Distribution ofLGR5+ Cells and Associated Implications during the Early Stage of Gastric Tumorigenesis

Lgr5 was identified as a promising gastrointestinal tract stem cell marker in mice. Lineage tracing indicates 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 was remarkably increased in intestinal metaplasia. In total, 76% of gastric adenomas 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. Thus, our findings show that Lgr5+ cells are present at the base of the antral glands in the human stomach and that this cell population significantly expands in intestinal metaplasias. Furthermore, Lgr5+ cells are seen in a large number of gastric tumors ; their frequent basal arrangements and coexpression of ISC markers support the idea that Lgr5+ cells act as stem cells during the early stage of intestinal-type gastric tumorigenesis.Lgr5已被鉴定为小鼠体内极具应用前景的胃肠道干细胞标志物。谱系示踪研究表明，Lgr5阳性细胞不仅是肿瘤起源的关键细胞群，同时也属于所谓的癌症干细胞。本研究探讨了Lgr5阳性细胞在正常人胃黏膜及胃部肿瘤中的存在情况及其生物学意义。采用新型RNA原位杂交技术RNAscope，可特异性标记胃窦部基底腺体中的Lgr5阳性细胞。值得注意的是，肠上皮化生组织中Lgr5阳性细胞的数量显著增多。总计76%的胃腺瘤与43%的早期胃癌呈LGR5阳性表达。Lgr5阳性细胞更常见于存在活跃Wnt信号通路且呈肠型的低级别肿瘤中，提示LGR5可能参与胃部Wnt信号驱动的肿瘤发生早期阶段。有趣的是，与正常组织中的干细胞类似，Lgr5阳性细胞通常局限于肿瘤腺体的基底部位，且这种分布局限特征与EPHB2、OLFM4及ASCL2等肠干细胞标志物的高表达密切相关。综上，本研究结果显示，Lgr5阳性细胞存在于人胃窦腺体的基底部位，且该细胞群在肠上皮化生组织中显著扩增。此外，Lgr5阳性细胞可见于大量胃部肿瘤中；其常见的基底分布模式及肠干细胞标志物的共表达特征，支持Lgr5阳性细胞在肠型胃部肿瘤发生的早期阶段充当干细胞的观点。