title: Systemic Delivery of an Oncolytic Adenovirus Expressing Decorin for the Treatment of Breast Cancer Bone Metastases.
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.
authors.affiliation: 1 Gene Therapy Program, Department of Medicine, NorthShore Research Institute, An Affiliate of the University of Chicago , Evanston, Illinois.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1 Gene Therapy Program, Department of Medicine, NorthShore Research Institute, An Affiliate of the University of Chicago , Evanston, Illinois.
authors.forename: Weidong
authors.initials: W
authors.lastname: Xu
authors.affiliation: 2 Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.affiliation: 3 1st Division of In Vitro Diagnostic Reagents, National Institutes for Food and Drug Control , Beijing, China.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: 4 Department of Surgery, NorthShore Research Institute , Evanston, Illinois.
authors.forename: Chi-Hsiung
authors.initials: CH
authors.lastname: Wang
authors.affiliation: 5 Advanced Photon Source, Argonne National Lab. , Argonne, Illinois.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Xiao
authors.affiliation: 6 Department of Cell and Molecular Biology, Northwestern University , Chicago, Illinois.
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Stock
authors.affiliation: 7 Department of Medicine, Indiana University , Indianapolis, Indiana.
authors.forename: Theresa
authors.initials: T
authors.lastname: Guise
authors.affiliation: 8 Department of Bioengineering, Hanyang University , Seoul, Korea.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
authors.affiliation: 4 Department of Surgery, NorthShore Research Institute , Evanston, Illinois.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Brendler
authors.affiliation: 2 Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: 1 Gene Therapy Program, Department of Medicine, NorthShore Research Institute, An Affiliate of the University of Chicago , Evanston, Illinois.
authors.forename: Prem
authors.initials: P
authors.lastname: Seth
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D058575:Decorin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; C546879:Dcn protein, mouse; D058575:Decorin; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C467480:vascular endothelial growth factor A, mouse; D008156:Luciferases; D019859:Proto-Oncogene Proteins c-met