title: CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth.
abstract: The growth and metastasis of human solid tumors and the development of conditions such as diabetic retinopathy, rheumatoid arthritis, inflammatory psoriasis, and others are regulated by the balance between angiogenic stimulators and inhibitors released in the angiogenic-pathological microenvironment. Vascular endothelial growth factor (VEGF), an angiogenic factor, is a potent endothelial-specific mitogen that activates endothelial cells in pathological angiogenesis. Recently, we demonstrated that caffeic acid phenethyl ester (CAPE) inhibits tumor growth, invasion, and metastasis. However, the precise molecular mechanism underlying the inhibitory effect of CAPE on VEGF-mediated angiogenesis remains unknown. Here, we show that CAPE suppressed VEGF-induced proliferation, tube formation, migration, the formation of actin stress fibers and loss of VE-cadherin at cell-cell contacts in endothelial cells, indicating the inhibition of VEGF-mediated VEGF receptor-2 (VEGFR-2) and its downstream signal activation in vitro. CAPE blocked VEGF-stimulated neovascularization in the Matrigel plugs assay, and reduced vascular permeability in mouse skin capillaries in vivo. CAPE inhibited the growth and neovascularization of primary tumor cells in C57BL/6 and BALB/c mice inoculated with Lewis lung carcinoma, colon carcinoma, and melanoma cells. These results suggest that CAPE negatively modulates VEGF-induced angiogenesis by suppressing VEGFR-2 activation, and might be a therapeutic avenue for anti-angiogenesis.
authors.affiliation: Molecular and Cellular Glycobiology Unit, Department of Biological Science, SungKyunKwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon City, Kyunggi-Do, 440-746, South Korea.
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.forename: Seok-Jo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Choong-Hwan
authors.initials: CH
authors.lastname: Kwak
authors.forename: Kwon-Ho
authors.initials: KH
authors.lastname: Song
authors.forename: Seok-Jong
authors.initials: SJ
authors.lastname: Suh
authors.forename: Keuk-Jun
authors.initials: KJ
authors.lastname: Kim
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Ha
authors.forename: Young-Guk
authors.initials: YG
authors.lastname: Park
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
authors.forename: Hyeun Wook
authors.initials: HW
authors.lastname: Chang
authors.forename: Young-Choon
authors.initials: YC
authors.lastname: Lee
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D002109:Caffeic Acids; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol