期刊
CANCER SCIENCE
卷 100, 期 12, 页码 2318-2324出版社
WILEY
DOI: 10.1111/j.1349-7006.2009.01322.x
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资金
- Integrative Research Program of the Graduate School of Medical Science
- Kitasato University School of Medicine
- Parent's Association of Kitasato University School of Medicine
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [12470529, 12670094]
- Grants-in-Aid for Scientific Research [12670094, 12470529] Funding Source: KAKEN
Cyclooxygenase (COX)-2 is known to correlate with poor cancer prognosis and to contribute to tumor metastasis. However, the precise mechanism of this phenomenon remains unknown. We have previously reported that host stromal prostaglandin E-2 (PGE(2))-prostaglandin E2 receptor (EP)3 signaling appears critical for tumor-associated angiogenesis and tumor growth. Here we tested whether the EP3 receptor has a critical role in tumor metastasis. Lewis lung carcinoma (LLC) cells were intravenously injected into WT mice and mice treated with the COX-2 inhibitor NS-398. The nonselective COX inhibitor aspirin reduced lung metastasis, but the COX-1 inhibitor SC560 did not. The expression of matrix metalloproteinases (MMP)-9 and vascular endothelial growth factor (VEGF)-A was suppressed in NS-398-treated mice compared with PBS-treated mice. Lungs containing LLC colonies were markedly reduced in EP3 receptor knockout (EP3-/-) mice compared with WT mice. The expression of MMP-9 and VEGF-A was downregulated in metastatic lungs of EP3-/- mice. An immunohistochemical study revealed that MMP-9-expressing endothelial cells were markedly reduced in EP3-/- mice compared with WT mice. When HUVEC were treated with agonists for EP1, EP2, EP3, or EP4, only the EP3 agonist enhanced MMP-9 expression. These results suggested that EP3 receptor signaling on endothelial cells is essential for the MMP-9 upregulation that enhances tumor metastasis and angiogenesis. An EP3 receptor antagonist may be useful to protect against tumor metastasis. (Cancer Sci 2009; 100: 2318-2324).
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