The importance of
cancer-mesenchymal interactions in the aggressive behavior of scirrhous
gastric cancer is supported by experimental and clinical evidences. We have previously reported that gastric fibroblasts secretion of
keratinocyte growth factor (KGF) underline the remarkable proliferation of scirrhous
gastric cancer cells.
Cyclooxygenase-2 (COX-2) is not only expressed in
cancer cells, but also in interstitial fibroblasts in gastric
carcinoma. To clarify the mechanisms responsible for the antiproliferation effect of
COX-2 inhibitors, effect of
COX-2 inhibitor on the paracrine epithelial-mesenchymal interactions of growth was examined. Scirrhous
gastric cancer cell line, OCUM-2M, gastric fibroblasts, NF-21, and
COX-2 inhibitor,
JTE-522, were used. Growth-interaction was examined by calculating the number of
cancer cells or by measuring [(3)H]
thymidine incorporation of
cancer cells. Effect of
JTE-522 on KGF expression from NF-21 cells and OCUM-2M cells was analyzed by ELISA and RT-PCR. The
conditioned medium from gastric fibroblasts significantly stimulated the growth of scirrhous
gastric cancer cells.
JTE-522 at the concentrations of 10(-5) and 10(-6) M significantly decreased the growth-stimulating activity of gastric fibroblasts.
JTE-522 reduced the expression of KGF
mRNA and the production of KGF from gastric fibroblasts.
Oral administration of
JTE-522 significantly decreased the size of xenografted
tumor coinoculated with OCUM-2M cells and NF-21 cells in nude mice.
JTE-522 decreased COX-2 expression and Ki67 labeling index within the coinoculated
tumor. These findings suggested that a selective
COX-2 inhibitor,
JTE-522, downregulates KGF production from gastric fibroblasts, resulting in the inhibition of paracrine epithelial-mesenchymal interactions of proliferation between scirrhous
gastric cancer cells and gastric fibroblasts.