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

 I-K Choi  ;  Y-S Lee  ;  J Y Yoo  ;  A-R Yoon  ;  H Kim  ;  D-S Kim  ;  D G Seidler  ;  J-H Kim  ;  C-O Yun 
 GENE THERAPY, Vol.17(2) : 190-201, 2010 
Journal Title
Issue Date
Adenoviridae/genetics* ; Animals ; Cell Line, Tumor ; Decorin ; Extracellular Matrix/metabolism* ; Extracellular Matrix Proteins/genetics* ; Extracellular Matrix Proteins/metabolism ; Gene Transfer Techniques ; Genetic Therapy ; Mice ; Mice, Nude ; Oncolytic Virotherapy/methods* ; Proteoglycans/genetics* ; Proteoglycans/metabolism ; Spheroids, Cellular/metabolism ; Transduction, Genetic ; Xenograft Model Antitumor Assays
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-DeltaE1B-DCNG, Ad-DeltaE1B-DCNQ and Ad-DeltaE1B-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-DeltaE1B-DCNQ and Ad-DeltaE1B-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-DeltaE1B-DCNG substantially decreased ECM components within the tumor tissue. Finally, intratumoral injection of Ad-DeltaE1B-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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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Dong Seok(김동석)
Kim, Hogeun(김호근)
Yoo, Ji Yeong(유지영)
Yun, Chae Ok(윤채옥)
Lee, Young Sook(이영숙)
Choi, Il Kyu(최일규)
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