Carcinogenesis at the gastroesophageal junction: Free radicals at the frontier

doi:10.1053/gast.2002.33368

Gastroenterology

Volume 122, Issue 5, May 2002, Pages 1518-1520

https://doi.org/10.1053/gast.2002.33368 Get rights and content

Abstract

GASTROENTEROLOGY 2002;122:1518-1520

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Cited by (33)

Chemoprevention in Barrett's Esophagus: Current Status
2015, Gastroenterology Clinics of North America
Citation Excerpt :
A preclinical study conducted by us established that the use of selective and nonselective COX-2 inhibitors in a rodent model of chronic reflux produced a statistically significant reduction in relative risk of developing EAC by 55% in rats treated with MF-tricyclic and 79% (P<.01) in those treated with sulindac as compared with the control group. The degree of inflammation was found to be more severe in the control group compared with the study group.22 In summary, downregulation of PGE2 levels, either by KLF11-mediated inhibition of cPLA2α or through COX2 inhibition, reduces cell growth in vitro and neoplastic transformation in Barrett’s and mucosa of animals with reflux injury.24,25,28,29
Chemoprevention in Barrett's oesophagus
2015, Best Practice and Research: Clinical Gastroenterology
Citation Excerpt :
Oral microbes on the tongue reduce the salivary nitrates to nitrites [82]. When these nitrites come into contact with contents of gastro-duodenal reflux in the lower oesophagus, they change to nitrous acid that decomposes immediately into nitric oxide [83]. Nitric oxide is considered tumorigenic via DNA damage, lipid peroxidation and mutagenesis.
Increasing incidence of oesophageal adenocarcinoma along with poor survival entails novel preventive strategies. Agents that target pro-oncogenic pathways in Barrett's mucosa could halt this neoplastic transformation. In this review, we will use epidemiological associations and molecular mechanisms to identify novel chemoprevention targets in Barrett's oesophagus. We will also discuss recent chemoprevention trials.
Esophageal adenocarcinoma arising in Barrett esophagus
2009, Cancer Letters
Citation Excerpt :
Following World War II, Western countries sharply increased their use of nitrate-based fertilizers, resulting in an increased concentration of nitrates in vegetables. It is conceivable that this has contributed to the rising frequency of esophageal adenocarcinoma [11,12]. Despite this attractive theory, the bulk of available epidemiological data suggest that a diet high in fruits and vegetables may protect against Barrett and adenocarcinoma of the esophagus.
The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and Barrett esophagus, a squamous-to-columnar cell metaplasia that predisposes to malignancy. Adenocarcinomas in Barrett esophagus are thought to arise through a sequence of growth-promoting, genetic alterations that accumulate until the cells have acquired the physiologic hallmarks of cancer proposed by Hanahan and Weinberg. Moreover, GERD and Barrett esophagus are associated with chronic esophagitis, and inflammation is a well known risk factor for cancer formation. The cell that gives rise to Barrett metaplasia is not known. It has been proposed that the metaplasia may arise from a change in the differentiation pattern of stem cells that either reside in the esophagus or are recruited to the esophagus from the bone marrow. Alternatively, it is possible that Barrett metaplasia develops through the conversion of one differentiated cell type into another. Regardless of the cell of origin, Barrett metaplasia ultimately must be sustained by stem cells, which might be identified by intestinal stem cell markers. An emerging concept in tumor biology is that cancer stem cells are responsible for sustaining tumor growth. If Barrett cancers develop from Barrett stem cells, then a therapy targeted at those stem cells might prevent esophageal adenocarcinoma. This report reviews the risk factors for Barrett esophagus and esophageal adenocarcinoma, the mechanisms by which genetic alterations might contribute to carcinogenesis in Barrett esophagus, and the role of stem cells in the development of Barrett metaplasia and adenocarcinoma.
Nitric Oxide and Acid Induce Double-Strand DNA Breaks in Barrett's Esophagus Carcinogenesis via Distinct Mechanisms
2007, Gastroenterology
Citation Excerpt :
In addition, we showed for the first time that acid can induce double-strand DNA breaks in these same esophageal cell lines and that this is mediated by intracellular production of ROS. Our data provide a mechanistic rationale for previously proposed hypotheses linking increased nitrate intake because of use of nitrogen-based fertilizers50 or economic status51 with trends in the incidence of EAC. This study also lends support to the idea that antioxidant therapy, other than vitamin C, may be an appropriate strategy in preventing the progression of BE to EAC.
