Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin

Ai-Li Shiau,Julie Chao,Che-Hsin Lee,Lee Chao,Meng-Ya Chang,Shin-Yao Chen,Jeng-Long Hsieh,Chao-Liang Wu,Chrong-Reen Wang,Min-Li Teo,Chih-Jui Chang

doi:10.1186/1471-2407-10-245

Abstract

BackgroundAngiogenesis 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.MethodsLentiviral 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.ResultsThe 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.ConclusionResults 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.

Highlights

Angiogenesis plays an important role in the development and progression of tumors
It has been reported that kallistatin inhibited vascular endothelial growth factor (VEGF)-induced or basic fibroblast growth factor-induced the proliferation, migration and adhesion of endothelial cells and attenuated bFGF-induced capillary density in mice
Expression of bioactive kallistatin via lentivirus-mediated gene transfer To test the feasibility of exploiting recombinant lentiviruses for gene delivery in cells, the expression of kallistatin was examined and characterized in TE671 cells infected with LV-Kallistatin or LV-green fluorescence protein (GFP)

Summary

Introduction

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. Kallistatin, a serine proteinase inhibitor, is first identified as a tissue kallikrein-binding protein, and has emerged as a novel inhibitor of angiogenesis. Kallistatin exerts a variety of biological effects in physiologic and pathologic responses, such as blood pressure regulation, inflammation and anti-angiogenesis [1,2,3,4,5]. A growing body antitumor agent in syngeneic murine tumor models. Via dual effect of anti-angiogenic and anti-inflammatory activities, LV-Kallistatin has the therapeutic potential for treatment of lung tumors

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Discussion

Conclusion