Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Screening and surveillance
 

Can prostaglandin E2 be considered as involved in degeneration of Barrett's and colonic mucosa?

G. Morgan (Swansea)

The role of prostaglandin E2 (PGE2) in the degeneration of Barrett's and colonic mucosa is best illustrated by firstly considering the pharmacology of non-steroidal antiinflammatory drugs (NSAIDs) such as aspirin. The therapeutic and toxic properties of NSAIDs can be explained pharmacologically. In 1971 [1] it was discovered that NSAIDs inhibit the cyclo-oxygenase (COX) enzyme and thus prevent the formation of prostaglandins and thromboxanes from precursor arachidonic acid. Arachidonic acid is an essential polyunsaturated fatty acid that is derived from the diet. It is believed that the analgesic, anti-inflammatory and antipyretic effects of NSAIDs are related, at least in part, to prostaglandin inhibition. Aspirin prevention of cardiovascular disease is thought to be related to thromboxanes inhibition in platelets leading to a reduced risk of potentially dangerous blood clots forming in the heart and brain blood vessels. Research published in 1991 and 1992 identified and characterised a second COX isoform (COX-2) [2-4]. COX-1 is expressed constitutively and produces prostaglandins and thromboxanes such that are important in many physiological processes but most notably within the stomach and kidney. In contrast with COX-1, COX-2 is not expressed in normal tissues but its expression is greatly increased (more than 20-fold) at sites of inflammation. The overexpression of COX-2 can be rapidly induced by a variety of stimuli including cytokines, growth factors and hormones. It is believed that the therapeutic effects of NSAIDs against pain, inflammation and fever are largely related to COX-2 inhibition while the toxic effects of NSAIDs to the stomach and kidney are largely related to COX-1 inhibition. Aspirin cardiovascular protection is an important exception to this COX-1 (toxicity) and COX-2 (therapeutic) principle. Protection appears to be related to COX-1 inhibition in the platelets leading to a reduction in the synthesis of platelet thromboxanes. This appears to be related to a unique pharmacological property of aspirin over other NSAIDs. Only aspirin can irreversibly inhibit the COX-1 enzyme in platelets and thus prevent the platelet ever producing thromboxanes again.

Evidence that prostaglandin E2 is involved in degeneration

There is good evidence that NSAIDs reduce the risk of both esophageal and colorectal cancers [5-7]. It therefore follows the PGE2 inhibition is a plausible candidate for the reduced cancer risk which in turn implicates PGE2 as a potential mediator of degeneration. Esophageal and colorectal cancer development arise following a multistage process known as carcinogenesis. PGE2 is likely to play a different role at each stage of carcinogenesis although it is worth emphasizing that carcinogenesis is a complex process and a number mediators other than prostaglandins will exert effects. With respect to esophageal carcinogenesis, there is evidence that long standing reflux disease is associated with an increase risk of esophageal adenocarcinoma [8]. PGE2 may play a role in reflux disease by driving the vicious cycle of reflux, inflammation, reduced pressure of the lower esophageal sphincter and further reflux [9]. The treatment of long standing reflux disease with NSAIDs is logical but controversial. The enzymic origin of PGE2 in reflux disease remains to be identified but COX-2 is a likely and logical source. COX-2 inhibitors such as celecoxib and rofecoxib may be helpful in the treatment long standing reflux disease in conjunction with conventional treatment agents such as acid suppressant. In addition, breaking the vicious PGE2 cycle would reduce the risk of developing Barrett's esophagus and adenocarcinoma. Barrett's esophagus is associated with the overexpression of COX-2 [10, 11]. The pathophysiological role of COX-2 in Barrett's esophagus is not fully understood [11] although it is likely to be a marker for cancer risk. At the very least, COX-2 expression would be expected to result in a high level of PGE2 synthesis which would maintain and perpetuate the vicious cycle described earlier. At present, no clinical trials have been conducted on NSAIDs (particularly COX-2 inhibitors) in Barrett's esophagus patients and such studies are warranted. COX-2 is also overexpressed in esophageal adenocarcinomas and esophageal squamous cell carcinomas [12, 13]. Again the role of COX-2 is not fully understood but PGE2 is known to be a potent vasodilator. It is plausible that COX-2 derived PGE2 helps to maintain carcinoma blood flow thus promoting the conditions for carcinoma survival and growth. Selective COX-2 inhibitors may thus have a therapeutic remit in the treatment of established esophageal cancers. With respect to colorectal carcinogenesis, it is known the COX-2 is overexpressed in precancerous and cancerous tissues [5, 6]. Good evidence for the role of COX-2 in colonic degeneration has been provided by Oshima et al. [14]. They bred mice carrying a mutation to the adenomatous polyposis coli gene with other mice having a disrupted COX-2 gene. Mice that had 2 normal COX-2 genes developed an average of 652 polyps at 10 weeks; those with one COX-2 gene had 224 while those with no active gene had only 93 polyps. These data provide definitive data that COX-2 is an early rate limiting for precancerous adenomatous poly formation in experimental animals. COX-2 inhibitors thus hold promise as chemoprevention agents for colorectal cancer and clinical trials are in progress with celecoxib and rofecoxib in patients with the precancerous syndrome known as familial adenomatous polyposis [15].

