Advertisement

Regional administration of oncolytic Echovirus 1 as a novel therapy for the peritoneal dissemination of gastric cancer

  • Erin S. Haley
  • Gough G. Au
  • Brian R. Carlton
  • Richard D. Barry
  • Darren R. ShafrenEmail author
Original Article

Abstract

The dissemination of malignant gastric cells to the peritoneum occurs frequently, usually as an early event in disease, and results in poor patient prognosis. Surgery and chemotherapy offer limited therapeutic success. The low-pathogenic human enterovirus, Echovirus 1 (EV1), is an oncolytic virus that selectively targets and destroys malignant prostate and ovarian cancer xenografts in vivo. Lytic EV1 infection requires the cell surface expression of α2β1, an integrin involved in the dissemination of gastric cancer cells to the peritoneum. Herein, we evaluated the capacity of EV1 for anti-neoplastic cell action in gastric peritoneal carcinomatosis. Flow cytometric analysis demonstrated that α2β1 was abundantly surface expressed on a panel of gastric cancer cell lines, rendering the majority of lines highly susceptible to in vitro lytic EV1 infection and supportive of efficient viral progeny production. A bioluminescent MKN-45-Luc SCID mouse model of peritoneal dissemination was developed to allow real-time non-invasive monitoring of peritoneal tumor burden. Employing this mouse model, we demonstrated a therapeutic dose-response for escalating oncolytic EV1 doses. Taken together, these results emphasize the exciting potential for EV1 as a single or adjunct therapy for the control of the peritoneal dissemination of gastric cancer.

Keywords

Echovirus 1 Oncolytic virus Virotherapy Gastric cancer Peritoneal dissemination 

Notes

Acknowledgements

We gratefully acknowledge those investigators mentioned in the text for the provision of monoclonal antibodies, vectors, cell lines, and virus that enabled this study to be undertaken. We would also like to thank Dr Erin O’Neill, Jaclyn Stewart, Elise Mac Pherson, Debbie Pepperall, Matthew Bowman, and Brian Krishnan for their valuable technical assistance throughout the project and Dr E. S. Johansson for revision of the manuscript. Funding for this work was provided by Viralytics Ltd.

Funding

Darren R. Shafren is a director of Viralytics Pty Ltd. Gough G. Au, Richard D. Barry and Darren R. Shafren hold stock of Viralytics Pty Ltd. and are currently conducting research sponsored by this company.

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Crew KD, Neugut AI (2006) Epidemiology of gastric cancer. World J Gastroenterol 12:354–362PubMedGoogle Scholar
  3. 3.
    Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, Fontaumard E, Brachet A, Caillot JL, Faure JL, Porcheron J, Peix JL, Francois Y, Vignal J, Gilly FN (2000) Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 88:358–363PubMedCrossRefGoogle Scholar
  4. 4.
    Fujiwara Y, Doki Y, Taniguchi H, Sohma I, Takiguchi S, Miyata H, Yamasaki M, Monden M (2007) Genetic detection of free cancer cells in the peritoneal cavity of the patient with gastric cancer: present status and future perspectives. Gastric Cancer 10:197–204PubMedCrossRefGoogle Scholar
  5. 5.
    Chu DZ, Lang NP, Thompson C, Osteen PK, Westbrook KC (1989) Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer 63:364–367PubMedCrossRefGoogle Scholar
  6. 6.
    Yonemura Y, Endo Y, Obata T, Sasaki T (2007) Recent advances in the treatment of peritoneal dissemination of gastrointestinal cancers by nucleoside antimetabolites. Cancer Sci 98:11–18PubMedCrossRefGoogle Scholar
  7. 7.
    Al-Shammaa HA, Li Y, Yonemura Y (2008) Current status and future strategies of cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. World J Gastroenterol 14:1159–1166PubMedCrossRefGoogle Scholar
  8. 8.
    Bell JC, Garson KA, Lichty BD, Stojdl DF (2002) Oncolytic viruses: programmable tumour hunters. Curr Gene Ther 2:243–254PubMedCrossRefGoogle Scholar
  9. 9.
    Parato KA, Senger D, Forsyth PA, Bell JC (2005) Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 5:965–976PubMedCrossRefGoogle Scholar
  10. 10.
    Bennett JJ, Kooby DA, Delman K, McAuliffe P, Halterman MW, Federoff H, Fong Y (2000) Antitumor efficacy of regional oncolytic viral therapy for peritoneally disseminated cancer. J Mol Med 78:166–174PubMedCrossRefGoogle Scholar
  11. 11.
    Bennett JJ, Delman KA, Burt BM, Mariotti A, Malhotra S, Zager J, Petrowsky H, Mastorides S, Federoff H, Fong Y (2002) Comparison of safety, delivery, and efficacy of two oncolytic herpes viruses (G207 and NV1020) for peritoneal cancer. Cancer Gene Ther 9:935–945PubMedCrossRefGoogle Scholar
  12. 12.
    Stanziale SF, Stiles BM, Bhargava A, Kerns SA, Kalakonda N, Fong Y (2004) Oncolytic herpes simplex virus-1 mutant expressing green fluorescent protein can detect and treat peritoneal cancer. Hum Gene Ther 15:609–618PubMedCrossRefGoogle Scholar
  13. 13.
    Kangasniemi L, Kiviluoto T, Kanerva A, Raki M, Ranki T, Sarkioja M, Wu H, Marini F, Hockerstedt K, Isoniemi H, Alfthan H, Stenman UH, Curiel DT, Hemminki A (2006) Infectivity-enhanced adenoviruses deliver efficacy in clinical samples and orthotopic models of disseminated gastric cancer. Clin Cancer Res 12:3137–3144PubMedCrossRefGoogle Scholar
  14. 14.
    Huang X, Zhuang L, Cao Y, Gao Q, Han Z, Tang D, Xing H, Wang W, Lu Y, Xu G, Wang S, Zhou J, Ma D (2008) Biodistribution and kinetics of the novel selective oncolytic adenovirus M1 after systemic administration. Mol Cancer Ther 7:1624–1632PubMedCrossRefGoogle Scholar
  15. 15.
    Shafren DR, Au GG, Nguyen T, Newcombe NG, Haley ES, Beagley L, Johansson ES, Hersey P, Barry RD (2004) Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, Coxsackievirus A21. Clin Cancer Res 10:53–60PubMedCrossRefGoogle Scholar
  16. 16.
    Au G, Lincz LF, Enno A, Shafren DR (2007) Oncolytic Coxsackievirus A21 as a novel therapy for multiple myeloma. Br J Haematol 137:133–141PubMedCrossRefGoogle Scholar
  17. 17.
    Skelding KA, Barry RD, Shafren DR (2008) Systemic targeting of metastatic human breast tumor xenografts by Coxsackievirus A21. Breast Cancer Res Treat. doi: 10.1007/s10549-008-9899-2
