiterrez P, Wilson K, Fu S et al. Interleukin-10 gene transfer inhibits murine mammary tumors and elevates nitric oxide. Int J Cancer 1998; 76: 713–719.

    Article  CAS  PubMed  Google Scholar 

  15. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A . Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765.

    Article  CAS  PubMed  Google Scholar 

  16. Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB et al. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol 1995; 154: 5492–5499.

    CAS  PubMed  Google Scholar 

  17. Kokura S, Yoshida N, Ishikawa T, Higashihara H, Sakamoto N, Takagi T et al. Interleukin-10 plasmid DNA inhibits subcutaneous tumor growth of Colon26 adenocarcinoma in mice. Cancer Lett 2005; 218: 171–179.

    Article  CAS  PubMed  Google Scholar 

  18. Benevolo M, Mottolese M, Cosimelli M, Tedesco M, Giannarelli D, Vasselli S et al. Diagnostic and prognostic value of peritoneal immunocytology in gastric cancer. J Clin Oncol 1998; 16: 3406–3411.

    Article  CAS  PubMed  Google Scholar 

  19. Gosselin R, Berndt W . Diffusional transport of solutes through mesentery and peritoneum. J Theor Biol 1962; 3: 487.

    Article  CAS  Google Scholar 

  20. Topley N, Jorres A, Luttmann W, Petersen MM, Lang MJ, Thierauch KH et al. Human peritoneal mesothelial cells synthesize interleukin-6: induction by IL-1β and TNF α. Kidney Int 1993; 43: 226–233.

    Article  CAS  PubMed  Google Scholar 

  21. Betjes MG, Tuk CW, Struijk DG, Krediet RT, Arisz L, Hart M et al. Interleukin-8 production by human peritoneal mesothelial cells in response to tumor necrosis factor-α, interleukin-1, and medium conditioned by macrophages cocultured with Staphylococcus epidermidis. J Infect Dis 1993; 168: 1702–1710.

    Article  Google Scholar 

  22. Lanfrancone L, Boraschi D, Ghiara P, Falini B, Grignani F, Peri G et al. Human peritoneal mesothelial cells produce many cytokines (granulocyte colony-stimulating factor [CSF], granulocyte-monocyte-CSF, macrophage-CSF, interleukin-1 [IL-1], and IL-6) and are activated and stimulated to grow by IL-1. Blood 1992; 80: 2835–2842.

    CAS  PubMed  Google Scholar 

  23. Jayne DG, Perry SL, Morrison E, Farmery SM, Guillou PJ . Activated mesothelial cells produce heparin-binding growth factors: implications for tumour metastasis. Br J Cancer 2000; 82: 1233–1238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sako A, Kitayama J, Yamaguchi H, Kaisaki S, Suzuki H, Fukatsu K et al. Vascular endothelial growth factor synthesis by human omental mesothelial cells is augmented by fibroblast growth factor-2: possible role of mesothelial cell on the development of peritoneal metastasis. J Surg Res 2003; 115: 113–120.

    Article  CAS  PubMed  Google Scholar 

  25. Balabanian K, Foussat A, Bouchet-Delbos L, Couderc J, Krzysiek R, Amara A et al. Interleukin-10 modulates the sensitivity of peritoneal B lymphocytes to chemokines with opposite effects on stromal cell-derived factor-1 and B-lymphocyte chemoattractant. Blood 2002; 99: 427–436.

    Article  CAS  PubMed  Google Scholar 

  26. Sako A, Kitayama J, Koyama H, Ueno H, Uchida H, Hamada H et al. Transduction of soluble Flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastric cancer. Cancer Res 2004; 64: 3624–3628.

    Article  CAS  PubMed  Google Scholar 

  27. Fujikawa K, Takai K, Suga A, Naito K, Ohata A, Nakasone S et al. Expression of mRNA for growth factors and extracellular matrix proteins after injury to cultured peritoneal cells: does the healing process contribute to peritoneal ultrastructural alteration? J Artif Organs 2003; 6: 253–259.

