Abstract
Gastric intestinal metaplasia (IM) is a highly prevalent preneoplastic lesion; however, the molecular mechanisms regulating its development remain unclear. We have previously shown that a population of cells expressing the intestinal stem cell (ISC) marker LGR5 increases remarkably in IM. In this study, we further investigated the molecular characteristics of these LGR5 + cells in IM by examining the expression profile of several ISC markers. Notably, we found that ISC markers—including OLFM4 and EPHB2—are positively associated with the CDX2 expression in non-tumorous gastric tissues. This finding was confirmed in stomach lesions with or without metaplasia, which demonstrated that OLFM4 and EPHB2 expression gradually increased with metaplastic progression. Moreover, RNA in situ hybridization revealed that LGR5 + cells coexpress several ISC markers and remained confined to the base of metaplastic glands, reminiscent to that of normal intestinal crypts, whereas those in normal antral glands expressed none of these markers. Furthermore, a large number of ISC marker-expressing cells were diffusely distributed in gastric adenomas, suggesting that these markers may facilitate gastric tumorigenesis. In addition, Barrett’s esophagus (BE)—which is histologically similar to intestinal metaplasia—exhibited a similar distribution of ISC markers, indicating the presence of a stem cell population with intestinal differentiation potential. In conclusion, we identified that LGR5 + cells in gastric IM and BE coexpress ISC markers, and exhibit the same expression profile as those found in normal intestinal crypts. Taken together, these results implicate an intestinal-like stem cell population in the pathogenesis of IM, and provide an important basis for understanding the development and maintenance of this disease.
Highlights
Preneoplastic intestinal metaplasia (IM) is associated with an increased risk of gastric carcinoma and presents in approximately one-fourth of individuals worldwide.[1]
We aimed to discover additional intestinal stem cell (ISC) markers involved in the genesis and maintenance of gastric IM and Barrett’s esophagus (BE), and examine their colocalization with LGR5+ cells by RNA in situ hybridization to further reveal the molecular characteristics of LGR5+ cells in IM with regards to the intestinal-like stem cell phenotype
To determine if a direct relationship existed between LGR5 and ISC markers in IM, we examined whether their coexpression by RNA in situ hybridization
Summary
Preneoplastic intestinal metaplasia (IM) is associated with an increased risk of gastric carcinoma and presents in approximately one-fourth of individuals worldwide.[1]. Intestinal Stem Cell Markers in the Intestinal Metaplasia of Stomach from chronic atrophic gastritis following infection with Helicobacter pylori, which can advance to gastric epithelial dysplasia or carcinoma.[2] A variety of genetic and epigenetic alterations have been implicated in the pathogenesis of human IM.[3] long-term IM induced by CDX2 expression has been shown to lead to gastric cancer in transgenic mice, indicating that IM itself plays a significant role in the genesis of gastric carcinoma.[4]. CDX2 autoregulation is suggested to have a major impact on the stability of IM lesions.[7] While IM crypts in the human stomach are clonal and contain multipotent stem cells,[8] it remains poorly understood whether native gastric stem cells are the initial source of metaplasia or if they only serve to maintain established lesions
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