Cyclooxygenase-2 promotes tumor lymphangiogenesis and lymph node metastasis             in oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) is the sixth most common cancer and             frequently metastasizes to the cervical lymph nodes, leading to poor survival             of patients with OSCC. However, the mechanism of lymph node metastasis is not             fully understood. To clarify the molecular mechanism underlying OSCC metastasis             to regional lymph nodes, the highly metastatic fluorescent labeled OSCC cell line             SAS-LM3 was successfully established allowing us to monitor the progression of             lymph node metastases in a non-invasive manner. SAS-LM3 tumors showed increased             lymphangiogenesis and elevated expression of VEGF-C, a potent stimulator of lymphangiogenesis,             compared to parental SAS tumors. SAS-LM3 showed high expression of cyclooxygenase-2             (COX-2) compared to parental SAS cells and immunohistochemical analysis demonstrated             intense COX-2 expression at the primary site. Inactivation of COX-2 by knockdown             or the COX-2 inhibitor NS-398 decreased VEGF-C expression. Administration of COX-2             inhibitor NS-398 in SAS-LM3 tumor-bearing mice suppressed tumor lymphangiogenesis             and lymphatic metastases. Collectively, our results indicate that COX-2 promotes             tumor lymphangiogenesis and lymph node metastasis of OSCC. COX-2 ablation holds             promise as a potential therapeutic approach for lymph node metastasis in OSCC.
Department of Molecular and Cellular Biochemistry, Osaka University                     Graduate School of Dentistry, Osaka, Japan.
Yoshihiro
Y
Morita
Kenji
K
Hata
Masako
M
Nakanishi
Toshihiko
T
Nishisho
Yoshiaki
Y
Yura
Toshiyuki
T
Yoneda
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000556:secondary*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000201:enzymology / Q000473:pathology*; D009578:Nitrobenzenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human