Mechanisms of Barrett’s esophagus (BE) pathogenesis are discussed in a review article by Jianwen Que et al in the August issue of Gastroenterology, including cell transdifferentiation and transcommitment. The authors discuss potential cells of origin for Barrett’s metaplasia, and the possibility that there could be more than 1 type of BE progenitor cell. Que et al discuss the concept of metaplasia as an initial wound healing response and clinical implications.
In BE, metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD). BE is estimated to affect 5.6% of adults in the United States, and is a risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin.
One potential mechanism of BE development involves transdifferentiation, in which fully differentiated esophageal squamous cells change into fully differentiated columnar cells—either directly (without undergoing a cell division) or indirectly (via cell division). Que et al propose that transdifferentiation in the esophagus might occur via a 2-stage process of GERD-induced reprogramming, in which mature squamous cells reverse their differentiation to acquire progenitor cell-like plasticity before changing to a columnar phenotype.
In the fundus of mouse stomach injured by infection with Helicobacter pylori or by drugs toxic to parietal cells, the death of parietal cells appears to be accompanied by transdifferentiation of chief cells into proliferative cells that expresses trefoil factor 2 (TFF2). In mice with acute injury, there is evidence that development of spasmolytic polypeptide-expressing metaplasia (SPEM) occurs when mature chief cells dedifferentiate and re-enter the cell cycle. However, there is also evidence that for an alternative mechanism, in which SPEM develops and persists through the abnormal differentiation of stem cells in the isthmus of gastric glands.
BE pathogenesis might also involve transcommitment—the process in which immature progenitor cells that are able to proliferate and differentiate into different cell types are reprogrammed to alter their normal pattern of differentiation. In contrast to transdifferentiation, transcommitment starts with immature progenitor cells that differentiate abnormally, possibly due to environmental factors such as GERD. The development of Barrett’s metaplasia from reprogrammed progenitor cells could account for the different cell types and their persistence even when GERD is controlled.
Que et al explain that we do not know which progenitor cells give rise to Barrett’s metaplasia, but there are 4 groups of candidates (see figure). These include basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). (see Table 1).
The authors discuss the mechanisms by which GERD might reprogram progenitor cells to lead to development of BE. For example, acid and bile salts also can activate signaling pathways in esophageal squamous cells (such as hedgehog and BMP4) that control activity of transcription factors that regulate development and cell phenotypes. Esophageal submucosal glands, which contain plastic progenitor cells capable of differentiating either into squamous or Barrett’s epithelium, might also be involved.
Although Barrett’s metaplasia is considered to be intestinal, because it contains goblet cells and expresses some intestinal markers, it also contains gastric-type cells that express gastric protein, so stomach cells might serve as BE progenitor cells.
Que et al explain concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Although cardiac mucosa lacks the goblet cells required for a histologic diagnosis of intestinal metaplasia, cardiac mucosa has other intestinal features, including expression of intestinal-type acidic mucins and proteins. However, cardiac mucosa appears to have minimal risk for malignant transformation until it develops goblet cells, so gastroenterology societies require an esophageal biopsy showing intestinal metaplasia for a diagnosis of BE, and reject that diagnosis if biopsies show only cardiac mucosa. Researchers have proposed that cardiac mucosa is a GERD-induced metaplasia and, potentially, the precursor of intestinal metaplasia that predisposes to malignancy.
Que et al’s review of BE reveals shortcomings that have important implications for its clinical definitions. Some guidelines require at least 1 cm of esophageal metaplasia for a diagnosis of BE—a restriction based primarily on the assumption of negligible cancer risk for patients with shorter segments of cardiac mucosa and intestinal metaplasia. The review authors state that metaplastic esophageal segments less than 1 cm in length can develop, via GERD, from the same progenitor cells that give rise to long-segment BE, with probably similar risk of malignancy. A study of patients with newly diagnosed esophageal adenocarcinomas found that tumors that developed from short segments of Barrett’s metaplasia were even more aggressive than those arising from longer segments.
The authors conclude that BE appears to develop to its full extent all at once. Barrett’s metaplasia does not progress in extent over time and endoscopically identified short segments of Barrett’s metaplasia rarely, if ever, evolve into long segments. If tumors arise from millimeter-long segments of metaplastic mucosa at the esophageal junction in individuals without GERD symptoms, then screening and surveillance policies might not be able to prevent esophageal cancer. Most patients at risk will not be screened because they have no GERD symptoms, and screening would not detect the few millimeters of esophageal metaplasia that requires endoscopic surveillance or other interventions. Que et al state that clinicians should be aware of the limitations of screening due to our incomplete understanding of BE pathogenesis.