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.

  • Research Article
  • Published:

Direct in vivo transfection of antisense Fas-ligand reduces tumor growth and invasion

Gene Therapy volume 8, pages 209–214 (2001)Cite this article

Abstract

The expression of Fas ligand (FasL) by tumor cells has been reported to have multiple, conflicting effects on tumor growth. The majority of the data support the theory that FasL expressing tumor cells evade immune surveillance by killing T cells expressing Fas. However, the role of the humoral immune-blockade by FasL expressing tumor cells has not been assessed. Using immune-competent mice, we observed that FasL expressing tumor cells reduced the antitumor antibody production together with the T and B cell content of the spleen in these mice. Further, to determine if the expression of FasL in the environment of the tumor suppresses the humoral antitumor immune response and influences tumor growth, a mouse model lacking T cells was used. To assess whether a local reduction of FasL could reduce tumor progression, a plasmid encoding antisense FasL cDNA was delivered directly into a growing tumor (SW620 colon carcinoma). Intratumoral delivery of the plasmid was able to transfect tumor cells, stromal cells, and peritumoral muscle cells. This antisense FasL tumor tissue transfection persisted for at least 25 days, produced a systemic decrease in soluble FasL, and resulted in a 50% reduction in the rate of tumor growth when compared with tumor tissue of the control groups. These results suggest that direct transfection of antisense FasL cDNA impairs FasL translation in tumor and stromal cells, and can inhibit tumor progression by impairing the FasL-mediated, stromal cell-assisted, tumor counter-attack.

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

Similar content being viewed by others

References

  1. Watanabe R et al. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen J Immunol 1992 148: 1274–1279

    Google Scholar 

  2. Leithäuser F et al. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells Lab Invest 1993 69: 415–429

    Google Scholar 

  3. French LE et al. Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and co-expression in adult tissues characterized by apoptotic cell turnover J Cell Biol 1996 133: 335–343

    Article  CAS  Google Scholar 

  4. Schelling JR et al. Fas-dependent fratricidal apoptosis is a mechanism of tubular epithelial cell deletion in chronic renal failure Lab Invest 1998 78: 813–824

    CAS  Google Scholar 

  5. Ashany D et al. Th1 CD4+ lymphocytes delete activated macrophages through the Fas/APO-1 antigen pathway Proc Natl Acad Sci USA 1995 92: 11225–11229

    Article  CAS  Google Scholar 

  6. Rensing-Ehl A et al. Local Fas/APO-1 (CD95) ligand-mediated tumor cell killing in vivo Eur J Immunol 1995 25: 2253–2258

    Article  CAS  Google Scholar 

  7. White CA, McCombe PA, Pender MP . Microglia are more susceptible than macrophages to apoptosis in the central nervous system in experimental autoimmune encephalomyelitis through a mechanism not involving Fas (CD95) Int Immunol 1998 10: 935–941

    Article  CAS  Google Scholar 

  8. Garrone P et al. Fas ligation induces apoptosis of CD40-activated human B-lymphocytes J Exp Med 1995 182: 1265–1273

    Article  CAS  Google Scholar 

  9. Griffith TS et al. Fas ligand-induced apoptosis as a mechanism of immune privilege Science 1995 270: 1189–1192

    Article  CAS  Google Scholar 

  10. Bennett MW et al. Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer Gut 1999 44: 156–162

    Article  CAS  Google Scholar 

  11. Gutierrez LS et al. The Fas/Fas-ligand system: a mechanism for immune evasion in human breast carcinomas Breast Cancer Res Treat 1999 54: 245–253

    Article  CAS  Google Scholar 

  12. Hahne M et al. Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape Science 1996 274: 1363–1366

    Article  CAS  Google Scholar 

  13. O'Connell J et al. The Fas counterattack: Fas-mediated T-cell killing by colon cancer cells expressing Fas ligand J Exp Med 1996 184: 1075–1082

