Selective cyclooxygenase-2 inhibitor downregulates the paracrine epithelial-mesenchymal interactions of growth in scirrhous gastric carcinoma.
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.[1]References
- Selective cyclooxygenase-2 inhibitor downregulates the paracrine epithelial-mesenchymal interactions of growth in scirrhous gastric carcinoma. Yashiro, M., Nakazawa, K., Tendo, M., Kosaka, K., Shinto, O., Hirakawa, K. Int. J. Cancer (2007) [Pubmed]
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