Public health considerations

Selective COX-2 inhibitors have potential for preventing esophageal and colorectal cancer. An important, if not exclusive, mechanism of action is likely to be PGE2 inhibition. Thus PGE2 can be considered to be an important mediator of degeneration during carcinogenesis.

COX-2 inhibitors may be particularly useful as chemoprevention agents in patients with precancerous lesions such as Barrett's esophagus and familial adenomatous polyposis but there wider public health potential remains unclear. From a public health viewpoint, most patients will be without precancerous lesions and aspirin may be a more beneficial drug for cancer prevention in the general population due to the attendant risk reduction from cardiovascular disease.

Closing remarks

PGE2 can be considered to be important in degeneration of Barrett's and colonic mucosa. COX-2 inhibitors may have therapeutic remits in treating reflux disease, the chemoprevention of esophageal and colorectal cancers and treating established cancers. At the public health level, aspirin may be an optimum NSAID to use to reduce cancer risk due to additional benefits against cardiovascular disease risk.

References

1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971;231:232235.

2. O'Banion MK, Sadowski HB, Winn V, Young DA. A serum- and glucocorticoid regulated 4-kilobase mRNA encodes a cyclooxygenase related protein. J Biol Chem 1991;266:23261-23267.

3. Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991;88:2692-2696.

4. Sirois J, Richards JS. Purification and characterisation of a novel, distinct isoform of prostaglandin endoperoxide synthase induced by human chorionic gonadotrophin in granulosa cells of rat preovulatory follicles. J Biol Chem 1992;267:6382-6388.

5. IARC Handbooks of Cancer Prevention. Volume 1 - Non-steroidal anti-inflammatory drugs. International Agency for Research on Cancer, Lyon, 1997.

6. Morgan G. Beneficial effects of NSAIDs in the gastrointestinal tract. Eur J Gastroenterol Hepatol 1999;11:393-400.

7. Langman MJS, Cheng KK, Gilman R, Lancashire RJ. Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database. Br Med J 2000;320:1642-1646.

8. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. New Engl J Med 1999;340:825-831.

9. Mason J. NSAIDs and the oesophagus. Eur J Gastroenterol Hepatol 1999;11:369-373.

10. Fu S, Ramanujam KS, Meltzer SJ, Wilson KT. Expression and localisation of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus. Gastroenterology 1997;114(2):A565.

11. Shirvani VN, Ouatu-Lascar R, Kaur BS, Omary B, Triadafilopoulos G. Cyclooxygenase 2 expression in Barrett's esophagus and adenocarcinoma: ex vivo induction by bile salts and acid exposure. Gastroenterology 2000;118:487-496.

12. Zimmerman K, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 1999;59:198-204.

13. Ratnasinghe D, Tangrea J, Roth MJ, Dawsey MJ, Hu N, Anver MN, Wang QH, Taylor PR. Expression of cyclooxygenase-2 in human squamous cell carcinoma of the esophagus; an immunohistochemical study. Anticancer Res 1999;19:171-174.

14. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E. Suppression of intestinal polyposis in Apc knockout mice by inhibition of cyclooxygenase 2 (COX-2) Cell 1996;87:803-809.

15. Gottlieb S. COX-2 inhibitors might be useful in cancer prevention. Br Med J 1999;319:1155.


Publication date: August 2003 OESO©2015