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.
Highlights
Lymph node metastasis is a common occurrence in cancer, and lymphatic vessels serve as an important route for the spread of cancer cells [1, 2]
To examine whether COX-2 is involved in lymphatic metastasis, we evaluated the effects of treatment with a COX-2 selective inhibitor, etodolac [29, 30], on tumor lymphangiogenesis and extent of lymph node metastasis using a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN [31]
There is no direct evidence of a relationship between COX-2 and lymphangiogenesis, some clinical and animal studies have suggested that level of COX-2 expression in tumor tissue is correlated with lymph node metastasis and/or unfavorable prognosis [24,25,26,27,28, 35]
Summary
Lymph node metastasis is a common occurrence in cancer, and lymphatic vessels serve as an important route for the spread of cancer cells [1, 2]. Lymphatic metastasis was previously believed to be a passive process in which detached cancer cells reach lymph nodes through preexisting local lymphatic vessels [3]. Recent studies have suggested that lymphangiogenesis actively contributes to metastasis based on the observations that lymphatic vessel density is correlated with the extent of lymph node metastasis and/or unfavorable prognosis of certain cancers [2, 4, 5]. Requests for reprints: Kohei Miyazono, Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-5841-3345; Fax: 81-3-5841-3354; E-mail: miyazono-ind@ umin.ac.jp
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
