Skip to main content
NCBI home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;95(12):990–998. doi: 10.1111/j.1349-7006.2004.tb03188.x

Herpes simplex virus‐induced, death receptor‐dependent apoptosis and regression of transplanted human cancers

Hironaga Kamiyama 1,2,5, Kunikazu Kurosaki 1,2, Masanori Kurimoto 2, Toyomasa Katagiri 3, Yusuke Nakamura 3, Masahiko Kurokawa 4, Hitoshi Sato 1, Shunro Endo 2, Kimiyasu Shiraki 1,✉
PMCID: PMC11158949  PMID: 15596049

Abstract

Inoculation of a live attenuated herpes simplex virus (HSV) vector, bH1, into human U87MG glioblastoma cells transplanted into athymic nude mice induced complete regression of tumors. The infected cells underwent histochemically confirmed apoptosis without lymphocyte infiltration after expressing CD30, CD30 ligand (CD30L), tumor necrosis factor (TNF)‐a, TNF receptor 1 (TNF‐R1), FAS, and FAS ligand (FAS‐L) with activation of caspases 3 and 8. Induction of the transcripts of these receptors and ligands in inoculated tumors was confirmed by quantitative RT‐PCR. To examine the specificity of apoptosis in the transplanted tumor, we inoculated bH1 into transplanted human lung, breast, gastric, and colon cancer tumors, and similar tumor regression with apoptosis was observed in all tumors. We analyzed the roles of expression of CD30, CD30L, TNF‐a, TNF‐R1, FAS, and FAS‐L in the tumors, and found that HSV‐induced apoptosis was suppressed by the respective antibodies. These findings indicate that the CD30/CD30L, TNF‐a/TNF‐R1, and FAS/FAS‐L interactions resulted in apoptosis and tumor regression in immunocompromised mice. In addition to the death receptor‐dependent apoptosis induced by HSV, the expressed ligands and receptors might enhance the susceptibility of tumor cells to cell‐mediated cyto‐toxicity and augment the activation of tumor‐killing lymphocytes in immunocompetent models.

Abbreviations:

