Gastrin stimulates the growth of gastric pit cell precursors by inducing its own receptors

Abstract

.-Gastrin/CCK-B receptors (CCKB-Rs) are present on parietal and enterochromaffin-like cells in the gastric mucosa but not on pit cells in the proliferative zone. Because serum gastrin levels are well correlated with the growth of the gastric pit, we examined whether pit precursor cells express CCKB-Rs using hypergastrinemic transgenic mice and a mouse pit precursor cell line, GSM06. In situ hybridization indicated that CCKB-R mRNA was limited to the lower one-third of the mucosa in control mice, whereas it was faintly distributed along the midto low glandular region in the hypergastrinemic transgenic mouse mucosa. CCKB-R-positive midglandular cells appear to have a pit cell lineage; therefore, GSM06 cells were used for an [ 125 I]gastrin binding study. [ 125 I]gastrin bound to the membrane fraction of the GSM06 cells when precultured with gastrin. Gastrin dose dependently induced CCKB-R expression in GSM06 cells and stimulated their growth. Thus these findings suggest that gastrin directly stimulates the growth of the pit cell lineage by inducing its own receptor in pit cell precursors. gastric mucosal growth; gastric surface mucous cell; gastrin/ cholecystokinin-B receptor GASTRIN CONTROLS THE GROWTH of gastric mucosa (14,15). Hypertrophied gastric mucosa is observed in patients with gastrin-producing tumors and also in rats infused continuously with gastrin (5, 31). In contrast, hypotrophic or atrophic mucosa results from fasting in rats whose serum gastrin levels become low (35). The glandular cell components, which include parietal, chief, and enterochromaffin-like (ECL) cells, have relatively long lifespans of 3, 5, and 2 mo, respectively (17). Thus the atrophic change induced by fasting in rats appears to be due mainly to a shortage of pit/gastric surface mucous cells that survive only 3 days in rodents (18). It is not known, however, whether the pit cells and their precursors express gastrin receptors.The physiological roles of gastrin in mucosal growth were recently studied using hypergastrinemic animal models. Wang et al. (45) produced transgenic (TG) mice expressing gastrin under the control of an insulin promoter, which resulted in gastrin production in pancreatic ␤-cells. They reported that gastrin enhances gastric mucosal growth, whereas progastrin preferentially stimulates colonic mucosal growth. They further demonstrated that hypergastrinemic TG mice develop gastric atrophy and eventually gastric cancer (44) and postulated that the hyperplasia of the foveolar pit cell region and the decrease in the parietal cell mass are due, at least in part, to gastrin-stimulated upregulation of growth factors, including heparin binding-epidermal growth factor-like growth factor (HB-EGF) and transforming growth factor-␣ (TGF-␣). Moreover, infection with Helicobacter felis accelerates the formation of gastric cancer in a synergistic manner with hypergastrinemia in hypergastrinemic TG mice (44).We generated TG mice with hypergastrinemia by expressing a human gastrin transgene (19). The gastric mucosa of these mice...

Gastrin: old hormone, new functions

“…In a transgenic mouse model of hypergastrinaemia in which there is a gastric hyperproliferative condition, there is reported to be induction of the CCK-2 receptor on proliferating cells [80]. Moreover, there is now evidence for rapid, specific, increases in expression at the margin of cryoulcers induced in rat stomach [104].…”

Effects of Helicobacter pylori Infection on the Link between Regenerating Gene Expression and Serum Gastrin Levels in Mongolian Gerbils

“…Moreover, Hirayama et al (1999) have shown that poorly differentiated adenocarcinomas as well as carcinoid tumors develop during H. pylori-induced gastritis with hypergastrinemia. Recent studies have shown that gastrin receptors are present on gastric mucosal progenitor cells, suggesting that gastrin has direct trophic actions on gastric mucosal cells (Kazumori et al, 2001;Nakajima et al, 2002). On the other hand, several investigators have reported that gastrin promotes gastric mucosal cell proliferation indirectly by stimulating the production of growth factors such as TGF-␣, heparinbinding epidermal growth factor-like growth factor, and Reg (Fukui et al, 1998;Miyazaki et al, 1999;Wang et al, 2000).…”

Expression of gastrin and its receptor in human gastric cancer tissues

“…Recent studies have shown that the biological action of gastrin is mediated by its receptor, gastrin/CCKB receptor (Nakajima et al 2002). Gastrin possesses the same five amino acids on its carboxyl terminal end as cholecystokinin (CCK).…”