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:

In vivo safety, biodistribution and antitumor effects of uPAR retargeted oncolytic measles virus in syngeneic cancer models

Gene Therapy volume 21, pages 289–297 (2014)Cite this article

Subjects

Abstract

The urokinase receptor (uPAR) is a clinically relevant target for novel biological therapies. We have previously rescued oncolytic measles viruses fully retargeted against human (MV-h-uPA) or murine (MV-m-uPA) uPAR. Here, we investigated the in vivo effects of systemic administration of MV-m-uPA in immunocompetent cancer models. MV-m-uPA induced in vitro cytotoxicity and replicated in a receptor-dependent manner in murine mammary (4T1) and colon (MC-38 and CT-26) cancer cells. Intravenous administration of MV-m-uPA to 4T1 tumor-bearing mice was not associated with significant clinical or laboratory toxicity. Higher MV-N RNA copy numbers were detected in primary tumors, and viable viral particles were recovered from tumor-bearing tissues only. Non-tumor-bearing organs did not show histological signs of viral-induced toxicity. Serum anti-MV antibodies were detected at day 14 of treatment. Immunohistochemistry and immunofluorescence studies confirmed successful tumor targeting and demonstrated enhanced MV-m-uPA-induced tumor cell apoptosis in treated compared with control mice. Significant antitumor effects and prolonged survival were observed after systemic administration of MV-m-uPA in colon (CT-26) and mammary (4T1) cancer models. The above results show safety and feasibility of uPAR targeting by an oncolytic virus, and confirm significant antitumor effects in highly aggressive syngeneic immunocompetent cancer models.

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

Similar content being viewed by others

References

  1. Patel MR, Kratzke RA . Oncolytic virus therapy for cancer: the first wave of translational clinical trials. Translational Res 2013; 161: 355–364.

    Article  CAS  Google Scholar 

  2. Nakamura T, Russell SJ . Oncolytic measles viruses for cancer therapy. Exp Opin Biol Ther 2004; 4: 1685–1692.

    Article  CAS  Google Scholar 

  3. Russell SJ . RNA viruses as virotherapy agents. Cancer Gene Ther 2002; 9: 961–966.

    Article  CAS  PubMed  Google Scholar 

  4. Galanis E, Hartmann LC, Cliby WA, Long HJ, Peethambaram PP, Barrette BA et al. Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res 2010; 70: 875–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Allen C, Paraskevakou G, Iankov I, Giannini C, Schroeder M, Sarkaria J et al. Interleukin-13 displaying retargeted oncolytic measles virus strains have significant activity against gliomas with improved specificity. Mol Ther 2008; 16: 1556–1564.

    Article  CAS  PubMed  Google Scholar 

  6. Allen C, Vongpunsawad S, Nakamura T, James CD, Schroeder M, Cattaneo R et al. Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity. Cancer Res 2006; 66: 11840–11850.

    Article  CAS  PubMed  Google Scholar 

  7. Peng KW, Donovan KA, Schneider U, Cattaneo R, Lust JA, Russell SJ . Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker. Blood 2003; 101: 2557–2562.

    Article  CAS  PubMed  Google Scholar 

  8. Springfeld C, von Messling V, Frenzke M, Ungerechts G, Buchholz CJ, Cattaneo R . Oncolytic efficacy and enhanced safety of measles virus activated by tumor-secreted matrix metalloproteinases. Cancer Res 2006; 66: 7694–7700.

    Article  CAS  PubMed  Google Scholar 

  9. Blasi F, Carmeliet P . uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932–943.

    Article  CAS  PubMed  Google Scholar 

  10. Boyd D, Florent G, Kim P, Brattain M . Determination of the levels of urokinase and its receptor in human colon carcinoma cell lines. Cancer Res 1988; 48: 3112–3116.

    CAS  PubMed  Google Scholar 

  11. Dass K, Ahmad A, Azmi AS, Sarkar SH, Sarkar FH . Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 2008; 34: 122–136.

    Article  CAS  PubMed  Google Scholar 

  12. Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T, Kanetake H . Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis. J Urol 2005; 174: 461–465.

    Article  PubMed  Google Scholar 

  13. Gutova M, Najbauer J, Gevorgyan A, Metz MZ, Weng Y, Shih CC et al. Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS One 2007; 2: e243.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Rabbani SA, Xing RH . Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. Int J Oncol 1998; 12: 911–920.