HSV

herpes simplex virus

CD30L

CD30 ligand

TNF‐a

tumor necrosis factor‐a

TNF‐R1

TNF receptor 1

FAS‐L

FAS ligand

PBS

phosphate‐buffered saline

PFU

plaque‐forming units

RT‐PCR

reverse transcriptase polymerase chain reaction

NK

natural killer

CTL

cytotoxic T lymphocytes

REFERENCES

  • 1. Kirn DH. Replication‐selective microbiological agents: fighting cancer with targeted germ warfare. J Clin Invest 2000; 105: 837–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. 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: 602–14. [DOI] [PubMed] [Google Scholar]
  • 3. 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: 854–6. [DOI] [PubMed] [Google Scholar]
  • 4. Markert JM, Malick A, Coen DM, Martuza RL. Reduction and elimination of encephalitis in an experimental glioma therapy model with attenuated herpes simplex mutants that retain susceptibility to acyclovir. Neurosurgery 1993; 32: 597–603. [DOI] [PubMed] [Google Scholar]
  • 5. Mineta T, Rabkin SD, Martuza RL. Treatment of malignant gliomas using ganciclovir‐hypersensitive, ribonucleotide reductase‐deficient herpes simplex viral mutant. Cancer Res 1994; 54: 3963–6. [PubMed] [Google Scholar]
  • 6. 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: 938–43. [DOI] [PubMed] [Google Scholar]
  • 7. Andreansky SS, He B, Gillespie GY, Soroceanu L, Markert J, Chou J, Roizman B, Whitley RJ. The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors. Proc Natl Acad Sci USA 1996; 93: 11313–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Miyatake S, Iyer A, Martuza RL, Rabkin SD. Transcriptional targeting of herpes simplex virus for cell‐specific replication. J Virol 1997; 71: 5124–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Martuza RL. Conditionally replicating herpes vectors for cancer therapy. J Clin Invest 2000; 105: 841–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Kirn D, Martuza RL, Zwiebel J. Replication‐selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–7. [DOI] [PubMed] [Google Scholar]
  • 11. Todo T. Oncolytic virus therapy using genetically engineered herpes simplex viruses. Hum Cell 2002; 15: 151–9. [DOI] [PubMed] [Google Scholar]
  • 12. Yamamura H, Hashio M, Noguchi M, Sugenoya Y, Osakada M, Hirano N, Sasaki Y, Yoden T, Awata N, Araki N, Tatsuta M, Miyatake S, Takahashi K. Identification of the transcriptional regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors. Cancer Res 2001; 61: 3969–77. [PubMed] [Google Scholar]
  • 13. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, Palmer CA, Feigenbaum F, Tornatore C, Tufaro F, Martuza RL. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 2000; 7: 867–74. [DOI] [PubMed] [Google Scholar]
  • 14. Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, Petty R, MacLean A, Harland J, McKie E, Mabbs R, Brown M. Toxicity evaluation of replication‐competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther 2000; 7: 859–66. [DOI] [PubMed] [Google Scholar]
  • 15. Varghese S, Rabkin SD. Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther 2002; 9: 967–78. [DOI] [PubMed] [Google Scholar]
  • 16. Teshigahara O, Goshima F, Takao K, Kohno S, Kimata H, Nakao A, Nishiyama Y. Oncolytic viral therapy for breast cancer with herpes simplex virus type 1 mutant HF 10. J Surg Oncol 2004; 85: 42–7. [DOI] [PubMed] [Google Scholar]
  • 17. Toda M, Rabkin SD, Martuza RL. Treatment of human breast cancer in a brain metastatic model by G207, a replication‐competent multimutated herpes simplex virus 1. Hum Gene Ther 1998; 9: 2177–85. [DOI] [PubMed] [Google Scholar]
  • 18. Carew JF, Kooby DA, Halterman MW, Federoff HJ, Fong Y. Selective infection and cytolysis of human head and neck squamous cell carcinoma with sparing of normal mucosa by a cytotoxic herpes simplex virus type 1 (G207). Hum Gene Ther 1999; 10: 1599–606. [DOI] [PubMed] [Google Scholar]
  • 19. Kooby DA, Carew JF, Halterman MW, Mack JE, Bertino JR, Blumgart LH, Federoff HJ, Fong Y. Oncolytic viral therapy for human colorectal cancer and liver metastases using a multi‐mutated herpes simplex virus type‐1 (G207). FASEB J 1999; 13: 1325–34. [DOI] [PubMed] [Google Scholar]
  • 20. 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: 2237–43. [DOI] [PubMed] [Google Scholar]
  • 21. Wong RJ, Patel SG, Kim S, DeMatteo RP, Malhotra S, Bennett JJ, St‐Louis M, Shah JP, Johnson PA, Fong Y. Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. Hum Gene Ther 2001; 12: 253–65. [DOI] [PubMed] [Google Scholar]
  • 22. Takakuwa H, Goshima F, Nozawa N, Yoshikawa T, Kimura H, Nakao A, Nawa A, Kurata T, Sata T, Nishiyama Y. Oncolytic viral therapy using a spontaneously generated herpes simplex virus type 1 variant for disseminated peritoneal tumor in immunocompetent mice. Arch Virol 2003; 148: 813–25. [DOI] [PubMed] [Google Scholar]
  • 23. Gromeier M. Viruses for treating cancer. ASM News 2002; 68: 438–45. [Google Scholar]
  • 24. Andreansky S, He B, van Cott J, McGhee J, Markert JM, Gillespie GY, Roizman B, Whitley RJ. Treatment of intracranial gliomas in immunocom‐petent mice using herpes simplex viruses that express murine interleukins. Gene Ther 1998; 5: 121–30. [DOI] [PubMed] [Google Scholar]
