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Open Access Highly Accessed Research article

Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin

Ai-Li Shiau1, Min-Li Teo1, Shin-Yao Chen2, Chrong-Reen Wang3, Jeng-Long Hsieh4, Meng-Ya Chang5, Chih-Jui Chang6, Julie Chao7, Lee Chao7, Chao-Liang Wu2* and Che-Hsin Lee8*

Author Affiliations

1 Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan

2 Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

3 Section of Rheumatology, Department of Internal Medicine, National Cheng Kung University Medical College, Tainan, Taiwan

4 Department of Nursing, Chung Hwa University of Medical Technology, Tainan Hsien, Taiwan

5 Graduate Institute of Clinical Medicine, Tzu Chi University, Hualien, Taiwan

6 Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan

7 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, USA

8 Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan

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BMC Cancer 2010, 10:245  doi:10.1186/1471-2407-10-245

Published: 31 May 2010

Abstract

Background

Angiogenesis plays an important role in the development and progression of tumors. Kallistatin exerts anti-angiogenic and anti-inflammatory activities that may be effective in inhibiting tumor metastasis. We investigated the antitumor effect of lentivirus-mediated kallistatin gene transfer in a syngeneic murine tumor model.

Methods

Lentiviral vector encoding kallistatin (LV-Kallistatin) was constructed. The expression of kallistatin was verified by enzyme-linked immunosorbent assay (ELISA), and the bioactivity of kallistatin was determined by using cell proliferation, migration, and invasion assays. In addition, antitumor effects of LV-Kallistatin were evaluated by the intravenous injection of virus into tumor-bearing mice.

Results

The conditioned medium from LV-Kallistatin-treated cells inhibited the migration and proliferation of endothelial cells. Meanwhile, it also reduced the migration and invasion of tumor cells. In the experimental lung metastatic model, tumor-bearing mice receiving LV-Kallistatin had lower tumor nodules and longer survival than those receiving control virus or saline. Moreover, the microvessel densities, the levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, and nuclear factor κB (NF-κB) transcriptional activity were reduced in the LV-Kallistatin-treated mice.

Conclusion

Results of this study showed that systemic administration of lentiviral vectors encoding kallistatin inhibited the growth of metastatic tumor and prolonged the survival of tumor-bearing mice. These results suggest that gene therapy using lentiviruses carrying the kallistatin gene, which exerts anti-angiogenic and anti-inflammatory activities, represents a promising strategy for the treatment of lung cancer.