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Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy

Gene Therapy volume 17, pages 190–201 (2010)Cite this article

Abstract

The pressing challenge for contemporary gene therapy is to deliver enough therapeutic genes to enough cancer cells in vivo. With the aim of improving viral distribution and tumor penetration, we explored the use of decorin to enhance viral spreading and tumor tissue penetration. We generated decorin-expressing replication-incompetent (dl-LacZ-DCNG, dl-LacZ-DCNQ and dl-LacZ-DCNK) and replication-competent (Ad-ΔE1B-DCNG, Ad-ΔE1B-DCNQ and Ad-ΔE1B-DCNK) adenoviruses (Ads). Point mutants of decorin gene (DCNG), DCNK and DCNQ, have a negative and moderate binding affinity to type-I collagen fibril, respectively. In both tumor spheroids and established solid tumors in vivo, tissue penetration potency of dl-LacZ-DCNG was greatly enhanced than those of dl-LacZ, dl-LacZ-DCNQ and dl-LacZ-DCNK, and this enhanced tissue penetration effect derived from decorin-expressing Ad was dependent on the binding affinity of decorin to collagen fibril. Expression of DCNG enhanced viral spread of replicating Ad, leading to improved tumor reduction and survival benefit. Moreover, the tumoricidal effects of Ad-ΔE1B-DCNQ and Ad-ΔE1B-DCNK were lessened, as the binding affinity to collagen was decreased, showing that the increased cancer cell cytotoxicity was driven by the action of decorin on extracellular matrix (ECM). Furthermore, Ad-ΔE1B-DCNG substantially decreased ECM components within the tumor tissue. Finally, intratumoral injection of Ad-ΔE1B-DCNG in primary tumor site greatly reduced the formation of B16BL6 melanoma cell pulmonary metastases in mice. Taken together, these data show the utility of decorin as a dispersion agent and highlight its utility and potential in improving the efficacy of replicating Ad-mediated cancer gene therapy.

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Acknowledgements

This work was supported by grants from the Ministry of Commerce Industry and Energy (10030051, Dr C-O Yun), the Korea Research Foundation (KRF-2005–042-C00148, Dr C-O Yun), the Korea Science and Engineering Foundation (KOSEF) (R01–2006–000–10084–0, R15–2004–024–02001–0, M10416130002–04N1613–00210, Dr C-O Yun) and through its National Nuclear Technology Program (2007–00299, Dr C-O Yun). Il-Kyu Choi is a graduate student sponsored by KOSEF through National Core Research Center for Nanomedical Technology. Young-Sook Lee, Ji Young Yoo and A-Rum Yoon are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.

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Author notes

  1. I-K Choi and J Y Yoo: These authors contributed equally to this work.

Authors and Affiliations

  1. Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    I-K Choi, Y-S Lee, J Y Yoo, A-R Yoon, J-H Kim & C-O Yun

  2. Graduate Program for Nanomedical Science, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    I-K Choi & C-O Yun

  3. Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

    H Kim

  4. Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea

    D-S Kim

  5. Department of Physiological Chemistry and Pathobiochemistry, University Hospital of Münster, Münster, Germany

    D G Seidler

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  1. I-K Choi
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Correspondence to C-O Yun.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Choi, IK., Lee, YS., Yoo, J. et al. Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy. Gene Ther 17, 190–201 (2010). https://doi.org/10.1038/gt.2009.142

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