Systemic delivery of an oncolytic adenovirus expressing decorin for the treatment of breast cancer bone metastases

Yuefeng Yang, Weidong Xu, Thomas Neill, Zebin Hu, Chi Hsiung Wang, Xianghui Xiao, Stuart R Stock, Theresa Guise, Chae Ok Yun, Charles B. Brendler, Renato V. Iozzo, Prem Seth*

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The development of novel therapies for breast cancer bone metastasis is a major unmet medical need. Toward that end, we have constructed an oncolytic adenovirus, Ad.dcn, and a nonreplicating adenovirus, Ad(E1-).dcn, both containing the human decorin gene. Our in vitro studies showed that Ad.dcn produced high levels of viral replication and the decorin protein in the breast tumor cells. Ad(E1-).dcn-mediated decorin expression in MDA-MB-231 cells downregulated the expression of Met, β-catenin, and vascular endothelial growth factor A, all of which are recognized decorin targets and play pivotal roles in the progression of breast tumor growth and metastasis. Adenoviral-mediated decorin expression inhibited cell migration and induced mitochondrial autophagy in MDA-MB-231 cells. Mice bearing MDA-MB-231-luc skeletal metastases were systemically administered with the viral vectors, and skeletal tumor growth was monitored over time. The results of bioluminescence imaging and X-ray radiography indicated that Ad.dcn and Ad(E1-).dcn significantly inhibited the progression of bone metastases. At the terminal time point, histomorphometric analysis, micro-computed tomography, and bone destruction biomarkers showed that Ad.dcn and Ad(E1-).dcn reduced tumor burden and inhibited bone destruction. A nonreplicating adenovirus Ad(E1-).luc expressing the luciferase 2 gene had no significant effect on inhibiting bone metastases, and in several assays, Ad.dcn and Ad(E1-).dcn were better than Ad.luc, a replicating virus expressing the luciferase 2 gene. Our data suggest that adenoviral replication coupled with decorin expression could produce effective antitumor responses in a MDA-MB-231 bone metastasis model of breast cancer. Thus, Ad.dcn could potentially be developed as a candidate gene therapy vector for treating breast cancer bone metastases.

Original languageEnglish (US)
Pages (from-to)813-825
Number of pages13
JournalHuman Gene Therapy
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2015

Fingerprint

Decorin
Bone Neoplasms
Adenoviridae
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Luciferases
Genes
Catenins
Autophagy
Growth
Tumor Burden
Radiography
Genetic Therapy
Vascular Endothelial Growth Factor A
Cell Movement
Down-Regulation
Biomarkers
Tomography
X-Rays

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Yang, Yuefeng ; Xu, Weidong ; Neill, Thomas ; Hu, Zebin ; Wang, Chi Hsiung ; Xiao, Xianghui ; Stock, Stuart R ; Guise, Theresa ; Yun, Chae Ok ; Brendler, Charles B. ; Iozzo, Renato V. ; Seth, Prem. / Systemic delivery of an oncolytic adenovirus expressing decorin for the treatment of breast cancer bone metastases. In: Human Gene Therapy. 2015 ; Vol. 26, No. 12. pp. 813-825.
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abstract = "The development of novel therapies for breast cancer bone metastasis is a major unmet medical need. Toward that end, we have constructed an oncolytic adenovirus, Ad.dcn, and a nonreplicating adenovirus, Ad(E1-).dcn, both containing the human decorin gene. Our in vitro studies showed that Ad.dcn produced high levels of viral replication and the decorin protein in the breast tumor cells. Ad(E1-).dcn-mediated decorin expression in MDA-MB-231 cells downregulated the expression of Met, β-catenin, and vascular endothelial growth factor A, all of which are recognized decorin targets and play pivotal roles in the progression of breast tumor growth and metastasis. Adenoviral-mediated decorin expression inhibited cell migration and induced mitochondrial autophagy in MDA-MB-231 cells. Mice bearing MDA-MB-231-luc skeletal metastases were systemically administered with the viral vectors, and skeletal tumor growth was monitored over time. The results of bioluminescence imaging and X-ray radiography indicated that Ad.dcn and Ad(E1-).dcn significantly inhibited the progression of bone metastases. At the terminal time point, histomorphometric analysis, micro-computed tomography, and bone destruction biomarkers showed that Ad.dcn and Ad(E1-).dcn reduced tumor burden and inhibited bone destruction. A nonreplicating adenovirus Ad(E1-).luc expressing the luciferase 2 gene had no significant effect on inhibiting bone metastases, and in several assays, Ad.dcn and Ad(E1-).dcn were better than Ad.luc, a replicating virus expressing the luciferase 2 gene. Our data suggest that adenoviral replication coupled with decorin expression could produce effective antitumor responses in a MDA-MB-231 bone metastasis model of breast cancer. Thus, Ad.dcn could potentially be developed as a candidate gene therapy vector for treating breast cancer bone metastases.",
author = "Yuefeng Yang and Weidong Xu and Thomas Neill and Zebin Hu and Wang, {Chi Hsiung} and Xianghui Xiao and Stock, {Stuart R} and Theresa Guise and Yun, {Chae Ok} and Brendler, {Charles B.} and Iozzo, {Renato V.} and Prem Seth",
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Yang, Y, Xu, W, Neill, T, Hu, Z, Wang, CH, Xiao, X, Stock, SR, Guise, T, Yun, CO, Brendler, CB, Iozzo, RV & Seth, P 2015, 'Systemic delivery of an oncolytic adenovirus expressing decorin for the treatment of breast cancer bone metastases', Human Gene Therapy, vol. 26, no. 12, pp. 813-825. https://doi.org/10.1089/hum.2015.098

Systemic delivery of an oncolytic adenovirus expressing decorin for the treatment of breast cancer bone metastases. / Yang, Yuefeng; Xu, Weidong; Neill, Thomas; Hu, Zebin; Wang, Chi Hsiung; Xiao, Xianghui; Stock, Stuart R; Guise, Theresa; Yun, Chae Ok; Brendler, Charles B.; Iozzo, Renato V.; Seth, Prem.

In: Human Gene Therapy, Vol. 26, No. 12, 01.12.2015, p. 813-825.

Research output: Contribution to journalArticle

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AU - Yang, Yuefeng

AU - Xu, Weidong

AU - Neill, Thomas

AU - Hu, Zebin

AU - Wang, Chi Hsiung

AU - Xiao, Xianghui

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AU - Guise, Theresa

AU - Yun, Chae Ok

AU - Brendler, Charles B.

AU - Iozzo, Renato V.

AU - Seth, Prem

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