Intestinal Stem Cell Markers in the Intestinal Metaplasia of Stomach and Barrett’s Esophagus

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.

A comprehensive analysis of single-cell transcriptome network underlying gastric premalignant lesions and early gastric cancer

“…As shown in Figure 3j, GMCs with expressing the OLFM4 were rarely detected in the CAG lesion (0.4%), while the number of them (remarkably) increase in the wild IM lesion (8%) and reach a peak in the severe IM lesion (26%). In the EGC lesion, the GMC disappeared and the proportion of OLFM4-expressing cells reach the peak, which have been confirmed by previous immunohistochemistry studies 36 . We further assessed the co-expression of MUC6 and OLFM4 within the GMCs in the IM lesion, and found that the expression of OLFM4 displayed a significant negative correlation with that of MUC6 (p = 0.003, Supplementary figure 10).…”

OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma

“…Inflammation‐related factors, such as activator protein 1, NF‐κB, retinoic acid, and granulocyte colony‐stimulating factor, have been reported to regulate OLFM4 expression . In addition, recent studies have demonstrated that LGR5 increases OLFM4 expression through the Wnt signaling pathway and promotes stem cell property in the intestine . LGR5 is reported to be expressed in HCC; however, no reports have focused on the interaction between LGR5 and OLFM4.…”

“…(20,(42)(43)(44) In addition, recent studies have demonstrated that LGR5 increases OLFM4 expression through the Wnt signaling pathway and promotes stem cell property in the intestine. (27)(28)(29) LGR5 is reported to be expressed in HCC (45,46) ; however, no reports have focused on the interaction between LGR5 and OLFM4. Moreover, no previous studies have shown the effects of LGR5 or OLFM4 on cancer stem cell-like property in any malignancies.…”

“…Moreover, recent studies have suggested the usefulness of OLFM4 as a stem cell marker of the intestine, because OLFM4 expression in the epithelium of the intestine is significantly correlated with the expression levels of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), which is known to enhance stem cell property in the intestine through the Wnt signaling pathway. (27)(28)(29) In contrast, several studies have demonstrated that OLFM4 suppressed tumor proliferation, invasion, and metastasis in prostate cancer (30,31) and triple-negative breast cancer. (32) Therefore, the role of OLFM4 in cancer progression remains uncertain.…”

“…OLFM4 is reported to increase in cancers, including gastric cancer, colon cancer, and pancreatic cancer, and to promote tumor progression by inducing cell‐cycle progression and enhancing tumor invasion and metastasis, which resulted in poor prognosis. Moreover, recent studies have suggested the usefulness of OLFM4 as a stem cell marker of the intestine, because OLFM4 expression in the epithelium of the intestine is significantly correlated with the expression levels of leucine‐rich repeat‐containing G protein‐coupled receptor 5 (LGR5), which is known to enhance stem cell property in the intestine through the Wnt signaling pathway . In contrast, several studies have demonstrated that OLFM4 suppressed tumor proliferation, invasion, and metastasis in prostate cancer and triple‐negative breast cancer .…”