Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice

Abstract

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. IntroductionGastric cancer is the fifth most common malignancy and the third leading cause of cancer mortality worldwide [1]. The vast majority of gastric cancer is adenocarcinoma, which consists of the intestinal-type and diffuse-type according to the Lauren classification, and it is thought to arise from the gastric epithelium via sequentially acquired mutations in specific genes. The gastric epithelium is organized into multiple gastric units that are fueled by a pool of stem cells capable of self-renewal and multilineage differentiation. In the adult gastric antrum, Results Deletion of Smad4 and PTEN in murine Lgr5 + stem cells resulted in gastric tumorSmad4, a central mediator of TGF-β signaling, is a well-known tumor suppressor, as evidenced by various murine models of different cancer types, including gastric cancer [12]. However, all of these murine models of gastric cancer arise from the germline heterozygous or T cell-specific deletion of Smad4 [13][14][15][16]. The epithelium-autonomous role of Smad4 in suppressing gastric cancer has not yet been clearly defined. Our previous study has demonstrated that PTEN deletion in the entire gastric epithelium leads to adenoma in the corpus and slight hyperplasia in the antrum [17] + cells. Cre-mediated recombination within the reporter locus activates the expression of a red fluorescent protein variant, tdTomato, which indelibly marks the recombined cells and their progenies through their entire lifespan. Due to the previously reported low activity of Lgr5-Cre ERT2 transgenic mice, tamoxifen was administered for 6 consecutive days in 6-week-old mice, and no morphological abnormality associated with tamoxifen was observed in the gastric antral epithelium (Supplementary information, Figure S1A Table 1). In addition, red polyps adjacent to forestomach, where a few Lgr5 + cells at the base of corpus glands near forestomach/esophageal border act as stem cells [2], were found in 25% (5/20) of mice lacking Smad4 and PTEN ( Figure 1B, blue arrowhead). Afterwards, double-mutant mice exhibited progressive weakness and died within 5 months ( Figure 1C).Red polyps indicated that the lesions might arise as a result of Cre activity in mutant Lgr5 + cells ( Figure 1B, arrowheads). Consistent with this, immunohistochemistry (IHC) analysis displayed clear loss of Smad4 and PTEN as well as consequent p-Akt activation, which were further supported by the western blot results ( Figure 1D and 1E). Taken together, the above data demonstrate that mutant gastric Lgr5 + cells produced gastric tumors.

Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells

“…In mice with altered/mutant Lgr5+ stem cells there was a rapid onset and progression from adenoma to invasive intestinal-type gastric cancer in the antrum 29 . Moreover, it has been shown in an organoid culture system that Lgr5+ gastric stem cell homeostasis is regulated by the Notch signaling pathway 30 .…”

YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC

“…Stem cells in the corpus express Sox2, Troy, Mist1, and eR1, whereas stem cells in the pyloric antrum express Sox2, Lgr5, CCK2R, eR1, Axin2, and Mist1 (18-25). Mouse model studies have shown that oncogenic events in gastric stem cells can frequently lead to carcinogenesis, although mutations targeted to chief cells also can cause these cells to dedifferentiate and acquire the potential to grow and regenerate gastric glands, sometimes forming metaplasia (17,21,22,(26)(27)(28)(29)(30).…”

Isolation, identification, and characterization of cancer stem cells: A review

“…Deletion of PTEN in a murine model of prostate cancer caused the expansion of CSCs. Similarly, knockout of PTEN in murine gastric Lgr5 + stem cells has demonstrated that these cells are cancer‐initiating cells and contribute to malignant progression (Li et al, ). Hence, Loss of PTEN activity led to development and proliferation of CSCs in several cancers, including colon, GBM, endometrial, lung, intestinal, and pancreatic cancer (Chow & Baker, ; Dong et al, ).…”