Inhibition of Cyclooxygenase‐2 Suppresses Lymph Node Metastasis via VEGF‐C

Most experimental work addressing cyclooxygenase‐2 (COX‐2) inhibitor has focused on suppressing hematogenic spread. Little is known about the mechanism by which this inhibitor can also block lymphatic metastasis. Here, the effects of COX‐2 inhibitor on vascular endothelial growth factor‐C (VEGF‐C) expression, lymphangiogenesis and lymph node metastasis were investigated. Utilizing the highly metastatic human lung adenocarcinoma cell line Anip973 and its parental line AGZY83‐a, which has a low metastatic capacity, we found elevated VEGF‐C and COX‐2 immunoreactivity in Anip973 cells compared with AGZY83‐a cells. Celecoxib down‐regulated expression of VEGF‐C mRNA and protein in Anip973 cells while PGE₂ up‐regulated expression of VEGF‐C mRNA and protein in AGZY83‐a cells in a concentration‐dependent manner. The expression of COX‐2 and VEGF‐C was significantly increased in xenografted Anip973 tumors compared with AGZY83‐a tumors. The Anip973 tumors showed more lymphatic vessels and lymph node metastasis than the AGZY83‐a tumors. In vivo, celecoxib decreased VEGF‐C expression in Anip973 tumor‐treated mice to a similar level to that in the AGZY83‐a tumor‐treated mice. Consistent with this decrease in VEGF‐C expression, the density of lymphatic vessels and lymph node metastasis in Anip973 tumor‐treated mice were suppressed to approximately that found in the AGZY83‐a tumor‐treated ones. Taken together, our results suggest that the differential expression of COX‐2 and VEGF‐C might help explain the different metastasis phenotype of lung adenocarcinoma cancer, and that COX‐2 inhibitor mediates VEGF‐C to block lymphangiogenesis and lymph node metastasis. Thus, COX‐2 may be a potential therapeutic target for blocking lymph node metastasis in lung adenocarcinoma. Anat Rec, 2009. © 2009 Wiley‐Liss, Inc.