Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin.

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)-alpha, and nuclear factor kappaB (NF-kappaB) 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.

• Authors: Ai-Li Shiau, Min-Li Teo, Shin-Yao Chen, Chrong-Reen Wang, Jeng-Long Hsieh, Meng-Ya Chang, Chih-Jui Chang, Julie Chao, Lee Chao, Chao-Liang Wu, Che-Hsin Lee
• Journal: BMC cancer (BMC Cancer) Vol. 10 Pg. 245 (May 31 2010) ISSN: 1471-2407 [Electronic] England
• PMID: 20509975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• Inflammation Mediators
• NF-kappa B
• Serpins
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• kallistatin

Topics

• Animals
• Carcinoma, Lewis Lung (blood supply, genetics, metabolism, pathology, prevention & control)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Culture Media, Conditioned (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Inflammation Mediators (metabolism)
• Injections, Intravenous
• Lentivirus (genetics)
• Lung Neoplasms (blood supply, genetics, metabolism, prevention & control, secondary)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Neoplasm Invasiveness
• Neovascularization, Pathologic (genetics, metabolism, prevention & control)
• Serpins (biosynthesis, genetics)
• Transfection
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays