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The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer

Gene Therapy volume 22, pages 247–256 (2015)Cite this article

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Abstract

In an effort to develop a new therapy for prostate cancer (PCa) bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/β-catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels and inhibited tumor cell migration. To examine the antitumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum tartrate-resistant acid phosphatase 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for PCa bone metastasis.

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Acknowledgements

The work was funded in part by the National Institutes of Health grant # R01CA12738 (PS), grant # RO1CA39481 (RVI), and philanthropic support through John and Carol Walter Center for Urological Health, NorthShore University HealthSystem. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. We are thankful to Janardan Khandekar, Theodore Mazzone, Bruce Brockstein and Michael Caplan for their continuous support.

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Authors and Affiliations

  1. Department of Medicine, Gene Therapy Program, NorthShore Research Institute, an affiliate of the University of Chicago, Evanston, IL, USA

    W Xu, Y Yang & P Seth

  2. Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    T Neill & R V Iozzo

  3. 1st Division of in Vitro Diagnostic Reagents, National Institutes for Food and Drug Control, Beijing, China

    Z Hu

  4. Department of Pathology, NorthShore Research Institute, Evanston, IL, USA,

    E Cleveland & K Kaul

  5. Department of Radiology, Image processing Lab, NorthShore Research Institute, Evanston, IL, USA,

    Y Wu & R Hutten

  6. Advanced Photon Source, Argonne National Lab, Lemont, IL, USA

    X Xiao

  7. Department of Cell and Molecular Biology, Northwestern University, Chicago, IL, USA

    S R Stock

  8. Department of Medicine, NorthShore Research Institute, Evanston, USA,

    D Shevrin

  9. Department of Surgery, NorthShore University HealthSytem, Evanston, IL, USA

    C Brendler

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Correspondence to P Seth.

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Xu, W., Neill, T., Yang, Y. et al. The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. Gene Ther 22, 247–256 (2015). https://doi.org/10.1038/gt.2014.110

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