Review Open Access
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Mar 21, 2008; 14(11): 1646-1651
Published online Mar 21, 2008. doi: 10.3748/wjg.14.1646
Gastric cancer: Animal studies on the risk of hypoacidity and hypergastrinemia
Reidar Fossmark, Gunnar Qvigstad, Helge L Waldum, Department of Gastroenterology and Hepatology, St. Olav’s Hospital, Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7006, Norway
Correspondence to: Reidar Fossmark, MD, PhD, Department of Gastroenterology and Hepatology. St. Olav’s Hospital, Olav Kyrres gate 17, Trondheim 7006, Norway. reidar.fossmark@ntnu.no
Telephone: +47-73688000
Fax: +47-73867546
Received: December 6, 2007
Revised: January 14, 2008
Published online: March 21, 2008

Abstract

Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.

Key Words: Gastrin; Gastric cancer; Proton pump inhibitors; Acid secretion; Animal model



INTRODUCTION

Gastric hypoacidity and subsequent hypergastrinaemia occur in patients with parietal cell loss due to atrophic gastritis as well as in patients using drugs inhibiting gastric acid secretion. The increased risk of developing gastric carcinoids as well as adenocarcinomas is well documented in patients with pernicious anemia[14], whereas there is no direct evidence that hypoacidity and hypergastrinaemia caused by proton pump inhibitors promote gastric carcinogenesis in humans. Proton pump inhibition for up to five years has led to enterochromaffin-like (ECL) hyperplasia related to hypergastrinaemia[5]. Patients with gastrinomas often develop ECL cell carcinoids secondary to hypergastrinaemia, as well as signet ring cell carcinoma[6]. ECL cell carcinoids develop more often in patients with multiple endocrine neoplasia type 1 (MEN1)[7], but are also found in patients without MEN1[89]. The common factor in the above mentioned conditions is prolonged hypergastrinaemia, and it has been presumed that hypergastrinemia in itself increases the risk of gastric neoplasia in humans[1011].

However, gastric carcinogenesis in humans is a process that progresses over years to decades and may be influenced by numerous factors. Dissecting the mechanisms of gastric carcinogenesis in humans is therefore difficult and several animal models have been used to reduce the number of variables affecting this process. Various animal models have demonstrated that regulation of acid secretion and oxyntic mucosal growth are interwoven and animal models have provided detailed knowledge regarding the role of hypoacidity as well as hormones and signal substances in gastric carcinogenesis. In this report, we briefly review findings from animal studies on the role of gastric hypoacidity and hypergastrinaemia in gastric carcinogenesis.

GASTRIN AND THE GASTRIN RECEPTOR

Gastrin, which stimulates gastric acid secretion, was the second hormone to be postulated to exist[12]. The release of gastrin from G cells is inhibited by hydrochloric acid. Gastrin exerts its effect on the CCK-B receptor, which was first localised in the brain[13], but later found to be identical to the gastric gastrin receptor[14]. Gastrin regulates gastric acid secretion through a cellular sequence in which gastrin stimulates ECL cells to secrete histamine, which in turn stimulates secretion of hydrochloric acid from parietal cells[1516]. However, parietal cells have also been reported to express gastrin receptors[1718] and whether or not these are functional has been debated. Very high concentrations of gastrin potentiates histamine-stimulated acid secretion from isolated parietal cells[19], suggesting the existence of a functional gastrin receptor on parietal cells. However, fluorescein-labeled CCK-8 binds to rat ECL cells, but not to parietal cells[20], and gastrin does not stimulate acid secretion in either histidine decarboxylase (HDC)-deficient[21] or H2 receptor-deficient[22] mice. Altogether, this implies the physiological effect of gastrin is fully mediated by histamine secreted by the ECL cell and that only the gastrin receptors on ECL cells are of physiological importance. These observations are also relevant to understanding the trophic and carcinogenic effects of gastrin on the oxyntic mucosa.