  • 25. Toda M, Martuza RL, Kojima H, Rabkin SD. In situ cancer vaccination: an IL‐12 defective vector/replication‐competent herpes simplex virus combination induces local and systemic antitumor activity. J Immunol 1998; 160: 4457–64. [PubMed] [Google Scholar]
  • 26. Liu BL, Robinson M, Han ZQ, Branston RH, English C, Reay P, McGrath Y, Thomas SK, Thornton M, Bullock P, Love CA, Coffin RS. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti‐tumour properties. Gene Ther 2003; 10: 292–303. [DOI] [PubMed] [Google Scholar]
  • 27. Shiraki K, Andoh T, Imakita M, Kurokawa M, Kuraishi Y, Niimura M, Kagayama S. Caffeine inhibits paresthesia induced by herpes simplex virus through action on primary sensory neurons in rats. Neurosci Res 1998; 31: 235–40. [DOI] [PubMed] [Google Scholar]
  • 28. Shiraki K, Yamamura J, Kurokawa M, Andoh T, Sato H, Yoshida Y, Li ZH, Kamiyama T, Kageyama S. A live non‐neurovirulent herpes simplex virus vector expresses beta‐galactosidase in the nervous system of the Wistar and Sprague‐Dawley strain rat for a prolonged period. Neurosci Lett 1998; 245: 69–72. [DOI] [PubMed] [Google Scholar]
  • 29. Yamamura J, Kageyama S, Uwano T, Kurokawa M, Shiraki K. Long‐term gene expression in the anterior horn motor neurons after intramuscular inoculation of a live herpes simplex virus vector. Gene Ther 2000; 7: 934–41. [DOI] [PubMed] [Google Scholar]
  • 30. Kamiyama H, Kurimoto M, Yamamura J, Uwano T, Hirashima Y, Kurokawa M, Endo S, Shiraki K. Effect of immunity on gene delivery into anterior horn motor neurons by live attenuated herpes simplex virus vector. Gene Ther 2001; 8: 1180–7. [DOI] [PubMed] [Google Scholar]
  • 31. Ono K, Tanaka T, Tsunoda T, Kitahara O, Kihara C, Okamoto A, Ochiai K, Takagi T, Nakamura Y. Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Cancer Res 2000; 60: 5007–11. [PubMed] [Google Scholar]
  • 32. Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y, Tsunoda T, Furukawa Y, Nakamura Y. Genome‐wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 2001; 61: 2129–37. [PubMed] [Google Scholar]
  • 33. Kleinschmidt‐DeMasters BK, Orr EA, Savelieva E, Owens GC, Kruse CA. Paucity of retinoic acid receptor alpha (RAR alpha) nuclear immunostaining in gliomas and inability of retinoic acid to influence neural cell adhesion molecule (NCAM) expression. J Neurooncol 1999; 41: 31–42. [DOI] [PubMed] [Google Scholar]
  • 34. Nagata S, Golstein P. The Fas death factor. Science 1995; 267: 1449–56. [DOI] [PubMed] [Google Scholar]
  • 35. Nagata S. Apoptosis by death factor. Cell 1997; 88: 355–65. [DOI] [PubMed] [Google Scholar]
  • 36. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998; 281: 1305–8. [DOI] [PubMed] [Google Scholar]
  • 37. Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt M, Diehl V. Production of a monoclonal antibody specific for Hodgkin and Sternberg‐Reed cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature 1982; 299: 65–7. [DOI] [PubMed] [Google Scholar]
  • 38. Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, Schwarting R, Lennert K. The expression of the Hodgkin's disease associated antigen Ki‐1 in reactive and neoplastic lymphoid tissue: evidence that Reed‐Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985; 66: 848–58. [PubMed] [Google Scholar]
  • 39. Smith CA, Gruss HJ, Davis T, Anderson D, Farrah T, Baker E, Sutherland GR, Brannan CI, Copeland NG, Jenkins NA, Grabstein KH, Gliniak B, McAlister IB, Fanslow W, Anderson M, Falk B, Gimpel S, Gillis S, Din WS, Goodwin RG, Armitage RJ. CD30 antigen, a marker for Hodgkin's lym‐phoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell 1993; 73: 1349–60. [DOI] [PubMed] [Google Scholar]
  • 40. Lee SY, Park CG, Choi Y. T cell receptor‐dependent cell death of T cell hy‐bridomas mediated by CD30 cytoplasmic domain in association with tumor necrosis factor receptor‐associated factors. J Exp Med 1996; 183: 669–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Mir SS, Richter BWM, Duckett CS. Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells. Blood 2000; 96: 4307–12. [PubMed] [Google Scholar]
  • 42. Fukuda Y, Yamamura J, Uwano T, Nishijo H, Kurokawa M, Fukuda M, Ono T, Shiraki K. Regulated transgene delivery by ganciclovir in the brain without physiological alterations by a live attenuated herpes simplex virus vector. Neurosci Res 2003; 45: 233–41. [DOI] [PubMed] [Google Scholar]
  • 43. Whitley RJ. Herpes simplex virus infection. In: Knipe DM, Howley PM, editors. Fields virology. 4th ed. Philadelphia : Lippincott Williams & Wilkins; 2001. p. 2461–509. [Google Scholar]
  • 44. Doherty PC. Cell‐mediated cytotoxicity. Cell 1993; 75: 607–12. [DOI] [PubMed] [Google Scholar]
  • 45. Kagi D, Vignaux F, Ledermann B, Burki K, Depraetere V, Nagata S, Hengartner H, Golstein P. Fas and perforin pathways as major mechanisms of T cell‐mediated cytotoxicity. Science 1994; 265: 528–30. [DOI] [PubMed] [Google Scholar]
  • 46. Bradley M, Zeytun A, Rafi‐Janajreh A, Nagarkatti PS, Nagarkatti M. Role of spontaneous and interleukin‐2‐induced natural killer cell activity in the cyto‐toxicity and rejection of Fas+ and Fas‐ tumor cells. Blood 1998; 92: 4248–55. [PubMed] [Google Scholar]
  • 47. Smyth MJ, Kelly JM, Baxter AG, Korner H, Sedgwick JD. An essential role for tumor necrosis factor in natural killer cell‐mediated tumor rejection in peritoneum. J Exp Med 1998; 188: 1611–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES