VEGI-192, a new isoform of TNFSF15, specifically eliminates tumor vascular endothelial cells and suppresses tumor growth

Purpose: We determined the antiangiogenic and anticancer activity of VEGI-192, a new isoform of TNFSF15 (VEGI,TL1), with a Lewis lung cancer murine tumor model. Experimental Design: Recombinant human VEGI-192 was produced in Escherichia coli and purified to apparent homogeneity. The protein was given systemically via i.p., i.v., or s.c. injections to tumor-bearing C57BL/6 mice. Tumor growth rates, animal survival rates, and general toxicity were determined. Effect on endothelial cell/smooth muscle cell ratio of the tumor vasculature was analyzed. Results: Systemic administration of VEGI-192 gave rise to a marked inhibition of tumor growth. As much as 50% inhibition of the tumor growth rate was achieved with treatment initiated when the tumor volumes reached nearly 5% of the body weight. Inhibition of tumor formation was also observed when VEGI-192 was given at the time of tumor inoculation. Consistently, we observed an increased survival time of the treated animals. The VEGI-192-treated animals showed no liver or kidney toxicity. The treatment eliminated tumor endothelial cells but not vascular smooth muscle cells, which remained associated with a residual vascular structure consisting of the basement membrane. In addition, we carried out immunohistochemical analysis of rat kidneys and found that vascular endothelial cell growth inhibitor (VEGI) expression is largely limited to endothelial cells. Conclusions: Our findings indicate that VEG1 is an endogenous inhibitor of angiogenesis, and that systemic administration of the VEGI-192 isoform resulted in inhibition of tumor angiogenesis and growth.