  18. 18.
    Berry LJ, Au GG, Barry RD, Shafren DR (2008) Potent oncolytic activity of human enteroviruses against human prostate cancer. The Prostate 68:577–587PubMedCrossRefGoogle Scholar
  19. 19.
    Shafren DR, Sylvester D, Johansson ES, Campbell IG, Barry RD (2005) Oncolysis of human ovarian cancers by echovirus type 1. Int J Cancer 115:320–328PubMedCrossRefGoogle Scholar
  20. 20.
    Bergelson JM, St John NF, Kawaguchi S, Pasqualini R, Berdichevsky F, Hemler ME, Finberg RW (1994) The I domain is essential for echovirus 1 interaction with VLA-2. Cell Adhes Commun 2:455–464PubMedCrossRefGoogle Scholar
  21. 21.
    Bergelson JM, Shepley MP, Chan BM, Hemler ME, Finberg RW (1992) Identification of the integrin VLA-2 as a receptor for echovirus 1. Science 255:1718–1720PubMedCrossRefGoogle Scholar
  22. 22.
    Kawamura T, Endo Y, Yonemura Y, Nojima N, Fujita H, Fujimura T, Obata T, Yamaguchi T, Sasaki T (2001) Significance of integrin alpha2/beta1 in peritoneal dissemination of a human gastric cancer xenograft model. Int J Oncol 18:809–815PubMedGoogle Scholar
  23. 23.
    Koike N, Todoroki T, Komano H, Shimokama T, Ban S, Ohno T, Fukao K, Watanabe T (1997) Invasive potentials of gastric carcinoma cell lines: role of alpha 2 and alpha 6 integrins in invasion. J Cancer Res Clin Oncol 123:310–316PubMedGoogle Scholar
  24. 24.
    Nishimura S, Chung YS, Yashiro M, Inoue T, Sowa M (1996) Role of alpha 2 beta 1- and alpha 3 beta 1-integrin in the peritoneal implantation of scirrhous gastric carcinoma. Br J Cancer 74:1406–1412PubMedGoogle Scholar
  25. 25.
    Matsuoka T, Yashiro M, Nishimura S, Inoue T, Fujihara T, Sawada T, Kato Y, Seki S, Hirakawa-Ys Chung K (2000) Increased expression of alpha2beta1-integrin in the peritoneal dissemination of human gastric carcinoma. Int J Mol Med 5:21–25PubMedGoogle Scholar
  26. 26.
    Lin MT, Chang CC, Lin BR, Yang HY, Chu CY, Wu MH, Kuo ML (2007) Elevated expression of Cyr61 enhances peritoneal dissemination of gastric cancer cells through integrin alpha2beta1. J Biol Chem 282:34594–34604PubMedCrossRefGoogle Scholar
  27. 27.
    Xing L, Huhtala M, Pietiainen V, Vuorinen K, Marjomaki V, Heino J, Johnson MS, Hyypia T, Cheng RH (2004) Structural and functional analysis of integrin a2I domain interaction with echovirus 1. J Biol Chem 279:11632–11638PubMedCrossRefGoogle Scholar
  28. 28.
    Bergelson JM, Chan BM, Finberg RW, Hemler ME (1993) The integrin VLA-2 binds echovirus 1 and extracellular matrix ligands by different mechanisms. J Clin Invest 92:232–239PubMedCrossRefGoogle Scholar
  29. 29.
    Kapyla J, Pentikainen OT, Nyronen T, Nissinen L, Lassander S, Jokinen J, Lahti M, Marjamaki A, Johnson MS, Heino J (2007) Small molecule designed to target metal binding site in the alpha2I domain inhibits integrin function. J Med Chem 50:2742–2746PubMedCrossRefGoogle Scholar
  30. 30.
    Melnick JL, Aagren K (1952) Poliomyelitis and coxsackie viruses isolated from normal infants in Egypt. Proc Soc Exp Biol Med 81:621–624PubMedGoogle Scholar
  31. 31.
    Couch RB, Cate TR, Gerone PJ, Fleet WF, Lang DJ, Griffith WR, Knight V (1965) Production of illness with a small-particle aerosol of Coxsackie A21. J Clin Invest 44:535–542PubMedCrossRefGoogle Scholar
  32. 32.
    Rancaniello VR (2001) Picornaviridae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (eds) Field’s virology. Lippincott Williman and Wilkins, Philadelphia, pp 685–722Google Scholar
  33. 33.
    Dougherty RM (1964) Animal virus titration techniques. In: Harris RJC (ed) Techniques in experimental virology. Academic, New York, pp 169–223Google Scholar
