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. 2013 Nov;14(11):1016-23.
doi: 10.4161/cbt.26043. Epub 2013 Aug 28.

Oncolytic adenovirus encoding tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits the growth and metastasis of triple-negative breast cancer

Wei Zhu  1 , Hongwei Zhang, Yi Shi, Mangen Song, Bijun Zhu, Lai Wei
Affiliations

Oncolytic adenovirus encoding tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits the growth and metastasis of triple-negative breast cancer

Wei Zhu et al. Cancer Biol Ther. 2013 Nov.

Abstract

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising cancer therapeutic target due to its selective apoptosis-inducing effect in cancer cells. To efficiently deliver TRAIL to the tumor cells, an oncolytic adenovirus (p55-hTERT-HRE-TRAIL) carrying the TRAIL coding sequence was constructed. In the present study, we aimed to investigate the effect of p55-hTERT-HRE-TRAIL on the growth and metastasis of triple-negative breast cancer (TNBC). We observed that infection of the recombinant adenovirus resulted in expression of TRAIL and massive cell death in a TNBC cell line MDA-MB-231. This effect is much weaker in MCF-10A, which is a normal breast cell line. Administration of P55-HTERT-HRE-TRAIL significantly reduced orthotopic breast tumor growth and extended survival in a metastatic model. Our results suggest the oncolytic adenovirus armed with P55-HTERT-HRE-TRAIL, which exhibited enhanced anti-tumor activity and improved survival, is a promising candidate for virotherapy of TNBC.

Keywords: adenovirus; triple-negative breast cancer (TNBC); tumor necrosis factor-related apoptosis inducing ligand (TRAIL); virotherapy.

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Figures

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Figure 1. Construction of the oncolytic adenovirus encoding the TRAIL coding sequence (P55-HTERT-HRE-TRAIL).
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Figure 2. P55-HTERT-HRE-TRAIL induced cell death in MDA-MB-231 and but not MCF-10A cells. (A) MDA-MB-231 and MCF-10A cells were infected with P55-HTERT-HRE-TRAIL at a MOI of 5 and virus titers from the supernatant were measured by the TCID50 method at indicated time points. *Indicates the statistical significance (P < 0.05). (B) Five days after infection with P55-HTERT-HRE-TRAIL or its vector control at the indicated range of MOI, the viability of the cells was measured by MTT assay and normalized against mock infected group. (C) MDA-MB-231 and MCF-10A cells were treated with recombinant TRAIL ligand at concentrations ranging from 10 to 80 ng/ml for 24 h and cell viability was measured by MTT assay.
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Figure 3. Expression of TRAIL in MDA-MB-231 and MCF-10A cells. (A) The concentration of TRAIL in the supernatant after infection of P55-HTERT-HRE-TRAIL, as measured by ELISA. (B) TRAIL expression was determined by western blotting, the expression of β-actin served as loading control. The quantity of TRAIL, normalized with β-actin, was estimated by densitometry.
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Figure 4. The effects of P55-HTERT-HRE-TRAIL and recombinant TRAIL on non-TNBC cell lines. (A) SK-BR-3, MDA-MB-453, and MCF-7 cells were infected with P55-HTERT-HRE-TRAIL at a MOI of 5 and virus titers from the supernatant were measured by the TCID50 method at indicated time points. (B) Five days after infection with P55-HTERT-HRE-TRAIL or its vector control at the indicated range of MOI, the viability of the cells was measured by MTT assay and normalized against mock infected group. (C) SK-BR-3, MDA-MB-453, and MCF-7 cells were treated with recombinant TRAIL ligand at concentrations ranging from 10 to 80 ng/ml for 24 h and cell viability was measured by MTT assay.
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Figure 5. Suppression of the tumor in nude mice bearing orthotopic breast cancer by P55-HTERT-HRE-TRAIL. Log phase MDA-MB-231-luc cells were injected into the fat pad of nude mice. At 14, 16, 18, 20, and 22 d after the injection of cells, viruses were administered through intravenous injection at the dose of 2 × 108 pfu. The doses for P55-HTERT-HRE low and high group were 1 × 108 and 4 × 108 pfu respectively. Luminescent images were visualized every week (A), photon counts (B), and tumor volume (C) were also measured. Mice were sacrificed and tumor weight was measured on day 42 (D). *Indicates statistical significance (P < 0.05).
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Figure 6. Infection of P55-HTERT-HRE-TRAIL induced apoptosis and enhanced TRAIL and Hexon expression. After infection with P55-HTERT-HRE (A, C, and E) or P55-HTERT-HRE-TRAIL (B, D, and F), the expression of TRAIL (A andB) and Hexon protein (C and D) were monitored by immunohistochemistry. Cell apoptosis were measured by TUNEL assay (E and F).
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Figure 7. Inhibition of breast tumor metastasis by P55-HTERT-HRE-TRAIL. (A) Survival curves of mice in the metastatic model created by left ventricular injection of cancer cells. n = 8 for each group. In vivo imaging of the control (B) and P55-HTERT-HRE-TRAIL infected group (C) were documented in the metastatic model.
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