title: Ig-like domain 6 of VCAM-1 is a potential therapeutic target in TNFα-induced angiogenesis.
abstract: Tumor necrosis factor alpha (TNFα)-induced angiogenesis plays important roles in the progression of various diseases, including cancer, wet age-related macular degeneration, and rheumatoid arthritis. However, the relevance and role of vascular cell adhesion molecule-1 (VCAM-1) in angiogenesis have not yet been clearly elucidated. In this study, VCAM-1 knockdown shows VCAM-1 involvement in TNFα-induced angiogenesis. Through competitive blocking experiments with VCAM-1 Ig-like domain 6 (VCAM-1-D6) protein, we identified VCAM-1-D6 as a key domain regulating TNFα-induced vascular tube formation. We demonstrated that a monoclonal antibody specific to VCAM-1-D6 suppressed TNFα-induced endothelial cell migration and tube formation and TNFα-induced vessel sprouting in rat aortas. We also found that the antibody insignificantly affected endothelial cell viability, morphology and activation. Finally, the antibody specifically blocked VCAM-1-mediated cell-cell contacts by directly inhibiting VCAM-1-D6-mediated interaction between VCAM-1 molecules. These findings suggest that VCAM-1-D6 may be a potential novel therapeutic target in TNFα-induced angiogenesis and that antibody-based modulation of VCAM-1-D6 may be an effective strategy to suppress TNFα-induced angiogenesis.
authors.affiliation: Laboratory of Molecular Cancer Therapeutics, Research Center, Scripps Korea Antibody Institute, Chuncheon, Republic of Korea.
authors.forename: Taek-Keun
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Cancer Therapeutics, Research Center, Scripps Korea Antibody Institute, Chuncheon, Republic of Korea.
authors.forename: Chang Sik
authors.initials: CS
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Cancer Therapeutics, Research Center, Scripps Korea Antibody Institute, Chuncheon, Republic of Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Na
authors.affiliation: Laboratory of Molecular Cancer Therapeutics, Research Center, Scripps Korea Antibody Institute, Chuncheon, Republic of Korea.
authors.forename: Kangseung
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Aerin
authors.initials: A
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Junho
authors.initials: J
authors.lastname: Chung
authors.affiliation: Laboratory of Molecular Cancer Therapeutics, Research Center, Scripps Korea Antibody Institute, Chuncheon, Republic of Korea.
authors.forename: Sukmook
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000070557:Immunoglobulin Domains; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1