Hypergastrinemia Expands Gastric ECL Cells Through CCK2R+ Progenitor Cells via ERK Activation

Abstract

Background & Aims Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified. Methods We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r - and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment). Results Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r -CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r -CreERT2 + isthmus progenitors, but not Hdc + mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2r + Hdc - cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro. Conclusions We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R + progenitors in the corpus. Gastrin-dependent function of CCK2R + progenitors is regulated by the extracellular signal-regulated kinase pathway.

Tumor microenvironment in gastric cancers

“…activation of the ERK pathway in progenitor cells. 100,101 Therefore, the tumor-promoting effects of gastrin in the proximal stomach probably occur via stimulation of CCK2R-expressing proliferating progenitors in the isthmus-neck region. Given that the serum gastrin level is usually elevated in patients with long-term proton pump inhibitor (PPI) use, increased gastric cancer risk in such patients might be affected by activation of the gastrin/CCK2R pathway.…”

Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection

“…In the mouse corpus, Wnt5a-dependent noncanonical Wnt signaling appears to be involved in stem cell function [ 10 , 14 ]. While other pathways such as gastrin, acetylcholine, R-spondin, BMP signaling likely contribute to gastric stem cell niche [ 11 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ], accumulating evidence highlighted the importance of MAPK pathway in gut stem cells. For example, it has been reported that JNK is one of Wnt activators in the intestine and thus promotes epithelial proliferation and carcinogenesis [ 84 ].…”

“…Parietal and chief cell loss is considered to alter the status of proliferation or differentiation in oxyntic glands, and lead to induce metaplastic changes [ 4 , 5 , 6 , 7 ]. Recent published papers have identified several stem cell markers in the stomach [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. However, it has been poorly understood how gastric stem/progenitor cells could differentiate to metaplasia or dysplasia during H. pylori infection.…”

Correct Identification of Cell of Origin May Explain Many Aspects of Cancer: The Role of Neuroendocrine Cells as Exemplified from the Stomach

“…However, since gastritis elevates gastrin, the normal upper level became too high [42]. Furthermore, there is no threshold for the tumorigenic effect of gastrin [51]. Both Helicobacter pylori infection and PPIs treatment alone or in combination may induce a degree of hypergastrinemia that in the long-term is sufficient to evoke gastric tumors based upon the gastrin values in patients with autoimmune gastritis and gastric NETs (carcinoids) [52].…”