The
cyclooxygenase (COX)-2 inhibitor has been reported to impede the progression of
gastric cancer, but underlying mechanisms remain unclear. We therefore investigated the effect of a
COX-2 inhibitor,
JTE-522, on the ability of orthotopic fibroblasts to stimulate invasion of scirrhous gastric
carcinoma cells. The human scirrhous
gastric cancer cell lines OCUM-2D or OCUM-2M, and human gastric fibroblasts (NF-21) were cultured in the absence or presence of
JTE-522 at various concentrations.
Cancer cells were then assayed for invasiveness in vitro by invasion assay. The effect of
prostaglandins (PG) on
growth factor production in NF-21 cells was examined by ELISA. Finally, the effects of orally administrated
JTE-522 on orthotopically transplanted
tumors were examined in nude mice. NF-21 cells stimulated invasion by OCUM-2D cells, an effect suppressed by
JTE-522 at 5 x 10(-6) M.
Hepatocyte growth factor (HGF) and
PGE2 production by NF-21 cells were suppressed by
JTE-522 (P < 0.01).
PGE2 stimulated HGF production by NF-21 cells in a dose-dependent manner.
JTE-522 significantly suppressed orthotopic
tumor growth and
lymph node metastasis, and also decreased HGF expression by fibroblasts within the gastric
tumor. In conclusion, we found that gastric fibroblasts stimulated invasiveness in scirrhous
gastric cancer cells, whereas a selective
COX-2 inhibitor inhibited this paracrine effect by decreasing fibroblast
PGE2 production, resulting in downregulation of HGF production.