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

Jiménez, Pilar; Piazuelo, Elena; Cebrián, Carmelo; Ortego, Javier; Strunk, Mark; Garcı́a-González, Maria Asunción; Santander, Sonia; Alcedo, Javier; Lanas, Ángel

doi:10.1111/j.1365-2036.2009.04172.x

Cited by 34 publications

(55 citation statements)

References 37 publications

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“…Our findings of the EP2 expression in TAFs in the mesenchyme are consistent with our previous finding that EP2 was expressed in stromal region in Apc D716 mice and Ptger2 deficiency suppressed intestinal polyp formation (43). Furthermore, several studies reported expression of EP2 in various types of cancers (44)(45)(46) and aspirin lowers the risk of solid tumors other than colorectal cancer (4,5). It is interesting to test how widely the EP2 actions we found here operate in microenvironment of cancers other than colorectal cancer.…”

Section: Ly-6gsupporting

confidence: 81%

Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth

et al. 2015

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Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation-and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFa and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFa, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFa, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer.

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Section: Ly-6gsupporting

confidence: 81%

Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth

et al. 2015

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“…In the esophagus, Jiménez et al (11) showed that, in addition to COX-2, EP 2 and EP 4 receptor expression and protein were increased in the Barrett's metaplasia-intraepithelial neoplasiaadenocarcinoma sequence. Among these two PGE 2 receptors, OE33 xenografts showed higher expression for EP 4 .…”

Section: Discussionmentioning

confidence: 99%

“…Evidence supporting the involvement of COX-2 in esophageal adenocarcinoma includes epidemiological studies which have demonstrated a protective effect of NSAIDs against esophageal adenocarcinoma (4,5), in vivo studies in experimental models of reflux-induced esophageal adenocarcinoma in rats, where administration of non-steroidal anti-inflammatory drugs (NSAIDs) or selective COX-2 inhibitors (coxibs) induced a reduction of esophageal cancer incidence (6)(7)(8)(9)(10). In addition, up-regulation of COX-2 has been described both at mRNA and protein level along the Barrett's metaplasia-dysplasia-adenocarcinoma sequence in humans (11)(12)(13)(14)(15)(16)(17) and COX-2 expression has been identified as an independent prognostic variable for esophageal adenocarcinoma (18), indicating that COX-2 could be a molecular target for specific chemotherapeutic treatment.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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Abstract. 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 E 2 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, PGE 2 receptors and PGE 2 content. All OE33 tumors were poorly differentiated esophageal adenocarcinomas. Tumors expressed COX-2, EP 1 , EP 2 and EP 4 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. PGE 2 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.

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“…Whereas its mechanisms of action have been well elucidated for inflammation, less is known for cancer promotion. Some experimental studies demonstrated that COX-2 over-expression is associated with a significant decrease of apoptosis, an increase in malignant cell invasiveness and an enhancement of prostaglandin synthesis and cell proliferation [22]. Opposite effects together with decreased angiogenesis are associated with COX-2 inhibition [23].…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 and Inflammation Mediators Have a Crucial Role in Reflux-Related Esophageal Histological Changes and Barrett’s Esophagus

et al. 2013

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Background Gastroesophageal reflux (GER) causes injury of the esophageal squamous epithelium, a condition called reflux esophagitis. The sequence reflux-esophagitisintestinal metaplasia-dysplasia-invasive cancer is widely accepted as the main adenocarcinogenetic pathway in the esophagus; however, the mechanisms of this progression need to be better defined. Aims We evaluated COX-2 expression and activity in biopsies from patients affected with GER, and these parameters have been correlated with the stage of the disease, ceramide expression, apoptotic process, and angiogenesis. The effects of celecoxib on bile acid-and EGFinduced mucosal proliferation, apoptosis and angiogenesis have been also investigated. Methods Four groups of patients were distinguished: non esophagitis, non erosive esophagitis, erosive esophagitis, and Barrett's esophagus. COX-2 expression, basal PGE 2 levels, proliferative activity, VEGF expression and apoptosis were evaluated in esophageal biopsies.

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

Abstract: SUMMARY BackgroundAccumulating evidence suggests that cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) is involved in oesophageal adenocarcinogenesis. PGE2 exerts its biological action by binding to specific receptors (EP1, EP2, EP3 and EP4).

Cited by 34 publications

References 37 publications

Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth

Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth

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

Cyclooxygenase-2 and Inflammation Mediators Have a Crucial Role in Reflux-Related Esophageal Histological Changes and Barrett’s Esophagus

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