  34. 34.
    Yousef GE, Brown IN, Mowbray JF (1987) Derivation and biochemical characterization of an enterovirus group-specific monoclonal antibody. Intervirology 28:163–170PubMedGoogle Scholar
  35. 35.
    Samuelson A, Forsgren M, Sallberg M (1995) Characterization of the recognition site and diagnostic potential of an enterovirus group-reactive monoclonal antibody. Clin Diagn Lab Immunol 2:385–386PubMedGoogle Scholar
  36. 36.
    Dikmen ZG, Gellert G, Dogan P, Mason R, Antich P, Richer E, Wright WE, shay JW (2005) A new diagnostic system in cancer research: bioluminescent imaging (BLI). Turk J Med Sci 35:65–70Google Scholar
  37. 37.
    Ura H, Denno R, Hirata K, Yamaguchi K, Yasoshima T (1998) Separate functions of alpha2beta1 and alpha3beta1 integrins in the metastatic process of human gastric carcinoma. Surg Today 28:1001–1006PubMedCrossRefGoogle Scholar
  38. 38.
    Zhang S, Racaniello VR (1997) Persistent echovirus infection of mouse cells expressing the viral receptor VLA-2. Virology 235:293–301PubMedCrossRefGoogle Scholar
  39. 39.
    Pietiainen V, Marjomaki V, Upla P, Pelkmans L, Helenius A, Hyypia T (2004) Echovirus 1 endocytosis into caveosomes requires lipid rafts, dynamin II, and signaling events. Mol Biol Cell 15:4911–4925PubMedCrossRefGoogle Scholar
  40. 40.
    Vaha-Koskela MJ, Heikkila JE, Hinkkanen AE (2007) Oncolytic viruses in cancer therapy. Cancer Lett 254:178–216PubMedCrossRefGoogle Scholar
  41. 41.
    Yanagihara K, Takigahira M, Tanaka H, Komatsu T, Fukumoto H, Koizumi F, Nishio K, Ochiya T, Ino Y, Hirohashi S (2005) Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer. Cancer Sci 96:323–332PubMedCrossRefGoogle Scholar
  42. 42.
    Kaneko K, Yano M, Tsujinaka T, Morita S, Taniguchi M, Fujiwara Y, Doki Y, Inoue M, Shiozaki H, Monden M (2000) Establishment of a visible peritoneal micrometastatic model from a gastric adenocarcinoma cell line by green fluorescent protein. Int J Oncol 16:893–898PubMedGoogle Scholar
  43. 43.
    Yanagihara K, Takigahira M, Takeshita F, Komatsu T, Nishio K, Hasegawa F, Ochiya T (2006) A photon counting technique for quantitatively evaluating progression of peritoneal tumor dissemination. Cancer Res 66:7532–7539PubMedCrossRefGoogle Scholar
  44. 44.
    Motoyama T, Hojo H, Watanabe H (1986) Comparison of seven cell lines derived from human gastric carcinomas. Acta Pathol Jpn 36:65–83PubMedGoogle Scholar
  45. 45.
    Nakano K, Todo T, Zhao G, Yamaguchi K, Kuroki S, Cohen JB, Glorioso JC, Tanaka M (2005) Enhanced efficacy of conditionally replicating herpes simplex virus (G207) combined with 5-fluorouracil and surgical resection in peritoneal cancer dissemination models. J Gene Med 7:638–648PubMedCrossRefGoogle Scholar
  46. 46.
    Novozhilov AS, Berezovskaya FS, Koonin EV, Karev GP (2006) Mathematical modeling of tumor therapy with oncolytic viruses: regimes with complete tumor elimination within the framework of deterministic models. Biol Direct 1:6PubMedCrossRefGoogle Scholar
  47. 47.
    Wodarz D (2001) Viruses as antitumor weapons: defining conditions for tumor remission. Cancer Res 61:3501–3507PubMedGoogle Scholar
  48. 48.
    Karttunen A, Poyry T, Vaarala O, Ilonen J, Hovi T, Roivainen M, Hyypia T (2003) Variation in enterovirus receptor genes. J Med Virol 70:99–108PubMedCrossRefGoogle Scholar
  49. 49.
    Khetsuriani N, Lamonte-Fowlkes A, Oberst S, Pallansch MA (2006) Enterovirus surveillance—United States, 1970–2005. MMWR Surveill Summ 55:1–20PubMedGoogle Scholar
  50. 50.
    Yoo CH, Noh SH, Shin DW, Choi SH, Min JS (2000) Recurrence following curative resection for gastric carcinoma. Br J Surg 87:236–242PubMedCrossRefGoogle Scholar
