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:

Calcium depletion enhances nectin-1 expression and herpes oncolytic therapy of squamous cell carcinoma

Cancer Gene Therapy volume 14, pages 738–747 (2007)Cite this article

Abstract

Attenuated, replication-competent, oncolytic herpes simplex virus type 1 (HSV-1) are effective at infecting and lysing many human malignancies in preclinical studies. Nectin-1 is a cell-surface receptor for HSV-1 envelope glycoprotein D (gD) that also forms a component of intercellular adherens junctions (AJs). We sought to determine if the disruption of AJs in squamous cell carcinoma (SCC) through calcium depletion could be utilized to increase nectin-1 exposure and enhance HSV therapy. NV1023 is a single copy γ134.5-deleted, lacZ-expressing, oncolytic HSV-1. Calcium depletion caused cell separation and increased nectin-1 expression for three SCC cell lines growing at confluence. NV1023 viral entry, soluble gD protein binding and NV1023 cytotoxicity were all significantly enhanced for these cell lines at low calcium conditions. The increase in NV1023 entry at low calcium conditions was abrogated by nectin-1 antibody blockade. Murine SCC flank tumors treated with ethylenediaminetetraacetic acid (EDTA) showed increased nectin-1 expression and increased susceptibility to NV1023 infection. Combined NV1023 and EDTA intratumoral injections demonstrated significantly enhanced tumor regression as compared to NV1023 alone. These findings establish, as proof-of-principle, that herpes viral receptor expression may be modulated on cancer cells to enhance oncolytic therapy. This strategy might have future application toward improving therapy with a variety of herpes vectors.

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
Figure 6

Similar content being viewed by others

References

  1. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM . Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991; 252: 854–856.

    Article  CAS  PubMed  Google Scholar 

  2. Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL . Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med 1995; 1: 938–943.

    Article  CAS  PubMed  Google Scholar 

  3. Kooby DA, Carew JF, Halterman MW, Mack JE, Bertino JR, Blumgart LH et al. Oncolytic viral therapy for human colorectal cancer and liver metastases using a multi-mutated herpes simplex virus type-1 (G207). FASEB J 1999; 13: 1325–1334.

    Article  CAS  PubMed  Google Scholar 

  4. Toyoizumi T, Mick R, Abbas AE, Kang EH, Kaiser LR, Molnar-Kimber KL . Combined therapy with chemotherapeutic agents and herpes simplex virus type 1 ICP34.5 mutant (HSV-1716) in human non-small cell lung cancer. Hum Gene Ther 1999; 10: 3013–3029.

    Article  CAS  PubMed  Google Scholar 

  5. Walker JR, McGeagh KG, Sundaresan P, Jorgensen TJ, Rabkin SD, Martuza RL . Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207. Hum Gene Ther 1999; 10: 2237–2243.

    Article  CAS  PubMed  Google Scholar 

  6. Cozzi PJ, Malhotra S, McAuliffe P, Kooby DA, Federoff HJ, Huryk B et al. Intravesicular oncolytic viral therapy using attenuated, replication-competent herpes simplex viruses G207 and NV1020 is effective in the treatment of bladder cancer in an orthotopic syngeneic model. FASEB J 2001; 15: 1306–1308.

    Article  CAS  PubMed  Google Scholar 

  7. Wong RJ, Kim SH, Joe JK, Shah JP, Johnson PA, Fong Y . Effective treatment of head and neck squamous cell carcinoma by an oncolytic herpes simplex virus. J Am Coll Surg 2001; 193: 12–21.

    Article  CAS  PubMed  Google Scholar 

  8. Yu Z, Eisenberg DP, Singh B, Shah JP, Fong F, Wong RJ . Treatment of aggressive thyroid cancer with an oncolytic herpes virus. Int J Cancer 2004; 112: 525–532.

    Article  CAS  PubMed  Google Scholar 

  9. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Therapy 2000; 7: 867–874.