Background & Aims: The luminal microenvironment including acid and nitric oxide (NO) has been implicated in Barrett’s esophagus carcinogenesis. We investigated the ability of acid and NO to induce DNA damage in esophageal cells. Methods: Transformed and primary Barrett’s esophagus and adenocarcinoma cells were exposed to either acid, (pH 3.5), ± antioxidant or NO from a donor or generated by acidification of nitrite in the presence of ascorbate ± NO scavenger. Phosphorylation of histone H2AX and the neutral comet assay were used to detect DNA double-strand breaks (DSBs). Intracellular levels of reactive oxygen species and NO were detected with fluorescent dyes. Mitochondrial viability was measured with a rhodamine dye. Long-term survival was assessed by clonogenic assay. Results: Exposure to acid (pH 3.5) for ≥15 minutes induced DSBs in all cell lines (P < .05). There was a concomitant increase in intracellular reactive oxygen species in the absence of mitochondrial damage, and pretreatment with antioxidants inhibited DNA damage. Exposure to physiologic concentrations of NO produced from the NO donor or acidification of salivary nitrite induced DSBs in a dose- (>25 μmol/L) and cell-dependent manner (adenocarcinoma >Barrett’s esophagus, P < .05). This occurred preferentially in S-phase cells consistent with stalled replication forks and was blocked with a NO scavenger. NO also induced DSBs in primary Barrett’s esophagus cells treated ex vivo. Cells were able to survive when exposed to acid and NO. Conclusions: Both acid and NO have the potential to generate DSBs in the esophagus and via distinct mechanisms.
Epidemiologic risk factors for Barrett's esophagus and associated adenocarcinoma
2005, Clinical Gastroenterology and Hepatology
The incidence of esophageal adenocarcinoma (AC) has increased dramatically in the Western world over the past 20 years and the majority of these cancers arise on the background of the preinvasive lesion Barrett’s esophagus. The epidemiologic factors that contribute to an individual’s susceptibility for Barrett’s esophagus and associated cancer are likely to be multifactorial. However, the short time frame over which the incidence of adenocarcinoma has increased, and the increase across populations, provides a strong argument for environmental factors as etiologic agents, perhaps interacting with genetically determined characteristics that define personal susceptibility. In this review we discuss the epidemiologic evidence for the proposed demographic and environmental risk factors for the development of both Barrett’s esophagus and AC. The current evidence suggests that significant risk factors include male sex, Caucasian race, and the presence of duodenogastroesophageal reflux disease. The susceptibility for reflux disease may in turn be influenced by factors such as obesity, the use of drugs that lower the lower-esophageal sphincter tone, and a protective effect of Helicobacter pylori colonization. There appears to be a weak association between smoking and AC. The role of dietary factors has not been studied adequately and deserves further attention. An understanding of the factors that predispose to the development and progression of Barrett’s esophagus is crucial to the implementation of effective screening and prevention programs.
Barrett's esophagus
2004, Journal of Gastrointestinal Surgery

View all citing articles on Scopus

^☆: Address requests for reprints to: Stuart Jon Spechler, M.D., Chief, Division of Gastroenterology (111B1), Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, Texas 75216. e-mail: [email protected]; Fax: (214) 857-1571.

^☆☆: Supported by Astra Zeneca and Wyeth-Ayerst. The author is a consultant for Astra Zeneca, TAP, and Janssen.

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EditorialsCarcinogenesis at the gastroesophageal junction: Free radicals at the frontier☆,☆☆

Abstract

Gastroenterology

Gastroenterology

Food Chem Toxicol

Mutat Res

J Biol Chem

Am J Clin Nutr

Gastroenterology

Gastroenterology

Changing patterns in the incidence of esophageal and gastric carcinoma in the United States

Cancer

Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate

Nat Med

Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans

Gut

Reaction of salivary nitrite with gastric acid and vitamin C relevant to proximal gastric cancer and Barrett's oesophagus (abstr)

Gastroenterology

Editorials
Carcinogenesis at the gastroesophageal junction: Free radicals at the frontier☆,☆☆