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Gastrin promotes gastric mucosal growth, and hypergastrinemia induces gastric mucosal hypertrophy. Recently, it has been reported that gastrin induces cyclooxygenase-2 (COX-2) in human gastric and colorectal cancer cell lines. However, whether COX-2 is involved in gastrin-induced gastric mucosal growth in vivo is unknown. We investigated the role of COX-2 in gastrin-induced gastric mucosal hypertrophy using gastrin transgenic mice. Hypergastrinemic mice [mice with mutated gastrin under the control of the [beta]-actin promoter (ACT-GAS mice)] received the COX-2 inhibitor celecoxib (0, 200, or 500 mg/kg of diet) from 5 wk of age and were killed at 16 or 24 wk. Some ACT-GAS mice received celecoxib from 16 wk and were killed at 24 wk. Eighty-week-old ACT-GAS mice without celecoxib treatment were also examined. The thickness of the gastric mucosa, cell populations, COX-2 expression, and PG[E.sub.2] levels were evaluated. All ACT-GAS mice showed gastric mucosal hypertrophy, and four of six 80-wk-old ACT-GAS mice developed gastric cancer. COX-2 was expressed in interstitial cells of the hypertrophic gastric mucosa and gastric cancers. Moreover, PGE2 levels in the gastric mucosa of ACT-GAS mice were significantly higher than those of normal mice. With treatment with celecoxib, PG[E.sub.2] levels, the gastric mucosal thickness, and the number of total gastric cells per gastric gland of ACT-GAS mice were significantly decreased. The decrease in gastric mucosal thickness was caused by a reduction of foveolar hyperplasia. The thickness of glandules and the number of Ki67-positive cells were not significantly changed. In conclusion, COX-2 contributes to gastrin-induced mucosal hypertrophy of the stomach. prostaglandin [E.sub.2]; gastric cancer; foveolar hyperplasia

Gastrin stimulates the growth of gastric pit cell precursors by inducing its own receptors. Am J Physiol Gastrointest Liver Physiol 282: G359-G366, 2002. First published September 21, 2001; 10.1152/ajpgi.00117. 2001.--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 mid- to 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 [[sup.125]I]gastrin binding study. [[sup.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

Research was conducted to examine the topological relation of furin-positive and transforming growth factor-alpha (TGF-alpha) positive cells in the rat gastric glands, the cellular characteristics of the furin-positive cells and the effect of TGF-alpha and the other growth factors on the expression of furin. The identification of furin-positive cells was investigated by the immunostaining of rat gastric mucosa. Regulators of the furin expression was examined by measuring the furin promoter activity by luciferase assay. Results indicate that the parietal cells of the pit region have furin-mediated functions that can be stimulated by epidermal growth factor receptor signaling.

Konda, Yoshitaka, Hitoshi Kamimura, Hiromi Yokota, Naoki Hayashi, Kentaro Sugano, and Toshiyuki Takeuchi. Gastrin stimulates the growth of gastric pit with less-differentiated features. Am. J. Physiol. 277 (Gastrointest. Liver Physiol. 40): G773-G784, 1999.--Gastrin stimulates the growth of gastric mucosa by increasing mostly its glandular region but is not known to induce the growth of a pit region where its major constituent cells, gastric surface mucous (GSM) cells, turn over rapidly. To investigate the effect ofgastrin on GSM cells, we generated hypergastrinemic mice by expressing a human gastrin transgene. We obtained a hypergastrinemic mouse line whose average serum gastrin level is 671 [+ or -] 252 pg/ml (normal level [is less than] 150 pg/ml). Gastrin-positive cells were found in the fundic mucosa. The gastric mucosa exhibited hypertrophic growth, which was characterized by an elongated pit with an active proliferative zone, but the glandular region containing parietal cells was normal or reduced in size. The GSM cells contained fewer mucous granules than those of control littermates and lost reactivity to the GSM cell-specific cholera toxin [Beta]-subunit lectin. GSM cells along the foveolar region and many mucous neck cells became Alcian blue positive, suggesting the appearance of sialomucin in these cells. We suggest that gastrin stimulates the growth of the proliferative zone of gastric glands, which results in the elongation of the pit region whose GSM cells exhibit less-differentiated features. gastric mucosa; gastric surface mucous cells; gastrin binding