Mechanisms of Disease: Carcinogenesis in Barrett's Esophagus

Navtej S Buttar; Kenneth K Wang

Disclosures

Nat Clin Pract Gastroenterol Hepatol. 2004;1(2) 

In This Article

Gastric Acid and Bile Reflux

Patients with complicated Barrett's esophagus (dysplasia and cancer) reflux significantly more gastric acid and duodenal bile into their esophagus than patients with uncomplicated Barrett's esophagus and gastroesophageal reflux.[4] Understanding how reflux contributes to esophageal cancer, however, is complicated by clinical observations that controlling reflux symptoms, by pharmacological intervention or by surgical repair of the lower esophageal sphincter, fails to prevent esophageal cancer.[5,6] The persistence of acid or bile salt reflux in a subset of patient with Barrett's esophagus, despite their having had treatment, may explain the progression of some patients to cancer. Reflux of duodenal bile persists in 20-34% of patients despite pharmacological intervention, and 10-50% of patients treated with fundoplication develop recurrence of reflux within years of their operation.[5,6]

Preclinical studies in rodent and canine models show that chronic reflux of gastric acid and/or duodenal contents into the esophagus results in dysplasia and esophageal adenocarcinoma in animals.[7,8] Reflux may cause chronic esophageal injury and promote carcinogenesis in Barrett's esophagus by several mechanisms (Figure 2).

A potential link between gastroesophageal reflux and esophageal cancer. Chronic reflux of duodenal bile and gastric acid into the esophagus cause chronic injury and inflammation, which activate signaling that promotes carcinogenesis in Barrett's esophagus. '+' sign indicates activation.

Chronic Injury and Inflammation. In patients with GERD and Barrett's esophagus, bile salts in duodenal bile can cause chronic esophageal injury and inflammation.[4,6,9] Bile salts can produce injury over a wide range of pH and chronic injury is dependent on the PKa of the bile salt. Taurine-conjugated bile salts cause chronic mucosal injury when the esophageal reflux is acidic (pH 4), glycine-conjugated bile salts cause injury when the pH is 4-6, and unconjugated bile salts cause mucosal injury when the pH is neutral or alkaline.[4,9] Prolonged esophageal aspiration studies show significantly increased amounts of taurine-conjugated and unconjugated bile salts in patients with Barrett's esophagus compared with patients with mild or minimal reflux.[9] In 80-90% of patients, the use of a proton pump inhibitor (PPI) heals endoscopically obvious esophagitis, but up to a third of these patients continue to reflux bile salts.[10] In addition, long-term use of PPIs causes bacterial colonization of the upper gut, which deconjugates bile salts.[11] In the high-pH environment created by PPIs, these unconjugated bile salts could cause chronic low-grade inflammation and promote carcinogenesis in Barrett's esophagus.

In canine and rodent models, bile reflux alone can promote carcinogenesis in Barrett's esophagus,[7,8] but well-designed human studies to substantiate this association have not been performed. At present, clinical evidence for or against the role of acid and bile reflux in the progression of neoplasia in Barrett's esophagus remains controversial.

Arachidonic Acid Pathway. The arachidonic acid pathway, which controls inflammation, can be activated by gastric acid or duodenal bile salts and may contribute to carcinogenesis in Barrett's esophagus (Figure 2). Low pH, as well as bile salts, can induce expression of cyclooxygenase-2 (COX-2), which is a key enzyme of the arachidonic acid pathway, in both an ex-vivo culture model of human Barrett's esophagus and in esophageal adenocarcinoma cell lines.[12,13] COX-2 expression increases concomitantly with neoplastic progression in Barrett's esophagus, supporting the association of the arachidonic acid pathway and esophageal adenocarcinoma development.[14] It is proposed that protein kinase C, ERK and p38 MAPK mediate bile- and acid-induced COX-2 expression.[12,13,15]

COX-2 can catalyze the conversion of arachidonic acid into various prostaglandins, including prostaglandin E2 (PGE2). PGE2 induces the proliferation of Barrett's epithelial cells, whereas inhibition of PGE2 can inhibit their proliferation.[16] PGE2-induced cell proliferation can provide an opportunity for premalignant Barrett's cells to accumulate replicative errors. In addition, PGE2 inhibits tumor surveillance by inhibiting natural killer cell activity. So chronic induction of PGE2 could facilitate the accumulation of abnormal cells with genomic instability, and therefore promote carcinogenesis.[17]

Oxidative Stress. Chronic injury related to acid and bile salts can also induce the production of REACTIVE OXYGEN SPECIES, deplete antioxidants and increase the expression of oxidative-stress-related genes.[18] Reduced levels of glutathione and vitamin C in the metaplastic epithelium indicate that antioxidant defenses are compromised in patients with Barrett's esophagus.[18] In addition, levels of oxygen radicals and lipid-peroxidation products are increased in these cells.[18] DNA damage by free radicals that results in mutations in key cell survival regulatory genes can have a significant role in carcinogenesis.[18] Normally, cells with such mutations do not proliferate further because they are forced into cell-cycle arrest or apoptosis by p53.[19] Unfortunately, bile salts can suppress this process by promoting PROTEOSOME- mediated degradation of p53.[20] The net result is the accumulation of genetically abnormal cells or the progression of carcinogenesis.

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