Fukashi Matsuzaki

High expression of cyclooxygenase-2 in macrophages of human colonic adenoma.

Cyclooxygenase (COX)‐2 is a possible molecular target for suppression of colon carcinogenesis by non‐steroidal anti‐inflammatory drugs (NSAIDs). However, the expression of COX‐2 in human colonic tumors during the adenoma‐carcinoma sequence has not been elucidated. In the present study, we examined immuno‐histochemically the expression and localization of the COX‐2 protein in human colonic adenomas and cancers. Twelve human colonic adenomas and 9 advanced cancers were studied. Immunoreactive COX‐2 was predominantly and strongly expressed in sub‐epithelial interstitial cells broadly present in the surface area of adenomas. The staining pattern of macrophages was similar to that observed for COX‐2 in adenomas. Adjacent normal colonic mucosa was negative for COX‐2 expression. In contrast, COX‐2 was relatively weakly expressed in both tumor cells and interstitial cells in advanced colon cancers. In conclusion, the target of NSAIDs in preventing colon carcinogenesis may be the COX‐2 expressed in interstitial cells, possibly macrophages, of colonic adenomas. Int. J. Cancer 83:470–475, 1999.

Nonsteroidal anti-inflammatory drugs may prevent colon cancer through suppression of hepatocyte growth factor expression.

Nonsteroidal anti-inflammatory drugs which inhibit cyclooxygenase have been reported to suppress colon carcinogenesis. However the mechanism has not yet been elucidated. Growth factors such as hepatocyte growth factor, which are produced by fibroblasts, have been shown to be important in carcinogenesis and the progression of various human cancers. In the present study, we tested the hypothesis that nonsteroidal anti-inflammatory drugs inhibit hepatocyte growth factor expression through an endogenous prostaglandin-mediated pathway in cultured human colonic fibroblasts. Human colonic fibroblasts were obtained from a resected colon and cultured. Hepatocyte growth factor and prostaglandin E2 were measured by enzyme-linked immunosorbent assay. Induction of cyclooxygenase-1 and cyclooxygenase-2 protein was estimated by immunoblotting. Prostaglandins increased hepatocyte growth factor production significantly in a dose- and time-dependent manner. Cholera toxin and 8-bromo cAMP also stimulated hepatocyte growth factor production. Further, prostaglandin E1 significantly increased cellular cAMP. The prostaglandin EP2 and EP4 receptors were detected by reverse transcription-polymerase chain reaction. Interleukin-1beta dramatically increased prostaglandin E2 production and significantly stimulated hepatocyte growth factor synthesis. Interleukin-1beta induced cyclooxygenase-2 but not cyclooxygenase-1 protein. Indomethacin significantly reduced interleukin-1beta-induced prostaglandin E2 release and hepatocyte growth factor production. These results suggest that prostaglandin is a factor for the production of hepatocyte growth factor by human colonic fibroblasts. Nonsteroidal anti-inflammatory drugs may suppress colon carcinogenesis, in part, through the suppression of hepatocyte growth factor expression by inhibiting endogenous prostaglandin production.