    Article  CAS  Google Scholar 

  14. Ungefroren H et al. Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis Cancer Res 1998 58: 1741–1749

    CAS  Google Scholar 

  15. Xerri L et al. Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis Leukemia 1997 11: 1868–1877

    Article  CAS  Google Scholar 

  16. Peduto Eberl L et al. Fas and Fas ligand expression in tumor cells and in vascular smooth-muscle cells of colonic and renal carcinomas Int J Cancer 1999 81: 772–778

    Article  CAS  Google Scholar 

  17. Brown SB, Savill J . Phagocytosis triggers macrophage release of Fas ligand and induces apoptosis of bystander leukocytes J Immunol 1999 162: 480–485

    CAS  Google Scholar 

  18. Yoong KF et al. Fas/Fas ligand interaction in human colorectal hepatic metastases: a mechanism of hepatocyte destruction to facilitate local tumor invasion Am J Pathol 1999 154: 693–703

    Article  CAS  Google Scholar 

  19. Ju DW, Cao X, Acres B . Intratumoral injection of GM-CSF gene encoded recombinant vaccinia virus elicits potent antitumor response in a mixture melanoma model Cancer Gene Therapy 1997 4: 139–144

    CAS  PubMed  Google Scholar 

  20. Morton D et al. Immunological factors which influence response to immunotherapy in malignant melanoma Surgery 1970 68: 158–163

    CAS  PubMed  Google Scholar 

  21. Ramsdell F et al. Differential ability of Th1 and Th2 T-cells to express Fas ligand and to undergo activation-induced cell death Int Immunol 1994 6: 1545–1553

    Article  CAS  Google Scholar 

  22. Alderson MR et al. Fas ligand mediates activation-induced cell death in human T lymphocytes J Exp Med 1995 181: 71–77

    Article  CAS  Google Scholar 

  23. Mandik L et al. Fas receptor expression on B-lineage cells Eur J Immunol 1995 25: 3148–3154

    Article  CAS  Google Scholar 

  24. Kume T et al. Relationship between Fas-ligand expression on carcinoma cell and cytotoxic T-lymphocyte response in lymphoepithelioma-like cancer of the stomach Int J Cancer 1999 84: 339–343

    Article  CAS  Google Scholar 

  25. Rafi AQ et al. Evidence for the involvement of Fas ligand and perforin in the induction of vascular leak syndrome J Immunol 1998 161: 3077–3086

    CAS  PubMed  Google Scholar 

  26. Allgaier B et al. Spontaneous and Fas-mediated apoptosis are diminished in umbilical cord blood neutrophils compared with adult neutrophils J Leuk Biol 1998 64: 331–336

    Article  CAS  Google Scholar 

  27. Jane SM, Cunningham JM, Vanin EF . Vector development: a major obstacle in human gene therapy Ann Med 1998 30: 413–415

    Article  CAS  Google Scholar 

  28. Lau HT et al. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice Science 1996 273: 109–112

    Article  CAS  Google Scholar 

  29. Kang SM et al. Immune response and myoblasts that express Fas ligand Science 1997 278: 1322–1324

    Article  CAS  Google Scholar 

  30. Manfred V, Jürgen M, Reet K . Inverse correlation between apoptotic (Fas ligand, caspase-3) and angiogenic factors (VEGF, microvessel density) in squamous cell lung carcinomas Anticancer Res 1999 19: 1669–1675

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. BioCrystal Ltd, Westerville, OH, USA

    JK Nyhus, C Wolford, L Feng & E Barbera-Guillem

Authors
  1. JK Nyhus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Wolford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Barbera-Guillem
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nyhus, J., Wolford, C., Feng, L. et al. Direct in vivo transfection of antisense Fas-ligand reduces tumor growth and invasion. Gene Ther 8, 209–214 (2001). https://doi.org/10.1038/sj.gt.3301372

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301372

Keywords

This article is cited by

Search

Advanced search

Quick links