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.