    CAS  PubMed  Google Scholar 

  15. Li P, Gao Y, Ji Z, Zhang X, Xu Q, Li G et al. Role of urokinase plasminogen activator and its receptor in metastasis and invasion of neuroblastoma. J Pediatr Surg 2004; 39: 1512–1519.

    Article  PubMed  Google Scholar 

  16. Lester RD, Jo M, Montel V, Takimoto S, Gonias SL . uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol 2007; 178: 425–436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bianchi E, Cohen RL, Thor AT, Todd RF 3rd, Mizukami IF, Lawrence DA et al. The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res 1994; 54: 861–866.

    CAS  PubMed  Google Scholar 

  18. Plesner T, Ralfkiaer E, Wittrup M, Johnsen H, Pyke C, Pedersen TL et al. Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue. Am J Clin Pathol 1994; 102: 835–841.

    Article  CAS  PubMed  Google Scholar 

  19. Romer J, Lund LR, Eriksen J, Pyke C, Kristensen P, Dano K . The receptor for urokinase-type plasminogen activator is expressed by keratinocytes at the leading edge during re-epithelialization of mouse skin wounds. J Invest Dermatol 1994; 102: 519–522.

    Article  CAS  PubMed  Google Scholar 

  20. Romer J, Nielsen BS, Ploug M . The urokinase receptor as a potential target in cancer therapy. Curr Pharm Des 2004; 10: 2359–2376.

    Article  CAS  PubMed  Google Scholar 

  21. Smith HW, Marshall CJ . Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11: 23–36.

    Article  CAS  PubMed  Google Scholar 

  22. Solberg H, Ploug M, Hoyer-Hansen G, Nielsen BS, Lund LR . The murine receptor for urokinase-type plasminogen activator is primarily expressed in tissues actively undergoing remodeling. J Histochem Cytochem 2001; 49: 237–246.

    Article  CAS  PubMed  Google Scholar 

  23. Uszynski M, Perlik M, Uszynski W, Zekanowska E . Urokinase plasminogen activator (uPA) and its receptor (uPAR) in gestational tissues; measurements and clinical implications. Eur J Obstet Gynecol Reprod Biol 2004; 114: 54–58.

    Article  CAS  PubMed  Google Scholar 

  24. D'Alessio S, Margheri F, Pucci M, Del Rosso A, Monia BP, Bologna M et al. Antisense oligodeoxynucleotides for urokinase-plasminogen activator receptor have anti-invasive and anti-proliferative effects in vitro and inhibit spontaneous metastases of human melanoma in mice. Int J Cancer 2004; 110: 125–133.

    Article  CAS  PubMed  Google Scholar 

  25. Gondi CS, Lakka SS, Dinh DH, Olivero WC, Gujrati M, Rao JS . Downregulation of uPA, uPAR and MMP-9 using small, interfering, hairpin RNA (siRNA) inhibits glioma cell invasion, angiogenesis and tumor growth. Neuron Glia Biol 2004; 1: 165–176.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gondi CS, Lakka SS, Yanamandra N, Olivero WC, Dinh DH, Gujrati M et al. Adenovirus-mediated expression of antisense urokinase plasminogen activator receptor and antisense cathepsin B inhibits tumor growth, invasion, and angiogenesis in gliomas. Cancer Res 2004; 64: 4069–4077.

    Article  CAS  PubMed  Google Scholar 

  27. Li H, Lu H, Griscelli F, Opolon P, Sun LQ, Ragot T et al. Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice. Gene Therapy 1998; 5: 1105–1113.

    Article  CAS  PubMed  Google Scholar 

  28. Rabbani SA, Gladu J . Urokinase receptor antibody can reduce tumor volume and detect the presence of occult tumor metastases in vivo. Cancer Res 2002; 62: 2390–2397.

    CAS  PubMed  Google Scholar 

  29. Yang L, Peng XH, Wang YA, Wang X, Cao Z, Ni C et al. Receptor-targeted nanoparticles for in vivo imaging of breast cancer. Clin Cancer Res 2009; 15: 4722–4732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jing Y, Tong C, Zhang J, Nakamura T, Iankov I, Russell SJ et al. Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor. Cancer Res 2009; 69: 1459–1468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bucheit AD, Kumar S, Grote DM, Lin Y, von Messling V, Cattaneo RB et al. An oncolytic measles virus engineered to enter cells through the CD20 antigen. Mol Ther 2003; 7: 62–72.

    Article  CAS  PubMed  Google Scholar 

  32. Bach P, Abel T, Hoffmann C, Gal Z, Braun G, Voelker I et al. Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus. Cancer Res 2013; 73: 865–874.

