Dissection of Lung Tumorigenesis Induced by Human Vascular Endothelial Growth Factor (hVEGF)‐A165 Overexpression in Clara Cells of Transgenic Mice

Abstract

Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF‐A165 (hVEGF‐A165) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF‐A165 in lung‐specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf‐A165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF‐A165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT‐PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up‐regulated genes (hvegf‐A165, cyclin b1, cdc2, egfr, mmp9, nrp‐1, and kdr) in VEGF tumors compared with wild‐type lung tissues. In conclusion, hVEGF‐A165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF‐targeted therapies in lung adenocarcinoma.