Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice
Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice
复制标题
胃Lgr5( )干细胞是小鼠侵袭性肠型胃癌的细胞起源。
DOI：
10.1038/cr.2016.47
复制
发表时间：
2016-07-01
期刊：
影响因子：
44.1
通讯作者：
Teng, Yan
中科院分区：
文献类型：
--
作者：
Li, Xiu-Bin;Yang, Guan;Teng, Yan
胃癌的细胞起源仍然是难以捉摸的。富含亮氨酸重复序列的G蛋白偶联受体5（Lgr 5）是第一个被鉴定的胃干细胞标志物。然而，Lgr 5（+）干细胞在驱动恶性胃癌中的作用尚未完全验证。在此，我们通过可诱导的Cre-LoxP系统在鼠胃Lgr 5（+）干细胞中缺失Smad 4和PTEN，并用Cre-reporter Rosa 26（tdTomato）标记突变的Lgr 5（+）干细胞及其后代。在胃窦部发现了从微腺瘤和宏观腺瘤到浸润性胃粘膜型胃癌（IGC）的快速发病和进展，Smad 4和PTEN缺失。此外，侵袭性IGC发生在小鼠胃-前胃连接处，其中存在少量Lgr 5（+）干细胞。相反，Smad 4和PTEN在分化细胞中的缺失，包括胃窦壁细胞、小凹细胞和体Lgr 5（+）主细胞，不能启动肿瘤生长。此外，突变型Lgr 5（+）细胞参与IGC的生长和进展。在TCGA（癌症基因组图谱）数据库中，发生在胃窦和胃食管交界处的人IGC中表现出LGR 5表达的增加。此外，SMAD 4和PTEN的同时缺失，以及它们的表达减少和下游通路失调，与人IGC相关。因此，我们证明胃Lgr 5（+）干细胞是癌症起始细胞，并可能充当癌症繁殖细胞，导致恶性进展。
The cellular origin of gastric cancer remains elusive. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is the first identified marker of gastric stem cells. However, the role of Lgr5(+) stem cells in driving malignant gastric cancer is not fully validated. Here, we deleted Smad4 and PTEN in murine gastric Lgr5(+) stem cells by the inducible Cre-LoxP system and marked mutant Lgr5(+) stem cells and their progeny with Cre-reporter Rosa26(tdTomato). Rapid onset and progression from microadenoma and macroscopic adenoma to invasive intestinal-type gastric cancer (IGC) were found in the gastric antrum with the loss of Smad4 and PTEN. In addition, invasive IGC developed at the murine gastro-forestomach junction, where a few Lgr5(+) stem cells reside. In contrast, Smad4 and PTEN deletions in differentiated cells, including antral parietal cells, pit cells and corpus Lgr5(+) chief cells, failed to initiate tumor growth. Furthermore, mutant Lgr5(+) cells were involved in IGC growth and progression. In the TCGA (The Cancer Genome Atlas) database, an increase in LGR5 expression was manifested in the human IGC that occurred at the gastric antrum and gastro-esophageal junction. In addition, the concurrent deletion of SMAD4 and PTEN, as well as their reduced expression and deregulated downstream pathways, were associated with human IGC. Thus, we demonstrated that gastric Lgr5(+) stem cells were cancer-initiating cells and might act as cancer-propagating cells to contribute to malignant progression.