    Article  CAS  PubMed  Google Scholar 

  33. Ungerechts G, Springfeld C, Frenzke ME, Lampe J, Parker WB, Sorscher EJ et al. An Immunocompetent murine model for oncolysis with an armed and targeted measles virus. Mol Ther 2007; 15: 1991–1997.

    Article  CAS  PubMed  Google Scholar 

  34. Bossow S, Grossardt C, Temme A, Leber MF, Sawall S, Rieber EP et al. Armed and targeted measles virus for chemovirotherapy of pancreatic cancer. Cancer Gene Ther 2011; 18: 598–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bhaskar A, Bala J, Varshney A, Yadava P . Expression of measles virus nucleoprotein induces apoptosis and modulates diverse functional proteins in cultured mammalian cells. PLoS One 2011; 6: e18765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Esolen LM, Park SW, Hardwick JM, Griffin DE . Apoptosis as a cause of death in measles virus-infected cells. J Virol 1995; 69: 3955–3958.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Laine D, Bourhis JM, Longhi S, Flacher M, Cassard L, Canard B et al. Measles virus nucleoprotein induces cell-proliferation arrest and apoptosis through NTAIL-NR and NCORE-FcgammaRIIB1 interactions, respectively. J Gen Virol 2005; 86: 1771–1784.

    Article  CAS  PubMed  Google Scholar 

  38. Borrego-Diaz E, Mathew R, Hawkinson D, Esfandyari T, Liu Z, Lee PW et al. Pro-oncogenic cell signaling machinery as a target for oncolytic viruses. Curr Pharm Biotechnol 2012; 13: 1742–1749.

    Article  CAS  PubMed  Google Scholar 

  39. Nguyen TL, Abdelbary H, Arguello M, Breitbach C, Leveille S, Diallo JS et al. Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis. Proc Natl Acad Sci USA 2008; 105: 14981–14986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakamura T, Peng KW, Harvey M, Greiner S, Lorimer IA, James CD et al. Rescue and propagation of fully retargeted oncolytic measles viruses. Nat Biotechnol 2005; 23: 209–214.

    Article  CAS  PubMed  Google Scholar 

  41. Jing Y, Kovacs K, Kurisetty V, Jiang Z, Tsinoremas N, Merchan JR . Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects. Mol Cancer Res 2012; 10: 1271–1281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Peng KW, Frenzke M, Myers R, Soeffker D, Harvey M, Greiner S et al. Biodistribution of oncolytic measles virus after intraperitoneal administration into Ifnar-CD46Ge transgenic mice. Hum Gene Ther 2003; 14: 1565–1577.

    Article  CAS  PubMed  Google Scholar 

  43. Iankov ID, Pandey M, Harvey M, Griesmann GE, Federspiel MJ, Russell SJ . Immunoglobulin g antibody-mediated enhancement of measles virus infection can bypass the protective antiviral immune response. J Virol 2006; 80: 8530–8540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Myers RM, Greiner SM, Harvey ME, Griesmann G, Kuffel MJ, Buhrow SA et al. Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide. Clin Pharmacol Ther 2007; 82: 700–710.

    Article  CAS  PubMed  Google Scholar 

  45. Merchan JR, Kovacs K, Railsback JW, Kurtoglu M, Jing Y, Pina Y et al. Antiangiogenic activity of 2-deoxy-D-glucose. PLoS One 2010; 5: e13699.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Littell RC, Henry PR, Ammerman CB . Statistical analysis of repeated measures data using SAS procedures. J Animal Sci 1998; 76: 1216–1231.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a research grant from the National Cancer Institute (1R01CA149659-01 to JRM, JZ, RD), and by the Sylvester Comprehensive Cancer Center (JRM).

Author information

Authors and Affiliations

  1. Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA

    Y Jing & J R Merchan

  2. Department of Veterinary Resources, University of Miami, Miami, FL, USA

    J Zaias

  3. Epidemiology and Public Health Department, University of Miami, Miami, FL, USA

    R Duncan

  4. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

    S J Russell

Authors
  1. Y Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Zaias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Duncan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S J Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J R Merchan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J R Merchan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jing, Y., Zaias, J., Duncan, R. et al. In vivo safety, biodistribution and antitumor effects of uPAR retargeted oncolytic measles virus in syngeneic cancer models. Gene Ther 21, 289–297 (2014). https://doi.org/10.1038/gt.2013.84

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2013.84

Keywords

This article is cited by

Search

Advanced search

Quick links