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CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth

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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.

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Acknowledgment

This work was supported by the 21st Frontier Human Genome Research (FG-1-1) of the Ministry of Science and Technology and KOBIC, KRIBB (C-H Kim).

Conflict of interest statement

All of authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Molecular and Cellular Glycobiology Unit, Department of Biological Science, SungKyunKwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon City, Kyunggi-Do, 440-746, South Korea

    Tae-Wook Chung, Seok-Jo Kim, Hee-Jung Choi, Choong-Hwan Kwak, Kwon-Ho Song, Seok-Jong Suh & Cheorl-Ho Kim

  2. Department of Clinical Pathology, Tae Kyeung College, Gyeongsan, 712-719, South Korea

    Keuk-Jun Kim

  3. Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan City, Gyeongsangnam-Do, 626-770, South Korea

    Hee-Jung Choi & Ki-Tae Ha

  4. Department of Orthodontics, Kyung-Hee University School of Dentistry, Hoegi-Dong 1, Dongdaemoon-Ku, Seoul, South Korea

    Young-Guk Park

  5. Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, 705-718, South Korea

    Young-Chae Chang

  6. College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, South Korea

    Hyeun Wook Chang

  7. Faculty of Biotechnology, Dong-A University, Saha-Gu, Busan, 604-714, South Korea

    Young-Choon Lee

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  1. Tae-Wook Chung
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Correspondence to Cheorl-Ho Kim.

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Chung, TW., Kim, SJ., Choi, HJ. et al. CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth. J Mol Med 91, 271–282 (2013). https://doi.org/10.1007/s00109-012-0952-6

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  • DOI: https://doi.org/10.1007/s00109-012-0952-6

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