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


METHODS
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 VEGI is an endogenous inhibitor of angiogenesis, and that systemic administration of the VEGI-192 isoform resulted in inhibition of tumor angiogenesis and growth.
Hou
Wen
W
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
Medynski
Dan
D
Wu
Shirley
S
Lin
Xinli
X
Li
Lu-Yuan
LY
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001835:Body Weight; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D020033:Protein Isoforms; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020033:Protein Isoforms; D011994:Recombinant Proteins; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha