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

doi:10.1038/gt.2009.142

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

Department of New Biology

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

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.

Original language	English
Pages (from-to)	190-201
Number of pages	12
Journal	Gene Therapy
Volume	17
Issue number	2
DOIs	https://doi.org/10.1038/gt.2009.142
State	Published - Feb 2010

Bibliographical note

Funding Information:
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.

Keywords

Adenovirus
Decorin
Extracellular matrix
Viral spreading

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/gt.2009.142

Cite this

@article{f40d3fd855c7483f9a21f20058e08a44,

title = "Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy",

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.",

keywords = "Adenovirus, Decorin, Extracellular matrix, Viral spreading",

author = "Choi, {I. K.} and Lee, {Y. S.} and Yoo, {J. Y.} and Yoon, {A. R.} and H. Kim and Kim, {D. S.} and Seidler, {D. G.} and Kim, {J. H.} and Yun, {C. O.}",

note = "Funding Information: 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.",

year = "2010",

month = feb,

doi = "10.1038/gt.2009.142",

language = "English",

volume = "17",

pages = "190--201",

journal = "Gene Therapy",

issn = "0969-7128",

publisher = "Springer Nature",

number = "2",

}

TY - JOUR

T1 - Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy

AU - Choi, I. K.

AU - Lee, Y. S.

AU - Yoo, J. Y.

AU - Yoon, A. R.

AU - Kim, H.

AU - Kim, D. S.

AU - Seidler, D. G.

AU - Kim, J. H.

AU - Yun, C. O.

N1 - Funding Information: 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.

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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.

KW - Adenovirus

KW - Decorin

KW - Extracellular matrix

KW - Viral spreading

UR - http://www.scopus.com/inward/record.url?scp=76749084190&partnerID=8YFLogxK

U2 - 10.1038/gt.2009.142

DO - 10.1038/gt.2009.142

M3 - Article

C2 - 19907500

AN - SCOPUS:76749084190

SN - 0969-7128

VL - 17

SP - 190

EP - 201

JO - Gene Therapy

JF - Gene Therapy

IS - 2

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this