The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Agoff, S. Nicholas; Brentnall, Teresa A.; Crispin, David A.; Taylor, Scott L.; Raaka, Stuart; Haggitt, Rodger C.; Reed, Michael W.; Afonina, Irina; Rabinovitch, Peter S.; Stevens, Alexander R.; Feng, Ziding; Bronner, Mary P.

doi:10.1016/s0002-9440(10)64587-7

Cited by 150 publications

(86 citation statements)

References 36 publications

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“…For example, prolonged ulcerative colitis is a known risk factor for the development of epithelial dysplasia and adenocarcinoma (44,55). Also, studies of colitis-associated neoplasia in humans show COX-2 overexpression in neoplastic lesions (1). Furthermore, in an animal model of colitis-associated cancer, increased mucosal EGFR phosphorylation and COX-2 expression have been reported (21).…”

Section: Discussionmentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2−/−mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1−/−cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR−/−and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

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Section: Discussionmentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…It is well-known that carcinogenesis in the H pylori-infected stomach also results from an inflammation-mediated sequence. Chronic inflammation is thought to play a cardinal role in the accumulation of genetic damages leading to transformation and cancer by inducing the proliferation of target cells [45][46][47] . Consequently, it is important to find the suitable time-point at which COX-2 inhibitors prevent the carcinogenesis.…”

Section: Figure 4 Effect Of Celecoxib On the Development Of Intestinamentioning

confidence: 99%

Short-term Celecoxib intervention is a safe and effective chemopreventive for gastric carcinogenesis based on a Mongolian gerbil model

Kuo¹,

Hu²,

Tsai³

et al. 2009

WJG

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AIM:To evaluate the optimal intervention point of a selective cyclooxygenase-2 (COX-2) inhibitor, Celecoxib, for inhibiting Helicobacter pylori (H pylori )-associated gastric carcinogenesis in Mongolian gerbils (MGs). METHODS:One hundred and twelve MGs were divided into six groups (A-F). One hundred gerbils were inoculated with H pylori (groups A-E). Twelve gerbils were inoculated with vehicle broth only (group F). After 4 wk, they were given N'-methyl-N' -nitro-N-nitroso-guanidine (MNNG) (50 mg/mL) in the drinking water for 20 wk. In groups B-E, the animals were given the stock Celecoxib (10 mg/kg per day) diet from the 21st, 31st, 21st and 41st week respectively. The periods of administering Celecoxib were 30, 20, 20, and 15 wk respectively. On the 51st week, the animals were sacrificed for histological examination. Local PCNA expression was examined by the immunohistochemistry method. The expression of COX-2 protein was assessed by Western Blot. Analysis used the χ 2 test. The difference was regarded as significant when P value was less than 0.05. RESULTS:Seventeen percent (17/100) of H pyloriinfected MGs developed gastric cancer. All of these lesions were well-differentiated adenocarcinoma. The incidence rates of adenocarcinoma in groups A-F were 40%, 0%, 0%, 20%, 25%, and 0% respectively. The inflammatory scores were higher in group B than in other groups. There was no inflammatory response noted in group F. Celecoxib treatment resulted in a significant reduction in the proliferation of H pyloriinfected mucosal cells (groups B, C and D) (P < 0.01). The expression of COX-2 protein was significantly attenuated in the groups which were Celecoxib-treated for more than 20 wk (groups B, C, D). The groups treated with Celecoxib had a significantly lower rate of advanced gastric cancer (34% vs 75%, P < 0.001)There were no sudden deaths in any of the groups. CONCLUSION:Short-term treatment with Celecoxib has an anti-carcinogenic effect, and resulted in less severe inflammation and inhibited the invasive degree of gastric cancer.

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“…Indeed, the incidence of colorectal cancer in patients with long-standing UC is higher than that of sporadic colorectal cancer (7). Therefore, a treatment that could prevent UC-associated neoplasia would be of great benefit by obviating the need for surveillance and, in some patients, the need for total colectomy for dysplasia or carcinoma (24). NSAIDs inhibit COX activity and have previously been considered as promising agents for the prevention of colon tumors based upon both epidemiological and animal model data (1)(2)(3)(4).…”

Section: Discussionmentioning

confidence: 99%

“…COX-2 is progressively overexpressed during the stepwise sequence from adenoma to cancer, and it is well known that selective COX-2 inhibitors prevent recurrence of adenoma among patients with a history of familial adenomatous polyposis (25). However, the role of selective COX-2 inhibitors in UC-associated neoplasia remains unexplored, because it has been widely believed that these agents may exacerbate UC inflammatory activity (24). To investigate the influence of the selective COX-2 inhibitor nimesulide on the active and/or remission phases that mimic human UC, we previously developed a murine model of long-standing UC induced by simple repeated administration of DSS (active phase, 4 cycles of 5% DSS for 7 days and distilled water for 14 days; remission phase, following 120 days of distilled water) according to Cooper et al (10,21,26), and mice were given nimesulide for various periods.…”

Section: Discussionmentioning

confidence: 99%

R-etodolac induces E-cadherin and suppresses colitis-related mouse colon tumorigenesis

Inoue

Murano²,

Yoda³

et al. 2010

Oncol Rep

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Abstract. Colorectal cancer is one of the most serious complications of ulcerative colitis (UC), and the risk of UCassociated neoplasia increases as the region and duration of the disease increase. Selective cyclooxygenase (COX)-2 inhibitors effectively diminish carcinogenesis in a murine UC model. However, this may exacerbate colitis. The selective COX-2 inhibitor etodolac is marketed as a racemic mixture of the R-and S-enantiomers. The biochemical and pharmacological effects of etodolac are caused by the S-enantiomer, while the R-enantiomer lacks COX-inhibitory activity. In this study, we evaluated the effect of R-etodolac on colitisrelated mouse colon tumorigenesis. The mice received 1,2-dimethlhydrazine (DMH), and then chronic colitis was induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). The mice were sacrificed 28 days after the completion of both cycles. Mice were divided into the following groups: group A served as a disease control; group B received a low (2-mg/kg) dose of R-etodolac every 3 days during the entire period; group C received a high (10-mg/kg) dose of R-etodolac on the same schedule as group B; and group D served as a normal control. Administration of R-etodolac decreased the disease activity index during the DSS administration cycle. The mean number of tumors was 17.8, 15.2, 6.0, and 0 in groups A-D, respectively. In group C, R-etodolac significantly suppressed the occurrence of neoplasia (p<0.05). Although R-etodolac treatment did not affect COX-2 expression, it significantly enhanced expression of E-cadherin in both neoplastic lesions and background mucosa (i.e., lesionfree colon). Thus, administration of R-etodolac exerts a suppressive effect on the development of neoplasia in a murine model of DSS-induced colitis without exacerbation of the colitis. These results suggest that R-etodolac could be useful in the prevention of UC-associated neoplasia.

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The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Cited by 150 publications

References 36 publications

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Short-term Celecoxib intervention is a safe and effective chemopreventive for gastric carcinogenesis based on a Mongolian gerbil model

R-etodolac induces E-cadherin and suppresses colitis-related mouse colon tumorigenesis

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