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 PGE(2) 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.
Liu
Huidong
H
Department of Anatomy, Harbin Medical University, Harbin, China.
Yang
Yanmei
Y
Xiao
Jianbing
J
Lv
Yanhong
Y
Liu
Yan
Y
Yang
Huike
H
Zhao
Linghui
L
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D000068579:Celecoxib; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010641:Phenotype; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; C119248:LYVE1 protein, human; D011720:Pyrazoles; D013449:Sulfonamides; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone