Abstract
BackgroundGastric/gastroesophageal junction (GEJ) adenocarcinomas are heterogeneous, comprising four molecularly distinct subtypes, namely EBV-positive, microsatellite instability (MSI), chromosomal instability (CIN) and genomically stable (GS) subtypes, and a part of this heterogeneity may hypothesized to be different cells-of-origin. Stem/progenitor cell hierarchy in the stomach is complex, which include the Lgr5(+) gastric stem cells (GSCs).MethodsWhile previous studies have focused on non-nuclear Lgr5 expression, nuclear Lgr5 expression has been reported in a subset of stem cells, and we examined nuclear Lgr5 expression in a local cohort of 95 cases of gastric/GEJ adenocarcinoma. mRNA levels for LGR5 and other stem cell marker genes were examined in the TCGA cohort.ResultsWe observed nuclear Lgr5 expression in a 18/95 cases. Near mutual exclusivity was seen between nuclear Lgr5 and strong non-nuclear Lgr5. Both strong non-nuclear and nuclear Lgr5 expression tended to be seen more frequently with the intestinal histotype and approximated CIN molecular subtype. With respect to overall survival (OS), nuclear Lgr5 expression appears to be protective, with the worst survival being seen in the cases lacking nuclear Lgr5 and with low non-nuclear Lgr5 expression. When compared to other stem/progenitor cell markers, LGR5 mRNA expression clusters with other GSC marker genes, including VIL1. Higher expression of these GSC marker genes was associated with better OS.ConclusionsOur results show that Lgr5 expression is dynamic in gastric/GEJ adenocarcinoma and heterogeneous across the several disease attributes. We postulate that this may reflect “retained stemness” in the form of Lgr5High-GSC signature that appears to be associated with better survival.
Highlights
Gastric/gastroesophageal junction (GEJ) adenocarcinomas are heterogeneous, comprising four molecularly distinct subtypes, namely Ebstein-Barr Virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN) and genomically stable (GS) subtypes, and a part of this heterogeneity may hypothesized to be different cells-of-origin
Synopsis Significance of Lgr5 expression in gastric/GE junction carcinomas is re-examined in the context of their molecular heterogeneity
High Lgr5/LGR5 expression is speculated to be a retained phenotype that may be reflecting the cellular origin in a subset of gastric carcinomas
Summary
Gastric/gastroesophageal junction (GEJ) adenocarcinomas are heterogeneous, comprising four molecularly distinct subtypes, namely EBV-positive, microsatellite instability (MSI), chromosomal instability (CIN) and genomically stable (GS) subtypes, and a part of this heterogeneity may hypothesized to be different cells-of-origin. The key signaling pathway behind this phenomenon is thought to be the canonical Wnt pathway, with Lgr functioning to potentiate Wnt/β-catenin signalling by interacting with R-spondin, among other factors [5, 6] This role of Lgr is presumably facilitated by its trans-membrane domain allowing for membranous localization, but Lgr is a spatially dynamic protein, with expression seen in the cytoplasm and even the nucleus [7,8,9]. The majority of the Lgr5(+) stem cells appear to divide symmetrically [11], and their proliferation can be accelerated by H. pylori infection [12]; this may represent a potential link between the epidemiological observation of increased risk of carcinogenesis associated with H. pylori infection
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