Are Gastric and Esophageal Metaplasia Relatives? The Case for Barrett's Stemming from SPEM

Abstract

Chronic injury and inflammation in the esophagus can cause a change in cellular differentiation known as metaplasia. Most commonly, the differentiation changes manifest as Barrett's esophagus (BE), characterized by the normal stratified squamous epithelium converting into a cuboidal-columnar, glandular morphology. BE cells can phenotypically resemble specific normal cell types of the stomach or intestine, or they can have overlapping phenotypes in disorganized admixtures. The stomach can also undergo metaplasia characterized by aberrant gastric or intestinal differentiation patterns. In both organs, it has been argued that metaplasia may represent a recapitulation of the embryonic or juvenile gastrointestinal tract, as cells access a developmental progenitor genetic program that can help repair damaged tissue. Here, we review the normal development of esophagus and stomach, and describe how BE represents an intermixing of cells resembling gastric pseudopyloric (SPEM) and intestinal metaplasia. We discuss a cellular process recently termed "paligenosis" that governs how mature, differentiated cells can revert to a proliferating progenitor state in metaplasia. We discuss the "Cyclical Hit" theory in which paligenosis might be involved in the increased risk of metaplasia for progression to cancer. However, somatic mutations might occur in proliferative phases and then be warehoused upon redifferentiation. Through years of chronic injury and many rounds of paligenosis and dedifferentiation, eventually a cell with a mutation that prevents dedifferentiation may arise and clonally expand fueling stable metaplasia and potentially thereafter acquiring additional mutations and progressing to dysplasia and cancer.

Keywords: Dedifferentiation; Injury response; Paligenosis; Transdifferentiation.

Fig. 1

Shared Metaplastic Pathway Between Esophagus and Stomach. In this model, we show how response to injury and infammation in the stratifed squamous epithelium of the esophagus and the invaginated columnar epithelium of the stomach might both become metaplastic and morphologically resemble distal gastric antral units. This change in the stomach is known as spasmolytic polypeptide-expressing metaplasia (SPEM) or “pseudopyloric metaplasia” because the glands, now lack mature chief (shown in red) and parietal (shown in blue) cells. The defning feature of SPEM is a metaplastic lineage (shown in yellow) that co-expresses both chief cell proteins and markers of normal mucus-secreting cells of the gland neck. It is in this background of SPEM that goblet cells (shown in orange) defning intestinal metaplasia or Barrett’s esophagus might emerge in the stomach or esophagus, respectively. Finally, with continued infammation/injury, dysplasia and neoplasia will form (shown in gray) in this metaplastic milieu. Currently, this pathway is drawn with black one-way arrows, but there are emerging data that this process is dynamic with constant cycles of diferentiation and paligenosis as cells mature and stop dividing, but then may be called back into the cell cycle when confronted again with infammation/injury