GASTRIC HYPOACIDITY, HYPERGASTRINEMIA AND GASTRIC NEOPLASIA

Gastrin was shown early to have a general trophic effect on the oxyntic mucosa[23]. In 1985 it was first published that rats develop ECL cell carcinoids after lifelong inhibition of gastric acid secretion by administration of the long-acting insurmountable histamine 2 receptor antagonist loxtidine[24]. At the time, it was speculated whether this effect was specific for one drug, but the following year it was found that life-long administration of the proton pump inhibitor omeprazole also caused hyperplasia of the oxyntic mucosa and carcinoids in rats[25]. Even the short-acting histamine 2 receptor antagonist ranitidine was later shown to cause ECL cell carcinoids in 19 of 100 rats after 2-year of administration, and these animals showed a 3-fold increase in plasma gastrin[26].

Short-term administration of omeprazole (400 &mgr;mol/kg) to rats caused a 15-fold increase in plasma gastrin as well as hyperplasia of the oxyntic mucosa[2729]. The ECL cell density was tripled after 10 wk, whereas the total oxyntic mucosal thickness increased 20%[28].

Hypoacidity and hypergastrinaemia are closely related in the normal state, but the effects of each factor can be studied separately in several animal models. Infusion of gastrin has been mentioned and is feasible for short-term proliferation studies in which the specific proliferative effect on ECL cells has been documented[3032].

Low pH in the antrum inhibits gastrin release, and, by removal of a large proportion of the oxyntic mucosa by partial corpectomy, the antral pH is raised and gastrin release is stimulated. Rats develop carcinoids in the remaining 25% of the oxyntic mucosa[33] demonstrating that acid-inhibiting drugs per se do not cause neoplasia, but antral hypoacidity and subsequent hypergastrinaemia. Furthermore, oral administration of ciprofibrate, which is a peroxisome proliferator and a hypolipidemic compound, induces hypergastrinemia and carcinoid formation after 2 years in rats[34]. Ciprofibrate does not cause gastric hypoacidity[35], but induces hypergastrinemia through a direct effect on the antral G cell[36]. Altogether, there is evidence that hypergastrinaemia induced by either method, whether accompanied by gastric hypoacidity or not, causes ECL cell carcinoids in rats.

After carcinoid development due to hypergastrinemia was demonstrated in the rat, similar experiments were performed in mice to examine possible species differences. Administration of loxtidine to mice at various doses for 2 year induced carcinoid tumors of the gastric corpus[37], whereas long-term studies with proton pump inhibitors in mice have been inconclusive, as mice require much higher doses of proton pump inhibitors than rats to maintain a high gastric pH[38].

Transgenic (INS-GAS) mice over-express gastrin and have a 4-fold increase in plasma gastrin at age 6 mo, which leads to an increased gastric acid secretion[39]. In this animal model it is possible to study the effects of hypergastrinemia without gastric hypoacidity, mimicking human gastrinomas. Young INS-GAS mice have an increased ECL cell number and a proportion of these mice develop adenocarcinomas in the gastric corpus at the end of their lifespan[39]. Inoculation with Helicobacter felis increases gastrin levels 7-fold and accelerates carcinogenesis considerably[39], but mice without Helicobacter infections also develop carcinomas, demonstrating that carcinogenesis does not depend on infection and inflammation. The reason why INS-GAS mice develop malignancy in the oxyntic mucosa with an adenocarcinoma phenotype, whereas mice and rats develop ECL cell carcinoids after long-term acid inhibition or ciprofibrate administration, is not known. A synergistic inhibitory effect of gastrin and histamine receptor antagonists on hypergastrinemia-driven carcinogenesis has been found in INS-GAS mice[40], suggesting a role for both gastrin and histamine, but leaves questions regarding the cellular location of the histamine 2 receptor, and thus, the cellular origin of the adenocarcinomas. It has been found H pylori lipopolysaccharides stimulate ECL cell proliferation and secretion in the rat[41], supporting a concept of synergism of gastrin and H pylori infection on ECL cell growth.

INS-GAS mice have been inoculated with a H pylori strain and only inoculated males developed gastric cancer, whereas serum gastrin concentrations did not differ between the sexes[42].

HDC-deficient mice show gastric hypoacidity and a threefold increase in plasma gastrin levels[21]. This model has been mainly used for studying acid secretion, and long-term studies examining the possible carcinogenetic effects of hypergastrinemia in the absence of histamine have not been published to date. However, in animals aged 8 to 12 wk there was no difference in mucosal thickness[21].

