A selective cyclooxygenase‐2 inhibitor prevents inflammation‐related squamous cell carcinogenesis of the forestomach via duodenogastric reflux in rats

Abstract

BACKGROUND:Duodenal reflux causes inflammation‐related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective cyclooxygenase (COX)‐2 inhibitor, meloxicam, in preventing this carcinogenesis.METHODS:A series of 188 rats underwent a surgical duodenogastric reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing meloxicam (0.3 mg/kg body weight/day) (meloxicam group). The animals were sequentially sacrificed at Weeks 20, 30, 40, 50, and 60 after surgery. The forestomach was examined for the presence of carcinoma, the incidence of reflux‐related morphological changes, COX‐2 expression, and its activity.RESULTS:At Week 60, squamous cell carcinoma developed in 8 of 21 animals (38%) in the control group, but none of 20 (0%) in the meloxicam group (P < .05). In addition, basal cell dysplasia developed in 19 of 21 (90%) animals in the control group, but only 4 of 20 (20%) in the meloxicam group (P < .01). COX‐2 immunoreactivity was predominantly detected in macrophages in the epithelial stroma. Compared with nonsurgical rats, RNA expression of COX‐2 in the epithelium was up‐regulated, reaching peak at an early stage of Week 20 in both groups (P < .005). The expression of microsomal prostaglandin E synthase‐1 was lower in the meloxicam group than in the control group. PGE2 production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (P < .005).CONCLUSIONS:Meloxicam was effective in preventing reflux‐induced squamous cell carcinogenesis via an inflamed squamous epithelium. Cancer 2009. © 2009 American Cancer Society.

Induction of Metastatic Gastric Cancer by Peroxisome Proliferator-Activated Receptorδ Activation

“…This paradigm is also consistent with GW501516-induced activation of Ptges and Ptgs2/Cox-2 expression [55, 56], which initiate the production of prostacyclins [14] and arachidonic acid metabolites [29] that serve as PPAR δ ligands [57]. Since Cox-2 inhibitors reduce inflammation-related gastrointestinal carcinogenesis [58], and overexpression or deletion of Ptgs2 increases or suppresses tumorigenesis, respectively [59, 60]; this suggests cooperativity between PPAR δ and inflammatory signaling pathways in gastric tumorigenesis. The ability of PPAR δ to have an anti-inflammatory effect in normal cells [51, 52] and a proinflammatory effect in tumors is reminiscent of the dual roles of TGF- β in tumor cells [61, 62].…”

Regulation of inflammation in cancer by eicosanoids

“…We and others have demonstrated the anti-tumor activity of COX-2 inhibitors in inflammation-associated experimental tumor models including transplantable and genetically engineered models of cancer (36, 43, 102-104). COX-2 inhibitors initially did not exhibit the toxicity associated with aspirin, such as gastrointestinal bleeding.…”

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

“…5 Selective cyclooxygenase-2 (COX-2) inhibitors have beneficial effects on preventing inflammation-related carcinogenesis and on the regression of advanced GC. 6,7 COX-2 induces the production of PGE 2 , which upregulates NR4A2 expression via sequential activation of the Rho, protein kinase A (PKA), and nuclear factor-jB signaling pathways.…”