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:

A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy

Oncogene volume 29, pages 1145–1154 (2010)Cite this article

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is related to asbestos exposure. MPM is characterized by rapid and diffuse local growth in the thoracic cavity, and it has a poor prognosis because it is often refractory to conventional therapy. Although MPM is an extraordinarily challenging disease to treat, locoregional virotherapy may be useful against this aggressive disease because of the accessibility by intrapleural virus delivery. In this study, we show that telomerase-specific, replication-selective adenovirus OBP-301 can efficiently infect and kill human mesothelioma cells by viral replication. Intrathoracic administration of virus significantly reduced the number and size of human mesothelioma tumors intrathoracically implanted into nu/nu mice. A high-definition, fluorescence optical imaging system with an ultra-thin, flexible fibered microprobe clearly detected intracellular replication of green fluorescent protein-expressing oncolytic virus in intrathoracically established mesothelioma tumors. As the extracellular matrix (ECM) may contribute to the physiological resistance of a solid tumor by preventing the penetration of therapeutic agents (including oncolytic viruses), we also examined whether the co-expression of heparanase, an endoglucuronidase capable of specifically degrading heparan sulfate, that influences the physiological barrier to macromolecule penetration, can modify the permeability of the ECM, resulting in profound therapeutic efficacy. Co-injection of OBP-301 and a replication-defective adenovirus (Ad-S/hep)-expressing heparanase resulted in more profound antitumor effects without apparent toxicity in an orthotopic pleural dissemination model. Our results suggest that intrathoracic dual virotherapy with telomerase-specific oncolytic adenovirus in combination with heparanase-expressing adenovirus may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma.

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

  • Alberts AS, Falkson G, Goedhals L, Vorobiof DA, Van der Merwe CA . (1988). Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. J Clin Oncol 6: 527–535.

    Article  CAS  PubMed  Google Scholar 

  • Ball DL, Cruickshank DG . (1990). The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 13: 4–9.

    Article  CAS  PubMed  Google Scholar 

  • Blackburn JS, Rhodes CH, Coon CI, Brinckerhoff CE . (2007). RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis. Cancer Res 67: 10849–10858.

    Article  CAS  PubMed  Google Scholar 

  • Chahinian AP, Pajak TF, Holland JF, Norton L, Ambinder RM, Mandel EM . (1982). Diffuse malignant mesothelioma. Prospective evaluation of 69 patients. Ann Intern Med 96: 746–755.

    Article  CAS  PubMed  Google Scholar 

  • Chailleux E, Dabouis G, Pioche D, de LM, de Lajartre AY, Rembeaux A et al. (1988). Prognostic factors in diffuse malignant pleural mesothelioma. A study of 167 patients. Chest 93: 159–162.

    Article  CAS  PubMed  Google Scholar 

  • Cheng J, Sauthoff H, Huang Y, Kutler DI, Bajwa S, Rom WN et al. (2007). Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus. Mol Ther 15: 1982–1990.

    Article  CAS  PubMed  Google Scholar 

  • Connelly RR, Spirtas R, Myers MH, Percy CL, Fraumeni Jr JF . (1987). Demographic patterns for mesothelioma in the United States. J Natl Cancer Inst 78: 1053–1060.

    CAS  PubMed  Google Scholar 

  • Eikenes L, Bruland OS, Brekken C, Davies CL . (2004). Collagenase increases the transcapillary pressure gradient and improves the uptake and distribution of monoclonal antibodies in human osteosarcoma xenografts. Cancer Res 64: 4768–4773.

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald M, Hayward IP, Thomas AC, Campbell GR, Campbell JH . (1999). Matrix metalloproteinase can facilitate the heparanase-induced promotion of phenotype change in vascular smooth muscle cells. Atherosclerosis 145: 97–106.

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara T, Tanaka N, Numunaitis JJ, Senzer NN, Tong A, Ichimaru D et al. (2008). Phase I trial of intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, in patients with advanced solid cancer: Evaluation of biodistribution and immune response. J Clin Oncol 26: 3572.

    Article  Google Scholar 

  • Ganesh S, Gonzalez EM, Idamakanti N, Abramova M, Vanroey M, Robinson M et al. (2007). Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. Cancer Res 67: 4399–4407.

    Article  CAS  PubMed  Google Scholar 

  • Goodrum FD, Ornelles DA . (1998). p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. J Virol 72: 9479–9490.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hioki M, Kagawa S, Fujiwara T, Sakai R, Kojima T, Watanabe Y et al. (2008). Combination of oncolytic adenovirotherapy and Bax gene therapy in human cancer xenografted models. Potential merits and hurdles for combination therapy. Int J Cancer 122: 2628–2633.

    Article  CAS  PubMed  Google Scholar 

  • Kawashima T, Kagawa S, Kobayashi N, Shirakiya Y, Umeoka T, Teraishi F et al. (2004). Telomerase-specific replication-selective virotherapy for human cancer. Clin Cancer Res 10: 285–292.

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Lee YS, Kim H, Huang JH, Yoon AR, Yun CO . (2006). Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst 98: 1482–1493.

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto H, Kojima T, Watanabe Y, Kagawa S, Fujiwara T, Uno F et al. (2006). In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus. Nat Med 12: 1213–1219.

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto H, Zhao M, Hayashi K, Urata Y, Tanaka N, Fujiwara T et al. (2009). In vivo internal tumor illumination by telomerase-dependent adenoviral GFP for precise surgical navigation. Proc Natl Acad Sci USA 106: 14514–14517.

    Article  CAS  PubMed  Google Scholar 

  • Kuriyama N, Kuriyama H, Julin CM, Lamborn KR, Israel MA . (2001). Protease pretreatment increases the efficacy of adenovirus-mediated gene therapy for the treatment of an experimental glioblastoma model. Cancer Res 61: 1805–1809.

    CAS  PubMed  Google Scholar 

  • McKee TD, Grandi P, Mok W, Alexandrakis G, Insin N, Zimmer JP et al. (2006). Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res 66: 2509–2513.

    Article  CAS  PubMed  Google Scholar 

  • McKenzie EA . (2007). Heparanase: a target for drug discovery in cancer and inflammation. Br J Pharmacol 151: 1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molnar-Kimber KL, Sterman DH, Chang M, Kang EH, ElBash M, Lanuti M et al. (1998). Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma. Hum Gene Ther 9: 2121–2133.

    Article  CAS  PubMed  Google Scholar 

  • Murayama T, Takahashi K, Natori Y, Kurumatani N . (2006). Estimation of future mortality from pleural malignant mesothelioma in Japan based on an age-cohort model. Am J Ind Med 49: 1–7.

    Article  PubMed  Google Scholar 

  • Price B . (1997). Analysis of current trends in United States mesothelioma incidence. Am J Epidemiol 145: 211–218.

    Article  CAS  PubMed  Google Scholar 

  • Ries SJ, Brandts CH, Chung AS, Biederer CH, Hann BC, Lipner EM et al. (2000). Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015). Nat Med 6: 1128–1133.

    Article  CAS  PubMed  Google Scholar 

  • Ruffie P, Feld R, Minkin S, Cormier Y, Boutan-Laroze A, Ginsberg R et al. (1989). Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 7: 1157–1168.

    Article  CAS  PubMed  Google Scholar 

  • Rusch VW, Piantadosi S, Holmes EC . (1991). The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 102: 1–9.

    CAS  PubMed  Google Scholar 

  • Ryan CW, Herndon J, Vogelzang NJ . (1998). A review of chemotherapy trials for malignant mesothelioma. Chest 113: 66S–73S.

    Article  CAS  PubMed  Google Scholar 

  • Sterman DH, Recio A, Carroll RG, Gillespie CT, Haas A, Vachani A et al. (2007). A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res 13: 4456–4466.

    Article  CAS  PubMed  Google Scholar 

  • Sterman DH, Recio A, Vachani A, Sun J, Cheung L, DeLong P et al. (2005). Long-term follow-up of patients with malignant pleural mesothelioma receiving high-dose adenovirus herpes simplex thymidine kinase/ganciclovir suicide gene therapy. Clin Cancer Res 11: 7444–7453.

    Article  CAS  PubMed  Google Scholar 

  • Sterman DH, Treat J, Litzky LA, Amin KM, Coonrod L, Molnar-Kimber K et al. (1998). Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 9: 1083–1092.

    Article  CAS  PubMed  Google Scholar 

  • Taki M, Kagawa S, Nishizaki M, Mizuguchi H, Hayakawa T, Kyo S et al. (2005). Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’). Oncogene 24: 3130–3140.

    Article  CAS  PubMed  Google Scholar 

  • Tango Y, Taki M, Shirakiya Y, Ohtani S, Tokunaga N, Tsunemitsu Y et al. (2004). Late resistance to adenoviral p53-mediated apoptosis caused by decreased expression of Coxsackie-adenovirus receptors in human lung cancer cells. Cancer Sci 95: 459–463.

    Article  CAS  PubMed  Google Scholar 

  • Umeoka T, Kawashima T, Kagawa S, Teraishi F, Taki M, Nishizaki M et al. (2004). Visualization of intrathoracically disseminated solid tumors in mice with optical imaging by telomerase-specific amplification of a transferred green fluorescent protein gene. Cancer Res 64: 6259–6265.

    Article  CAS  PubMed  Google Scholar 

  • Uno F, Fujiwara T, Takata Y, Ohtani S, Katsuda K, Takaoka M et al. (2001). Antisense-mediated suppression of human heparanase gene expression inhibits pleural dissemination of human cancer cells. Cancer Res 61: 7855–7860.

    CAS  PubMed  Google Scholar 

  • Yang CT, You L, Uematsu K, Yeh CC, McCormick F, Jablons DM . (2001). p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53. Cancer Res 61: 5959–5963.

    CAS  PubMed  Google Scholar 

  • Yang CT, You L, Yeh CC, Chang JW, Zhang F, McCormick F et al. (2000). Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells. J Natl Cancer Inst 92: 636–641.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank for K Nagai for his helpful discussion. We also thank Y Shirakiya, N Mukai, T Sueishi and M Yokota for their excellent technical support. The Cell∼VIZIO system was provided by Mauna Kea Technologies (Paris, France).

Author information

Authors and Affiliations

  1. Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, Japan

    Y Watanabe, S Kagawa, F Uno & T Fujiwara

  2. Oncolys BioPharma, Inc., Minato-ku, Tokyo, Japan

    Y Watanabe, Y Hashimoto, H Kawamura, D Ichimaru & Y Urata

  3. Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Y Watanabe, T Kojima, S Kagawa, F Uno, Y Hashimoto, N Tanaka & T Fujiwara

  4. Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, Kanazawa, Japan

    S Kyo

  5. Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    H Mizuguchi

Authors
  1. Y Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Kagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Uno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Kyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Mizuguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Ichimaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Y Urata
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. T Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Fujiwara.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watanabe, Y., Kojima, T., Kagawa, S. et al. A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy. Oncogene 29, 1145–1154 (2010). https://doi.org/10.1038/onc.2009.415

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.415

Keywords

This article is cited by

Search

Advanced search

Quick links