Role of prostaglandin receptor signaling inenhancement of lymphangiogenesis and application to metastasis treatment

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Lymphangiogesis, the formation of lymphatic vessels from pre-existing lymphatic vessels, plays an important role in homeostasis, metabolism and immunity. Recent evidenceindicates that lymphangiogenesis, similar to angiogenesis, also occurs during certain inflammatory and autoimmune conditions. I examined the effects of COX-2 and endogenous PGE2on lymphangiogenesis during chronic inflammation. Lymphangiogenesis was upregulated during the development of granulation tissues, which were formed around Matrigel plugs in response to inductions of COX-2 and mPGES-1. Administration of a COX-2 inhibitor (celecoxib) significantly reduced lymphatic vessel formation in granulationtissues, whereas topical PGE2administration enhanced lymphangiogenesis.Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors for PGE2. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, while an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. Thus, our findings demonstrate that EP3 and EP4 signaling contributes to inflammation-associated lymphangiogenesis by upregulating VEGF-C and VEGF-D in fibroblasts and macrophages. In addition, prostaglandin receptor signaling appears critical for tumorassociated lymphangiogenesis and tumor growth. From now on, I would like to continue an examinationbased on these findings about the metastasis in lymph node.