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[Cancer Research 63, 6651-6657, October 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Inhibition of Angiogenesis and Vascular Leakiness by Angiopoietin-Related Protein 41

Yasuhiro Ito2, Yuichi Oike2, Kunio Yasunaga2, Koichi Hamada, Keishi Miyata, Shun-ichiro Matsumoto, Sumio Sugano, Hidenobu Tanihara, Yasuhiko Masuho and Toshio Suda3

Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582, Japan [Y. I., Y. O., T. S.]; Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan [K. H., K. M.]; Molecular Medicine Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba 305-8585, Japan [K. Y., S-i. M.]; Helix Research Institute, Inc., Kisarazu 292-0812, Japan [S-i. M., Y. M.]; Department of Ophthalmology, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan [Y. I., H. T.]; and Department of Virology, Institute of Medical Science, University of Tokyo, Tokyo 113-8655, Japan [S. S.]

Angiopoietins and angiopoietin-related proteins (ARPs) have been shown to regulate angiogenesis, a process essential for various neovascular diseases including tumors. Here, we identify ARP4/fasting-induced adipose factor/peroxisome proliferator-activated receptor {gamma} angiopoietin-related as a novel antiangiogenic modulatory factor. We hypothesized that ARP4 may regulate angiogenesis. In vitro experiments using purified recombinant ARP4 protein revealed that ARP4 markedly inhibited the proliferation, chemotaxis, and tubule formation of endothelial cells. Moreover, using corneal neovascularization and Miles permeability assays, we found that both vascular endothelial growth factor-induced in vivo angiogenesis and vascular leakiness were significantly inhibited by the addition of ARP4. Finally, we found remarkable suppression of tumor growth within the dermal layer associated with decreased numbers of invading blood vessels in transgenic mice that express ARP4 in the skin driven by the keratinocyte promoter. These findings demonstrate that ARP4 functions as a novel antiangiogenic modulatory factor and indicate a potential therapeutic effect of ARP4 in neoplastic diseases.




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Copyright © 2003 by the American Association for Cancer Research.