Oncolytic Adenovirus rAd.DCN Inhibits Breast Tumor Growth and Lung Metastasis in an Immune-Competent Orthotopic Xenograft Model.
Hum Gene Ther
; 30(2): 197-210, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-30032645
ABSTRACT
The majority of advanced breast cancer patients develop distal metastasis, including lung and bone metastasis. However, effective therapeutic strategies to prevent metastasis are still lacking. Decorin is a natural inhibitor of transforming growth factor ß, which plays a pivotal role in tumor metastasis. An oncolytic adenovirus expressing decorin, rAd.DCN, has been developed previously. In an immune-competent breast tumor (4T1) model, intratumoral (i.t.) as well as intravenous (i.v.) delivery of rAd.DCN inhibited growth of orthotopic tumors and spontaneous lung metastasis. It was shown that i.t. delivery of rAd.DCN produced higher levels of transgene expression and evoked stronger oncolysis of the tumors compared to i.v. delivery. However, i.v. delivery resulted in higher amount of virus accumulation in the lungs and produced stronger responses to prevent tumor lung metastasis. Oncolytic adenovirus-mediated decorin expression in the tumors downregulated the decorin target genes and decreased epithelial mesenchymal transition markers. Decorin expression in lung tissues also increased Th1 cytokine expression, such as interleukin (IL)-2, IL-12, and tumor necrosis factor α, and decreased Th2 cytokines, such as transforming growth factor ß and IL-6. Moreover, rAd.DCN treatment induced strong systemic inflammatory responses and upregulated CD8+ T lymphocytes. In conclusion, rAd.DCN inhibits tumor growth and lung metastasis of breast cancer via regulating wnt/ß-catenin, vascular endothelial growth factor (VEGF), and Met pathways, and modulating the antitumor inflammatory and immune responses. Considering that i.v. delivery was much more effective in preventing lung metastasis, systemic delivery of rAd.DCN might be a promising strategy to treat breast cancer lung metastasis.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Adenoviridae
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Vírus Oncolíticos
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Terapia Viral Oncolítica
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Decorina
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article