Another genetically modified mouse model is H+K+ATPase beta subunit-deficient mice. These mice are anacidic, show a 7-fold increase in serum gastrin levels and hyperplasia in the oxyntic mucosa[4344]. H+K+ATPase-deficient mice have been followed for up to 14 wk only, and changes in the gastric mucosa in old mice have not been published. Gastrin and H+K+ATPase double knockout mice are anacidic without gastrin and do not develop hypertrophic changes in the oxyntic mucosa, demonstrating that gastrin is responsible for these changes[43].

Gastrin-deficient mice show no basal acid secretion[45] and provide a model for studying the effect of gastric hypoacidity without hypergastrinemia. Gastrin-deficient mice develop antral adenocarcinomas[46] through a mechanism that must be different from carcinogenesis in the oxyntic mucosa in hypoacidic and hypergastrinemic mice. The development of carcinomas in the absence of gastrin is attributed to bacterial overgrowth and subsequent formation of carcinogenic substances[4748]. However, gastric hypoacidity is also found in H+K+ATPase-deficient mice which do not develop antral carcinomas (Fossmark R et al unpublished observations) and it is possible the lack of gastrin itself induces the carcinomas.

GROWTH PROMOTION MEDIATED BY ECL CELLS

In the oxyntic mucosa, only ECL cells have gastrin receptors shown to have a functional role in mucosal growth regulation. Several studies mentioned have described the trophic effects of gastrin on the oxyntic mucosa, and the trophic effect on the ECL cell in particular, but less is known about the further mediation of the gastrin effect. It has been shown administration of gastrin has a proliferative effect in the neck region of the oxyntic glands[49], where stem cells are located. However, it has not been possible to settle whether this proliferative effect is a direct effect or mediated by growth factors released by ECL cells[50]. Several ECL cell products have been suggested to stimulate growth of the oxyntic mucosa, either on parietal cells, stem cells or ECL cells themselves.

Histamine was the first ECL cell product to be identified and has been suggested to have a trophic effect[50], but the effects of histamine are not fully understood. Histamine has been shown to stimulate proliferation of gastric cancer cell lines[51], but the histamine 1 receptor antagonist astemizole has an additional trophic effect when administered to rats with omeprazole-induced hypergastrinemia[52]. Histamine 2 receptor-deficient mice are hypergastrinemic and develop hypertrophy of the oxyntic mucosa[22], supporting previous studies suggesting the mediation of histamine’s trophic effect does not involve the H2 receptor[53]. However, in histamine decarboxylase-deficient mice there was no difference in parietal and ECL cell numbers compared with controls, in animals aged 8 to 12 wk, and no increase in oxyntic mucosal thickness[21], indicating an important role for histamine as a mediator of hypergastrinaemia-driven mucosal growth.

The regenerating gene (Reg) cDNA was first isolated from regenerating pancreatic islets in rats and its human homologue was named RegI alpha[54], but Reg protein is also expressed in ECL cells[55]. Gastrin stimulates Reg protein expression in ECL cells, and Reg protein is mitogenic to gastric mucosal cells[56], suggesting Reg protein is involved in gastrin-induced gastric mucosal cell growth. Reg expression is also increased in healing gastric mucosa[57]. Reg protein receptors are found on parietal cells and chief cells in the lower part of the corpus glands[58]. A recent study using INS-GAS mice has found expression of Reg1 is controlled through separate promoter elements by gastrin and Helicobacter[59], implying that these factors affect carcinogenesis through Reg protein. RegI alpha protein is also found in 35% of human gastric adenocarcinomas, particularly in those that are less well differentiated[60], and Reg protein expression is associated with higher proliferation rates in early gastric cancers[61]. Altogether, this makes Reg protein a strong candidate for mediating the general trophic effects of gastrin on the oxyntic mucosa.

