Distribution of LGR5+ cells and associated implications during the gastric tumorigenesis

Abstract

Lgr5 was identified as a promising gastrointestinal tract stem cell marker in mice, and lineage tracing experiments demonstrated that Lgr5+ cells may not only be the cells responsible for the origin of tumors

they may also be the so-called cancer stem cells. In the present study, we investigated the presence of LGR5+ cells and their biological significance in normal human gastric mucosa and gastric tumors. RNAscope, a newly developed RNA in situ hybridization technique, specifically labeled LGR5+ cells at the basal glands of the gastric antrum. Notably, the number of LGR5+ cells remarkably increased in intestinal metaplasia (IM). In total, 76% of gastric adenomas (GAs) and 43% of early gastric carcinomas were positive for LGR5. LGR5+ cells were found more frequently in low-grade tumors with active Wnt signaling and an intestinal gland type, suggesting that LGR5 is likely involved in the very early stages of Wnt-driven tumorigenesis in the stomach. Interestingly, similar to stem cells in normal tissues, LGR5+ cells were often restricted to the base of the tumor glands, and such LGR5+ restriction was associated with high levels of intestinal stem cell markers such as EPHB2, OLFM4, and ASCL2 supporting the idea that LGR5+ cells may act as stem cells in GAs. In addition, we found that LGR5 positivity is associated with worse clinical outcomes for the gastric cancer patients with nuclear -catenin expression. However, induced LGR5 overexpression showed no survival benefit in the gastric cancer cell lines. In conclusion, LGR5 positive cells are present at the base of gastric antrum of human, and their population dramatically expands in IM. Most gastric adenomas contain a large number of LGR5-expressing cells, which tend to locate at the base of tumor glands co-expressing other intestinal stem cell markers, suggesting the possibility of LGR5 functioning as tumor stem cells in human gastric adenomas.