    Article  CAS  PubMed  Google Scholar 

  28. Robson RL, McLoughlin RM, Witowski J, Loetscher P, Wilkinson TS, Jones SA et al. Differential regulation of chemokine production in human peritoneal mesothelial cells: IFN-γ controls neutrophil migration across the mesothelium in vitro and in vivo. J Immunol 2001; 167: 1028–1038.

    Article  CAS  PubMed  Google Scholar 

  29. Takakuwa T, Endo S, Shirakura Y, Yokoyama M, Tamatani M, Tohyama M et al. Interleukin-10 gene transfer improves the survival rate of mice inoculated with Escherichia coli. Crit Care Med 2000; 28: 2685–2689.

    Article  CAS  PubMed  Google Scholar 

  30. Kuwamura H, Tominaga K, Shiota M, Ashida R, Nakao T, Sasaki E et al. Growth inhibition of colon cancer cells by transfection of dominant-negative apoptosis signal-regulating kinase-1. Oncol Rep 2007; 17: 781–786.

    CAS  PubMed  Google Scholar 

  31. Suto R, Tominaga K, Mizuguchi H, Sasaki E, Higuchi K, Kim S et al. Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer. Gene Ther 2004; 11: 187–193.

    Article  CAS  PubMed  Google Scholar 

  32. Fujiki F, Mukaida N, Hirose K, Ishida H, Harada A, Ohno S et al. Prevention of adenocarcinoma colon 26-induced cachexia by interleukin 10 gene transfer. Cancer Res 1997; 57: 94–99.

    CAS  PubMed  Google Scholar 

  33. Giovarelli M, Musiani P, Modesti A, Dellabona P, Casorati G, Allione A et al. Local release of IL-10 by transfected mouse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic lymphocyte and antibody-dependent immune memory. J Immunol 1995; 155: 3112–3123.

    CAS  PubMed  Google Scholar 

  34. Zeni F, Tardy B, Vindimian M, Comtet C, Page Y, Cusey I et al. High levels of tumor necrosis factor-alpha and interleukin-6 in the ascitic fluid of cirrhotic patients with spontaneous bacterial peritonitis. Clin Infect Dis 1993; 17: 218–223.

    Article  CAS  PubMed  Google Scholar 

  35. Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB, Ellis LM . Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol 1999; 6: 373–378.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports Science and Technology of Japan and the Yasuda Medical Foundation.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan

    F Tanaka, K Tominaga, M Ochi, H Kuwamura, T Tanigawa, T Watanabe, Y Fujiwara, N Oshitani, K Higuchi & T Arakawa

  2. Department of Pharmacology, Osaka City University Graduate School of Medicine, Osaka, Japan

    M Shiota & H Iwao

Authors
  1. F Tanaka
    View author publications

    Search author on:PubMed Google Scholar

  2. K Tominaga
    View author publications

    Search author on:PubMed Google Scholar

  3. M Shiota
    View author publications

    Search author on:PubMed Google Scholar

  4. M Ochi
    View author publications

    Search author on:PubMed Google Scholar

  5. H Kuwamura
    View author publications

    Search author on:PubMed Google Scholar

  6. T Tanigawa
    View author publications

    Search author on:PubMed Google Scholar

  7. T Watanabe
    View author publications

    Search author on:PubMed Google Scholar

  8. Y Fujiwara
    View author publications

    Search author on:PubMed Google Scholar

  9. N Oshitani
    View author publications

    Search author on:PubMed Google Scholar

  10. K Higuchi
    View author publications

    Search author on:PubMed Google Scholar

  11. H Iwao
    View author publications

    Search author on:PubMed Google Scholar

  12. T Arakawa
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to K Tominaga.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, F., Tominaga, K., Shiota, M. et al. Interleukin-10 gene transfer to peritoneal mesothelial cells suppresses peritoneal dissemination of gastric cancer cells due to a persistently high concentration in the peritoneal cavity. Cancer Gene Ther 15, 51–59 (2008). https://doi.org/10.1038/sj.cgt.7701104

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.cgt.7701104

Keywords

This article is cited by

Search

Advanced search

Quick links