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

Authors

  • Chikara Muraki,

    1. Division of Oral Pathology and Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
    2. Division of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
    3. Division of Oral and Maxillofacial Surgery, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
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  • Noritaka Ohga,

    1. Division of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
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  • Yasuhiro Hida,

    1. Department of Surgical Oncology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
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  • Hiroshi Nishihara,

    1. Laboratory of Translational Pathology, Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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  • Yasutaka Kato,

    1. Laboratory of Cancer Research, Department of Pathology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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  • Kunihiko Tsuchiya,

    1. Division of Oral Pathology and Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
    2. Division of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
    3. Department of Renal and Genitourinary surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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  • Kohei Matsuda,

    1. Division of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
    2. Division of Oral and Maxillofacial Surgery, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
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  • Yasunori Totsuka,

    1. Division of Oral and Maxillofacial Surgery, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
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  • Masanobu Shindoh,

    1. Division of Oral Pathology and Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
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  • Kyoko Hida

    Corresponding author
    1. Division of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
    • Department of Oral Pathology and Biology, Division of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, N13 W7 Kita-ku, Sapporo 060-8586, Japan
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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.

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