OTHER ANIMAL MODELS OF HYPOACIDITY AND HYPERGASTRINEMIA IN GASTRIC CARCINOGENESIS

A strain of Japanese cotton rats develops spontaneous carcinomas in the oxyntic mucosa with a marked female predominance[62]. Animals developing carcinomas have gastric hypoacidity of an unknown cause and secondary hypergastrinemia[63]. The tumors develop from an oxyntic mucosa with marked hyperplasia of chromogranin A, synaptophysin and HDC-immunoreactive cells, and a proportion of the tumor cells are chromogranin A-, pancreastatin-, HDC- and Sevier-Munger-positive[6366]. Carcinomas develop after 4 mo of hypergastrinemia, but are prevented by the gastrin receptor antagonist YF486[64], demonstrating gastrin is essential in carcinoma development in cotton rats. Carcinomas can also be induced in male cotton rats by administration of the histamine 2 receptor antagonist loxtidine[67], as well as by partial corpectomy[68], two different methods of inducing pronounced hypergastrinemia. It has also been found ECL cells in hypergastrinemic animals gradually lose ultrastructural characteristics as well as chromogranin A and pancreastatin immunoreactivity[66] suggesting ECL cells dedifferentiate during long-term stimulation by gastrin. The cotton rat model is important as it demonstrates tumors with an adenocarcinoma phenotype, but with neuroendocrine differentiation, are induced by gastric hypoacidity and hypergastrinemia and develop through dedifferentiation of ECL cells.

In the African rodent Mastomys, multicentric gastric carcinoids frequently develop in the oxyntic mucosa of a proportion of aging animals. Serum gastrin levels in Mastomys developing tumors is normal[69] and the development of spontaneous ECL cell tumors is most likely related to a gastrin receptor mutant which shows ligand-independent activity; that is, the receptor is constitutively activated[70]. However, endogenous gastrin is involved in the growth of ECL cell carcinoids in Mastomys as the development of these tumors is significantly enhanced by loxtidine-induced hypoacidity and hypergastrinemia[7172] and carcinoid development is inhibited by a gastrin receptor antagonist[73]. There is no sex-difference in the occurrence of such tumors. The development of carcinoids in Mastomys is prevented by a somatostatin analogue[74].

Mongolian gerbils inoculated with H pylori are used extensively in research on H pylori-related gastric carcinogenesis. In the context of this paper, Mongolian gerbils are interesting as they become hypergastrinemic in response to H pylori infection and develop mainly ECL cell carcinoids, but also gastric adenocarcinomas[7576]. Inoculated animals show a five to ten-fold rise in serum gastrin, increasing with time after inoculation[77]. An increasing proportion of the gerbils develop ECL cell hyperplasia and carcinoids from 12 to 24 mo after inoculation[76]. Atrophic gastritis and focal intestinal metaplasia and dysplasia also appear 6 mo after inoculation, and premalignant changes can be reversed after H pylori eradication[78]. Hypergastrinemia in H pylori-infected animals is associated with increased Reg gene expression, and both plasma gastrin and Reg mRNA levels are normalized after H pylori eradication[79].

Finally, the possibility of species differences in relation to carcinoid development after long-term administration of acid inhibitors has also been studied in dogs. Beagle dogs were given omeprazole daily for 7 years, but there were no changes in the gastric mucosa at termination and there were specifically no increases in ECL cell numbers[80]. However, dogs receiving omeprazole had fasting and meal-stimulated plasma gastrin levels at the same level as controls, and changes in the oxyntic mucosa should therefore not be expected.

CONCLUSION

Animal models can provide valuable information about risk factors for gastric cancer as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. The various animal models of gastric hypoacidity and hypergastrinemia provide evidence hypergastrinemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinemia has been induced, a proportion of the animals develop neoplastic lesions. Bearing in mind that gastrin acts on gastrin receptors located on ECL cells, which are stimulated to secretion and proliferation, we find it obvious ECL cells have a pivotal role in the gastric carcinogenesis associated with hypergastrinemia. Findings in Japanese cotton rats and Mongolian gerbils in particular suggest carcinoids and adenocarcinomas develop though a similar mechanism, and derive from ECL cells. Hypergastrinemia induces gastric neoplasia whether accompanied by gastric hypoacidity or not, and experiments using the above-mentioned models could explain why carcinoids develop in some situations, whereas tumors with an adenocarcinoma phenotype develop in other models.