  51. 51.
    Ziprin P, Ridgway PF, Peck DH, Darzi AW (2003) Laparoscopic enhancement of tumour cell binding to the peritoneum is inhibited by anti-intercellular adhesion molecule-1 monoclonal antibody. Surg Endosc 17:1812–1817PubMedCrossRefGoogle Scholar
  52. 52.
    Oosterling SJ, van der Bij GJ, Bogels M, ten Raa S, Post JA, Meijer GA, Beelen RH, van Egmond M (2008) Anti-beta1 integrin antibody reduces surgery-induced adhesion of colon carcinoma cells to traumatized peritoneal surfaces. Ann Surg 247:85–94PubMedCrossRefGoogle Scholar
  53. 53.
    Jung IK, Kim MC, Kim KH, Kwak JY, Jung GJ, Kim HH (2008) Cellular and peritoneal immune response after radical laparoscopy-assisted and open gastrectomy for gastric cancer. J Surg Oncol 98:54–59PubMedCrossRefGoogle Scholar
  54. 54.
    Hegarty N, Dasgupta P (2008) Immunological aspects of minimally invasive oncologic surgery. Curr Opin Urol 18:129–133PubMedCrossRefGoogle Scholar
  55. 55.
    Fu X, Tao L, Zhang X (2007) An oncolytic virus derived from type 2 herpes simplex virus has potent therapeutic effect against metastatic ovarian cancer. Cancer Gene Ther 14:480–487PubMedCrossRefGoogle Scholar
  56. 56.
    Peng KW, TenEyck CJ, Galanis E, Kalli KR, Hartmann LC, Russell SJ (2002) Intraperitoneal therapy of ovarian cancer using an engineered measles virus. Cancer Res 62:4656–4662PubMedGoogle Scholar
  57. 57.
    Kanerva A, Zinn KR, Chaudhuri TR, Lam JT, Suzuki K, Uil TG, Hakkarainen T, Bauerschmitz GJ, Wang M, Liu B, Cao Z, Alvarez RD, Curiel DT, Hemminki A (2003) Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus. Mol Ther 8:449–458PubMedCrossRefGoogle Scholar
  58. 58.
    Sunamura M, Oonuma M, Motoi F, Abe H, Saitoh Y, Hoshida T, Ottomo S, Horii A, Matsuno S (2002) Gene therapy for pancreatic cancer targeting the genomic alterations of tumor suppressor genes using replication-selective oncolytic adenovirus. Hum Cell 15:138–150PubMedCrossRefGoogle Scholar
  59. 59.
    Guse K, Ranki T, Ala-Opas M, Bono P, Sarkioja M, Rajecki M, Kanerva A, Hakkarainen T, Hemminki A (2007) Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses. Mol Cancer Ther 6:2728–2736PubMedCrossRefGoogle Scholar
  60. 60.
    Schleissner LA, Portnoy B (1973) Spectrum of ECHO virus 1 disease in a young diabetic. CHEST 63:457–459PubMedCrossRefGoogle Scholar
  61. 61.
    Desmond RA, Accortt NA, Talley L, Villano SA, Soong SJ, Whitley RJ (2006) Enteroviral meningitis: natural history and outcome of pleconaril therapy. Antimicrob Agents Chemother 50:2409–2414PubMedCrossRefGoogle Scholar
  62. 62.
    McQuillan GM, Kruszon-Moran D, Hyde TB, Forghani B, Bellini W, Dayan GH (2007) Seroprevalence of measles antibody in the US population, 1999–2004. J Infect Dis 196:1459–1464PubMedCrossRefGoogle Scholar
  63. 63.
    Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D, Robbins PD, Gambotto A (2004) Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. Clin Diagn Lab Immunol 11:351–357PubMedCrossRefGoogle Scholar
  64. 64.
    Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, Berman SM, Markowitz LE (2006) Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. Jama 296:964–973PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Erin S. Haley
    • 1
  • Gough G. Au
    • 1
  • Brian R. Carlton
    • 2
  • Richard D. Barry
    • 1
  • Darren R. Shafren
    • 1
    • 3
    Email author
  1. 1.The Picornavirus Research Unit, School of Biomedical Sciences, Faculty of HealthThe University of NewcastleNewcastleAustralia
  2. 2.Animal Services UnitThe University of NewcastleNewcastleAustralia
  3. 3.Viralytics LtdPymbleAustralia

Personalised recommendations