The Journal of Experimental Medicine
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Published 20 January 2003. doi:10.1084/jem.20021408
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© Rockefeller University Press, 0022-1007/2003/1/221 $5.00
The Journal of Experimental Medicine, Volume 197, Number 2, 221-232

Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth

Hideki Amano1,2, Izumi Hayashi1, Hirahito Endo3, Hidero Kitasato4, Shohei Yamashina5, Takayuki Maruyama6, Michiyoshi Kobayashi6, Kazutoyo Satoh6, Masami Narita6, Yukihiko Sugimoto7, Takahiko Murata8, Hirokuni Yoshimura2, Shuh Narumiya8 and Masataka Majima1

1 Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 228-8555, Japan
2 Department of Thoracic Surgery, Kitasato University School of Medicine, Kanagawa 228-8555, Japan
3 Department of Internal Medicine, Kitasato University School of Medicine, Kanagawa 228-8555, Japan
4 Department of Microbiology, Kitasato University School of Medicine, Kanagawa 228-8555, Japan
5 Department of Anatomy, Kitasato University School of Medicine, Kanagawa 228-8555, Japan
6 Minase Research Institute, Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan
7 Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences
8 Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan

Address correspondence to Masataka Majima, Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan. Phone: 81-42-778-8822; Fax: 81-42-778-7604; E-mail: en3m-mjm{at}asahi-net.or.jp

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. 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 (WT) mice 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. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3-/-. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

Key Words: angiogenesis • tumor • prostaglandin E2 • EP3 receptor • vascular endothelial growth factor


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