Hiromi Bamba

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.

COX‐2, prostanoids and colon cancer

Epidemiological, experimental, and clinical studies have demonstrated that colon carcinogenesis may be prevented by nonsteroidal anti‐inflammatory drugs (NSAIDs). Although controversy remains, recent studies, including ours, have revealed that NSAIDs suppress colon carcinogenesis at the adenoma stage where cyclooxygenase‐2 (COX‐2), a major molecular target in this action, is mainly expressed in interstitial cells but not in tumour cells. Therefore, it is unlikely that NSAIDs prevent colon cancer formation through modulating the functions of tumour cells. A more possible assumption is that NSAIDs suppress colon carcinogenesis through the inhibition of prostaglandin formation. However, the mechanisms by which prostanoids promote colon carcinogenesis have not been elucidated to date. A prostanoids act through both membrane receptors and nuclear receptors such as peroxisome proliferator receptor (PPAR) γ or δ, one focus in this area is to investigate their roles in colon carcinogenesis, including the induction of growth factors.

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.

Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats

Background and Aim:  The mechanisms responsible for impaired regenerative ability after hepatic resection observed in chronic liver disease are not fully understood. We have examined the relationships between an altered expression of cell cycle‐related proteins in regenerating liver after partial hepatectomy and the impaired regenerative process observed in fibrotic and cirrhotic rats.

Effect of rebamipide on prostaglandin receptors-mediated increase of inflammatory cytokine production by macrophages

Background : Rebamipide (Reb) is an anti‐ulcer drug, and has unique properties such as anti‐inflammatory action. We previously reported that prostaglandins (PGs) dramatically increased vascular endothelial growth factor (VEGF), a known angiogenic factor and a vascular permeable factor, by activated macrophages through specific PGE receptor and peroxisome proliferator‐activated receptor γ (PPARγ, a nuclear receptor of PG) mediated process. Effects of PGs on the production of other cytokines such as interleukin (IL)‐6 and IL‐8 have been controversial.

ACCURACY OF ENDOSCOPIC DIAGNOSIS OF HELICOBACTER PYLORI IN PATIENTS WITH HEMORRHAGIC PEPTIC ULCERS

Background:  Recent progress in Helicobacter pylori eradication has resulted in dramatic improvements in the incidence of peptic ulcers and decreased rates of ulcer relapse. Because bleeding is an important complication of ulcer diseases, accurate diagnosis of H. pylori infection is necessary.

Cell cycle-related protein expression in regenerating fibrotic and cirrhotic rat liver following partial hepapectomy

Background and Aims: We previously reported that cyclin D1 accumulation facilitates assembly of enzymatically active cyclin Dl-cdk 4 complexes as liver cells progress through (31 phase in regenerative normal rat liver after partial hepatectomy (PH, BBRC 245: 70,1990). Clinically, liver cirrhosis is associated with prominent mortality, while cirrhotic liver is considered to regenerate less actively than normal liver. Although impaired regeneration creates several therapeutic problems, the mechanisms responsible for this step have not yet been elucidated. The aim of this study was to characterize the expression of cell cycle-related proteins in the regenerating fibrotic and cirrhotic rat liver. Methods: Liver fibrosis (F group) or cirrhosis (LC group) was induced by intraperitoneal injections of porcine serum (0.5 ml) or thioacetamide (200mg/kg B.W. in saline) into male F344 rats, twice a week for 12 weeks respectively. Control rats (C group) received intraperitoneal injections of 0.5 ml saline at the same time points. The rats were subjected to 70% PH (C and F groups) and 45% PH (LC groups), rsspectJvely, since more than 40% of the rats with cirrhosis died alter 70% PH. Development of hepatic fibrosis and cirrhosis was confirmed by Masson-trichrome staining. DNA synthesis was determined by the proliferating cell nuclear antigen (PCNA) labeling index. Protein expression of cyclin D1, cdk 4, and CDK inhibitors (p21 and p27) was measured throughout 48 hrs after PH by western blotting. In addition, the rate of formation of cyclin D1cdk 4 complexes was estimated. Results : PCNA labeling index increased significantly higher in C and F groups than that in LC groups after PH, although the index was higher in LC groups before hepatectomy. Interestingly, drastic induction of cyclin D1 and gradual increase of cdk 4 protein occurred after PH in C and F groups, whereas induction of cyclin D1 was not detected in LC group. In contrast, cdk 4 protein was detected at a high level in cirrhotic liver and did not change following PH. Although induction of p21 was detected in all groups, the level in LC group was lower than other groups for 48 hrs. p27 was constantly expressed at high levels in all groups. No significant change of this protein level was observed. Conclusion: The impaired regeneration of the cirrhotic liver is associated with a lowered level of cyclin D1 expression, whereas CDK inhibitors (p21 and p27) may not contribute to this process.