    Article  CAS  PubMed  Google Scholar 

  10. Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D et al. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Therapy 2000; 7: 859–866.

    Article  CAS  PubMed  Google Scholar 

  11. Kemeny N, Brown K, Covey A, Kim T, Bhargava A, Brody L et al. Phase 1, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Hum Gene Ther 2006; 17: 1214–1224.

    Article  CAS  PubMed  Google Scholar 

  12. Wong RJ, Patel SG, Kim S, DeMatteo RP, Malhotra S, Bennett JJ et al. Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. Hum Gene Ther 2001; 12: 253–265.

    Article  CAS  PubMed  Google Scholar 

  13. Wong RJ, Joe JK, Kim SH, Shah JP, Horsburgh B, Fong Y . Oncolytic herpesvirus effectively treats murine squamous cell carcinoma and spreads by natural lymphatics to treat sites of lymphatic metastases. Hum Gene Ther 2002; 13: 1213–1223.

    Article  CAS  PubMed  Google Scholar 

  14. Wong RJ, Chan MK, Yu Z, Kim TH, Bhargava A, Stiles BM et al. Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes virus expressing interleukin 12. Clin Cancer Res 2004; 10: 251–259.

    Article  CAS  PubMed  Google Scholar 

  15. Adusumilli PS, Stiles BM, Chan MK, Eisenberg DP, Yu Z, Stanziale SF et al. Real time imaging of tumors and metastases by use of a replication-competent herpes vector to facilitate minimally invasive oncological surgery. FASEB J 2006; 20: 726–728.

    Article  CAS  PubMed  Google Scholar 

  16. Spear PG, Longnecker R . Herpesvirus entry: an update. J Virol 2003; 77: 10179–10185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Krummenacher C, Baribaud F, Ponce de Leon M, Baribaud I, Whitbeck JC, Xu R et al. Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus. Virology 2004; 322: 286–299.

    Article  CAS  PubMed  Google Scholar 

  18. Yu Z, Adusumilli PS, Eisenberg DP, Darr E, Ghossein RA, Li S et al. Nectin-1 expression by squamous cell carcinoma is a predictor of herpes oncolytic sensitivity. Mol Ther 2007; 15: 103–113.

    Article  CAS  PubMed  Google Scholar 

  19. Takai Y, Irie K, Shimizu K, Sakisaka T, Ikeda W . Nectins and nectin-like molecules: roles in cell adhesion, migration, and polarization. Cancer Sci 2003; 94: 655–667.

    Article  CAS  PubMed  Google Scholar 

  20. Yoon M, Spear PG . Disruption of adherens junctions liberates nectin-1 to serve as receptor for herpes simplex virus and pseudorabies virus entry. J Virol 2002; 76: 7203–7208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meignier B, Longnecker R, Roizman B . In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020: construction and evaluation in rodents. J Infect Dis 1988; 158: 602–614.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Patricia Spear and Miri Yoon (Northwestern University) for their helpful advice and provision of the gD:Fc soluble fusion protein plasmid. RJW was supported by a Clinical Innovator Award from the Flight Attendant Medical Research Institute, and a Faculty Career Development Award from the American College of Surgeons and the American Head and Neck Society.

Author information

Authors and Affiliations

  1. Department of Surgery, Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Z Yu, S Li, Y-Y Huang & R J Wong

  2. Department of Otolaryngology, Beijing Tongren Hospital, Capital University of Medical Sciences, Beijing, China

    Z Yu

  3. Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Y Fong

Authors
  1. Z Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y-Y Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Fong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R J Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R J Wong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, Z., Li, S., Huang, YY. et al. Calcium depletion enhances nectin-1 expression and herpes oncolytic therapy of squamous cell carcinoma. Cancer Gene Ther 14, 738–747 (2007). https://doi.org/10.1038/sj.cgt.7701062

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7701062

Keywords

This article is cited by

Search

Advanced search

Quick links