Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus

Abstract

Neoplastic progression in Barrett's esophagus is a multistep process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasiacarcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barrett's esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-®xed, para n-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27 kip1 protein, but did not display appreciable nuclear staining for p16 kip4 , p21 cip1 or cyclins D1 and E. Barrett's metaplastic specimens displayed increased expression levels of p16 kip4 (74%), p21 cip1 (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a signi®cant correlation between the expression of p16 kip4 and cyclin E, and p21 cip1 and p27 kip4 with cyclin D1. DNA analysis did not reveal any ampli®cation or deletion of these genes. Acid suppression, however, was associated with signi®cantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barrett's esophagus. Treatment with proton pump inhibitors appears to alter this increased expression. Oncogene (2001) 20, 7987 ± 7991.

Efficacy of proton pump inhibitors for cellular proliferation and apoptosis in Barrett's oesophagus with different mucin phenotypes

“…32,33 Ouatu-Lascar et al reported that normalization of the intra-oesophageal pH by PPI reduces cellular proliferation and increases cellular differentiation, 34 and Umansky et al confirmed a reduction in abnormalities in the cell cycle of Barrett's oesophagus by acid suppressants. 35 Although it well known that continuous PPI administration provokes hypergastrinaemia which promotes the cellular proliferation of the mucosa in gastrointestinal tract, an important role of PPIs for the cellular proliferation in Comparison of cellular proliferation between non-treatment patients and chronic proton pump inhibitor (PPI) users in Barrett's oesophagus with different mucin phenotypes. Anti-proliferating cell nuclear antigen (PCNA) indices were significantly higher in Barrett's oesophagus with the intestinal-predominant than with the gastric-predominant mucin phenotype in both non-treatment patients and chronic PPI users (*P < 0.001).…”

Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis

“…The only available means of early detection of EAC is regular endoscopic surveillance for patients with BE. However, the clinical benefit of endoscopic surveillance remains to be established because the development of EAC from BE takes many years and occurs in only a limited percentage of BE subjects (Stoltzing et al, 1998;Umansky et al, 2001;Ferguson and Durkin, 2002;Spechler, 2002). Risk stratification of patients with BE for the progression to EAC has been attempted, with a relative paucity of biomarkers characteristic to the precancerous lesions BE, low-and high-grade dysplasia (Abraham et al, 1996;Going et al, 2002;Wang et al, 2003;Kimos et al, 2004;McManus et al, 2004).…”

Review: Chemoprevention of esophageal adenocarcinoma

“…An in vivo study of BE tissue demonstrated reduced cellular proliferation after six months of effective acid suppression with lansoprazole [Ouatu-Lascar et al 1999]. A separate study of patients with BE who received PPI therapy demonstrated reduced p16 and increased cyclin D1 expression as compared to BE patients not receiving acid suppressive therapy [Umansky et al 2001]. Effective acid suppression (as demonstrated by pH monitoring) in BE patients resulted in reduced cellular proliferation but had no effect on apoptosis or COX-2 expres-…”