Sonia Santander

Prostaglandin EP2 receptor expression is increased in Barrett’s oesophagus and oesophageal adenocarcinoma

Aliment Pharmacol Ther 31, 440–451

Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo

Background Barretts oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barretts oesophagus in animal models, harmful effects of prolonged PPI therapy in Barretts oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man. Methods We undertook detailed serological and tissue assessment of gastrin and CCK2 receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa. Results Gastrin and its cognate receptor CCK2R were expressed highest in the stomach, then less in Barretts oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barretts oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml±57 pg/ml to 103 pg/ml±94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)cckr Barretts oesophagus cells, but not OE21(E)cckr squamous cells, transfected with CCK2R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists. Conclusion While the short-term effects of gastrin enhance epithelial restitution in Barretts oesophagus (but not squamous mucosa) there is no clinical evidence that Barretts oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barretts oesophagus, is further proof of the clinical safety of PPI therapy.

Prevention of cancer in the upper gastrointestinal tract with COX-inhibition. Still an option?

Epidemiological studies have shown that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction of gastrointestinal cancer risk. Since up-regulation of COX-2 has been reported in different stages of the esophageal and gastric carcinogenic sequence, the cyclooxygenase-2 selective inhibitors (COXIBs) were considered a good alternative to traditional NSAIDs since they cause less injury to the gastrointestinal mucosa. However, recent chemoprevention trial data reporting an increased risk of cardiovascular events have raised serious concerns on the safety of COXIBs in chemoprevention strategies. Moreover, low expression of COX-2 has been reported in a subset of gastrointestinal cancers due to COX-2 methylation, indicating that these patients could be less responsive to treatment by specific COX-2 inhibitors. Furthermore, the COX-1 isoform may have a potential role in the angiogenic process associated with esophageal adenocarcinoma, which suggests that inhibition of COX-1 may be another effective therapeutic target in upper gastrointestinal cancer. Finally, lipoxygenase-derived products may be increased following COX-inhibition due to shunting of the arachidonic acid metabolism. Specifically, the 5-LOX pathway seems to be relevant in gastrointestinal cancer development. Taken together, these data indicate that a re-evaluation of potential chemoprevention strategies for cancers of the upper gastrointestinal tract needs to be considered.

Cyclooxygenase inhibitors decrease the growth and induce regression of human esophageal adenocarcinoma xenografts in nude mice

Cyclooxygenase (COX) inhibition has been shown to prevent the development of esophageal adenocarcinoma (EAC). However, the potential of this approach for treatment of established cancer has been poorly investigated. Our objective was to determine whether non-selective or selective inhibition of the COX pathway affects the growth of esophageal adenocarcinoma xenografts in nude mice. A human esophageal adenocarcinoma xenograft model was established by subcutaneous inoculation of OE33 cells in nude mice. Small tumor slices harvested from four OE33 xenografts were implanted in the flanks of new mice that were randomized to different treatments (6 animals per group): indomethacin (3 mg/kg/day), parecoxib (0.11 and 0.22 mg/kg/day) or a selective prostaglandin E₂ receptor antagonist (AH-23848B, 1 mg/kg/day). For each treatment, a control group of 6 animals (vehicle) carrying xenografts from the same OE33 tumor was included. Tumor growth was measured twice a week. After 8 weeks mice were euthanized. Tumors were assessed by histological analysis, mRNA expression of COX isoenzymes, PGE₂ receptors and PGE₂ content. All OE33 tumors were poorly differentiated esophageal adenocarcinomas. Tumors expressed COX-2, EP₁, EP₂ and EP₄ receptor mRNA. Treatment with parecoxib, higher dose or indomethacin significantly inhibited tumor growth. Furthermore, indomethacin induced tumor regression (74 vs 582% in control animals; p<0.01). However, AH-23848B or parecoxib low dose failed to affect tumor growth significantly. PGE₂ content in tumors was significantly decreased by high-dose parecoxib and indomethacin. Indomethacin and parecoxib inhibit the growth of human esophageal adenocarcinoma xenografts in nude mice, which suggests a potential role for NSAIDs or selective COX-2 inhibitors for EAC chemotherapy.

Characterization of the Prostaglandin E2 Pathway in a Rat Model of Esophageal Adenocarcinoma

UNLABELLED Accumulating evidence indicates that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a key role in esophageal carcinogenesis. A better understanding of the pathway downstream of COX-2 may reveal novel targets for the prevention of esophageal adenocarcinoma (EAC). The objective of this study was to characterize the profile of genes involved in PGE2 metabolism and signaling in an experimental model of EAC. Esophagojejunostomy with gastric preservation was performed in wistar rats to induce gastroduodenal reflux. Rats were sacrificed 2 or 4 months after surgery. Nine non-operated rats were used to obtain normal (control) esophageal tissues. RESULTS All rats that underwent esophagojejunostomy developed inflammation. In addition, 90% of the animals showed intestinal metaplasia; of those, 40% progressed to AC. This process was accompanied by a significant increase in esophageal PGE2 levels and the induction of both mRNA and protein levels of COX-2, COX-1, prostaglandin E synthase, 15-hydroxyprostaglandin dehydrogenase, and PGE2 receptors EP3, EP4 and especially EP2, which rose to particularly high levels in experimental rats. In addition, exposure to a selective COX-2 inhibitor (SC58125) or an EP1/EP2 antagonist (AH6809), but not an EP4 antagonist (AH23848B), significantly reduced cell proliferation of esophageal explants in 24 hour-organ culture experiments. Our data suggest that, in addition to COX-2, other components of the PGE2 pathway, including COX-1, may play important roles in the development of EAC induced by gastroduodenal reflux in the rat. Although it must be confirmed in vivo, the EP2 receptor may represent a promising selective target in the prevention of Barretts associated AC.