title: Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis.
abstract: Cyclooxygenase-2 (COX-2) inhibitor has been reported to suppress tumor progression. However, it is unclear whether this inhibitor can also prevent lymphatic metastasis. To determine the effects of COX-2 inhibitor on lymphatic metastasis, etodolac, a COX-2 inhibitor, was given p.o. to mice bearing orthotopic xenografts or with carcinomatous peritonitis induced with a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN. Tumor lymphangiogenesis was significantly decreased in etodolac-treated mice compared with control mice. Consistent with this decrease in lymphangiogenesis, the total weight of metastatic lymph nodes was less in etodolac-treated mice than in control mice. Immunohistochemical analysis revealed that the major source of vascular endothelial growth factor-C (VEGF-C) and VEGF-D was F4/80-positive macrophages in our models. The mRNA levels of VEGF-C in mouse macrophage-like RAW264.7 cells, as well as those in tumor tissues, were suppressed by etodolac. The growth of human dermal lymphatic microvascular endothelial cells was also suppressed by etodolac. Supporting these findings, etodolac also inhibited lymphangiogenesis in a model of chronic aseptic peritonitis, suggesting that COX-2 can enhance lymphangiogenesis in the absence of cancer cells. Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Caname
authors.initials: C
authors.lastname: Iwata
authors.forename: Mitsunobu R
authors.initials: MR
authors.lastname: Kano
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Komuro
authors.forename: Masako
authors.initials: M
authors.lastname: Oka
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kiyono
authors.forename: Erik
authors.initials: E
authors.lastname: Johansson
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Morishita
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
authors.forename: Michio
authors.initials: M
authors.lastname: Kaminishi
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000032:analysis; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D017308:Etodolac / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D042583:Lymphangiogenesis / Q000187:drug effects*; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D010538:Peritonitis / Q000503:physiopathology; D013274:Stomach Neoplasms / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D017308:Etodolac; D051546:Cyclooxygenase 2