Role of nitric oxide in the pathogenesis of Barrett's-associated carcinogenesis

Abstract

Barrett's esophagus (BE), a premalignant condition to Barrett's adenocarcinoma (BAC), is closely associated with chronic inflammation due to gastro-esophageal reflux. Caudal type homeobox 2 (CDX2), a representative marker of BE, is increased during the metaplastic and neoplastic transformation of BE. Nitric oxide (NO) has been proposed to be a crucial mediator of Barrett's carcinogenesis. We previously demonstrated that CDX2 might be induced directly under stimulation of large amounts of NO generated around the gastro-esophageal junction (GEJ) by activating epithelial growth factor receptor in a ligand-independent manner. Thus, we reviewed recent developments on the role of NO in Barrett's carcinogenesis. Notably, recent studies have reported that microbial communities in the distal esophagus are significantly different among groups with a normal esophagus, reflux esophagitis, BE or BAC, despite there being no difference in the bacterial quantity. Considering that microorganism components can be one of the major sources of large amounts of NO, these studies suggest that the bacterial composition in the distal esophagus might play an important role in regulating NO production during the carcinogenic process. Controlling an inflammatory reaction due to gastro-esophageal reflux or bacterial composition around the GEJ might help prevent the progression of Barrett's carcinogenesis by inhibiting NO production.

Keywords: Barrett’s esophagus; Caudal type homeobox 2; Epithelial growth factor receptor; Microbiome; Nitric oxide.

Figure 1

The process of nitric oxide generation. Exogenous NO is generated within the upper-gastrointestinal tract lumen from the reduction of salivary nitrite to NO in a reaction with acid refluxant. Endogenous NO is generated in chronic inflammation caused by gastro-esophageal reflux and bacterial composition. NO: Nitric oxide.