| Co-Investigator(Kenkyū-buntansha) |
HUJITA Tomoe Kitasato Univ. School of Medicine, Research Associate, 医学部, 助手 (20296510)
HATANAKA Ko Kitasato Univ. School of Medicine, Research Associate, 医学部, 助手 (00228470)
HAYASHI Izumi Kitasato Univ. School of Medicine, Associate Professor, 医学部, 助教授 (90172999)
KAWAMURA Michiko Kitasato Univ. School of Medicine, Research Associate, 医学部, 助手 (00154104)
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| Research Abstract |
Angiogenesis in chronic glanuloma formed around sponge discs implanted into subcutaneous tissues of rats was increased over a 14-day experimental period. In sponge granuloma, mRNA of COX-1 was constitutively expressed, whereas that of COX-2 was increased with neovascularization in pararell with that of vascular endothelial growth factor (VEGF). Topical injections of bFGF increased the expression of COX-2 mRNA without affecting that of COX-1 mRNA. The angiogenesis with bFGF was inhibited by indomethacin or selective COX-2 inhibitors, NS-398, nimesulide, and JTE-522. The expression of VEGF mRNA in the granuloma was also enhanced by bFGF, and was reduced by NS-398. The enhanced angiogenesis by bFGF was significantly inhibited by topical injections of VEGF anti-sense oligonucleotide. These results suggested that COX-2 may enhance the neovascularization in sponge granuloma by PG-mediated expression of VEGF, and that a COX-2 inhibitor would facilitate the management of conditions involving a
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ngiogenesis. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild type mice (WT) formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase(COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3-/-) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3-/-, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3-/-, compared with WT. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors. Less
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