The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer

W. Xu, T. Neill, Y. Yang, Z. Hu, E. Cleveland, Y. Wu, R. Hutten, X. Xiao, Stuart R Stock, D. Shevrin, K. Kaul, C. Brendler, R. V. Iozzo, P. Seth*

*Corresponding author for this work

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

In an effort to develop a new therapy for prostate cancer (PCa) bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wntβ-catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels and inhibited tumor cell migration. To examine the antitumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum tartrate-resistant acid phosphatase 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for PCa bone metastasis.

Original languageEnglish (US)
Pages (from-to)247-256
Number of pages10
JournalGene Therapy
Volume22
Issue number3
DOIs
StatePublished - Mar 9 2015

Fingerprint

Decorin
Adenoviridae
Prostatic Neoplasms
Neoplasm Metastasis
Bone and Bones
Bone Neoplasms
Heart Ventricles
Prostate
Neoplasms
Human Adenoviruses
Catenins
Cachexia
Osteocalcin
Hypercalcemia
Osteoclasts
Tumor Burden
Mitochondrial DNA
Nude Mice
Radiography
Vascular Endothelial Growth Factor A

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Xu, W. ; Neill, T. ; Yang, Y. ; Hu, Z. ; Cleveland, E. ; Wu, Y. ; Hutten, R. ; Xiao, X. ; Stock, Stuart R ; Shevrin, D. ; Kaul, K. ; Brendler, C. ; Iozzo, R. V. ; Seth, P. / The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. In: Gene Therapy. 2015 ; Vol. 22, No. 3. pp. 247-256.
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abstract = "In an effort to develop a new therapy for prostate cancer (PCa) bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wntβ-catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels and inhibited tumor cell migration. To examine the antitumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum tartrate-resistant acid phosphatase 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for PCa bone metastasis.",
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Xu, W, Neill, T, Yang, Y, Hu, Z, Cleveland, E, Wu, Y, Hutten, R, Xiao, X, Stock, SR, Shevrin, D, Kaul, K, Brendler, C, Iozzo, RV & Seth, P 2015, 'The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer', Gene Therapy, vol. 22, no. 3, pp. 247-256. https://doi.org/10.1038/gt.2014.110

The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. / Xu, W.; Neill, T.; Yang, Y.; Hu, Z.; Cleveland, E.; Wu, Y.; Hutten, R.; Xiao, X.; Stock, Stuart R; Shevrin, D.; Kaul, K.; Brendler, C.; Iozzo, R. V.; Seth, P.

In: Gene Therapy, Vol. 22, No. 3, 09.03.2015, p. 247-256.

Research output: Contribution to journalArticle

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AU - Xu, W.

AU - Neill, T.

AU - Yang, Y.

AU - Hu, Z.

AU - Cleveland, E.

AU - Wu, Y.

AU - Hutten, R.

AU - Xiao, X.

AU - Stock, Stuart R

AU - Shevrin, D.

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AU - Brendler, C.

AU - Iozzo, R. V.

AU - Seth, P.

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