Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells

Chikara Muraki, Noritaka Ohga, Yasuhiro Hida, Hiroshi Nishihara, Yasutaka Kato, Kunihiko Tsuchiya, Kohei Matsuda, Yasunori Totsuka, Masanobu Shindoh, Kyoko Hida

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42 Citations (Scopus)

Abstract

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Cyclooxygenase (COX)-2 is known to play an important role in cancer growth and invasion, and it activates the signaling pathways controlling cell proliferation, migration, apoptosis, and angiogenesis. COX-2 is reported to be expressed in many cancer cells. Several studies have reported successful treatment of cancer cells with COX-2 inhibitors (COX-2is). However, the effect of COX-2 inhibition on the tumor endothelium remains to be elucidated. Our study shows that COX-2 is expressed in the vasculature of surgically resected human tumors. To investigate the effects of COX-2 inhibition on the tumor endothelium in vitro, we isolated tumor endothelial cells (TECs) from human melanoma and oral carcinoma xenografts in mice, in which we confirmed that tumor growth was suppressed by inhibiting angiogenesis with the COX-2is NS398. COX-2 mRNA was upregulated in TECs compared to normal endothelial cells (NECs). Cell migration and proliferation were suppressed by NS398 in TECs but not in NECs. The effects of NS398 in vivo were consistent with the in vitro results. The number of CD133 +/vascular endothelial growth factor receptor-2 + cells in circulation was significantly suppressed by COX-2 inhibition. In addition, the number of progenitor marker-positive cells decreased in the tumor blood vessels after COX-2i treatment, which suggests that the homing of progenitor cells into the tumor was also blocked. We conclude that NS398 specifically targets both TECs and vascular progenitor cells without affecting NECs.

Original languageEnglish
Pages (from-to)59-70
Number of pages12
JournalInternational Journal of Cancer
Volume130
Issue number1
DOIs
Publication statusPublished - 2012 Jan 11

Keywords

  • COX-2
  • EPCs
  • TECs
  • angiogenesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Muraki, C., Ohga, N., Hida, Y., Nishihara, H., Kato, Y., Tsuchiya, K., Matsuda, K., Totsuka, Y., Shindoh, M., & Hida, K. (2012). Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells. International Journal of Cancer, 130(1), 59-70. https://doi.org/10.1002/ijc.25976