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Published on: March 24, 2017
Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy
1Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
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-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.
Insights
Decorin enhanced adenovirus (Ad) gene therapy by improving viral spread and tumor penetration. This decorin-modified Ad therapy led to significant tumor reduction and reduced metastasis, offering a promising approach for cancer treatment.
Area of Science:
- Oncology
- Gene Therapy
- Biotechnology
Background:
- Gene therapy faces challenges in delivering therapeutic genes effectively to cancer cells in vivo.
- Improving viral distribution and tumor penetration are critical for enhancing gene therapy efficacy.
Purpose of the Study:
- To investigate the potential of decorin as a tool to enhance viral spreading and tumor penetration in cancer gene therapy.
- To evaluate the efficacy of decorin-modified adenoviruses (Ads) in improving tumor reduction and survival rates.
Main Methods:
- Generation of replication-incompetent and replication-competent adenoviruses expressing decorin (DCNG, DCNK, DCNQ) with varying collagen-binding affinities.
- Assessment of viral tissue penetration in tumor spheroids and solid tumors in vivo.
- Evaluation of tumor reduction, survival benefit, and metastasis inhibition in mouse models.
Main Results:
- Decorin-expressing Ad (dl-LacZ-DCNG) significantly enhanced tissue penetration compared to controls, dependent on decorin's collagen-binding affinity.
- Decorin expression improved viral spread of replicating Ads, leading to better tumor reduction and survival.
- Decorin-modified Ads reduced extracellular matrix components and inhibited pulmonary metastasis formation.
Conclusions:
- Decorin acts as an effective dispersion agent, significantly improving the efficacy of Ad-mediated cancer gene therapy.
- The collagen-binding affinity of decorin is crucial for its enhanced tumor penetration and therapeutic effects.
- Decorin-modified Ads show potential for improving cancer treatment outcomes by enhancing gene delivery and reducing metastasis.
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