Footnotes

Supported by The Norwegian Gastroenterologist Association

References
1.  Kokkola A, Sjoblom SM, Haapiainen R, Sipponen P, Puolakkainen P, Jarvinen H. The risk of gastric carcinoma and carcinoid tumours in patients with pernicious anaemia. A prospective follow-up study. Scand J Gastroenterol. 1998;33:88-92.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Sjoblom SM, Sipponen P, Miettinen M, Karonen SL, Jrvinen HJ. Gastroscopic screening for gastric carcinoids and carcinoma in pernicious anemia. Endoscopy. 1988;20:52-56.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Hsing AW, Hansson LE, McLaughlin JK, Nyren O, Blot WJ, Ekbom A, Fraumeni JF Jr. Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer. 1993;71:745-750.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Sjoblom SM, Sipponen P, Karonen SL, Jarvinen HJ. Argyrophilic cell hyperplasia and carcinoid tumors in oxyntic mucosa of the stomach. Dependence on duration of pernicious aniaemia. Eur J Gastroenterol Hepatol. 1991;3:153-157.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Rindi G, Fiocca R, Morocutti A, Jacobs A, Miller N, Thjodleifsson B. Effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa. Eur J Gastroenterol Hepatol. 2005;17:559-566.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Schott M, Sagert C, Willenberg HS, Schinner S, Ramp U, Varro A, Raffel A, Eisenberger C, Zacharowski K, Perren A. Carcinogenic hypergastrinemia: signet-ring cell carcinoma in a patient with multiple endocrine neoplasia type 1 with Zollinger-Ellison's syndrome. J Clin Endocrinol Metab. 2007;92:3378-3382.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Lehy T, Cadiot G, Mignon M, Ruszniewski P, Bonfils S. Influence of multiple endocrine neoplasia type 1 on gastric endocrine cells in patients with the Zollinger-Ellison syndrome. Gut. 1992;33:1275-1279.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Cadiot G, Vissuzaine C, Potet F, Mignon M. Fundic argyrophil carcinoid tumor in a patient with sporadic-type Zollinger-Ellison syndrome. Dig Dis Sci. 1995;40:1275-1278.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Feurle GE. Argyrophil cell hyperplasia and a carcinoid tumour in the stomach of a patient with sporadic Zollinger-Ellison syndrome. Gut. 1994;35:275-277.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Waldum HL, Fossmark R, Bakke I, Martinsen TC, Qvigstad G. Hypergastrinemia in animals and man: causes and consequences. Scand J Gastroenterol. 2004;39:505-509.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Waldum HL, Gustafsson B, Fossmark R, Qvigstad G. Antiulcer drugs and gastric cancer. Dig Dis Sci. 2005;50 Suppl 1:S39-S44.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Edkins JS. On the chemical mechanism of gastric acid secretion. Proc R Soc Med. 1905;76:376.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Innis RB, Snyder SH. Distinct cholecystokinin receptors in brain and pancreas. Proc Natl Acad Sci USA. 1980;77:6917-6921.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Kopin AS, Lee YM, McBride EW, Miller LJ, Lu M, Lin HY, Kolakowski LF Jr, Beinborn M. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci USA. 1992;89:3605-3609.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Waldum HL, Sandvik AK, Brenna E, Petersen H. Gastrin-histamine sequence in the regulation of gastric acid secretion. Gut. 1991;32:698-701.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Shankley NP, Welsh NJ, Black JW. Histamine dependence of pentagastrin-stimulated gastric acid secretion in rats. Yale J Biol Med. 1992;65:613-619.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Kulaksiz H, Arnold R, Goke B, Maronde E, Meyer M, Fahrenholz F, Forssmann WG, Eissele R. Expression and cell-specific localization of the cholecystokinin B/gastrin receptor in the human stomach. Cell Tissue Res. 2000;299:289-298.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Schmitz F, Goke MN, Otte JM, Schrader H, Reimann B, Kruse ML, Siegel EG, Peters J, Herzig KH, Folsch UR. Cellular expression of CCK-A and CCK-B/gastrin receptors in human gastric mucosa. Regul Pept. 2001;102:101-110.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Cabero JL, Li ZQ, Mardh S. Gastrin potentiates histamine-stimulated aminopyrine accumulation in isolated rat parietal cells. Am J Physiol. 1991;261:G621-G627.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Bakke I, Qvigstad G, Sandvik AK, Waldum HL. The CCK-2 receptor is located on the ECL cell, but not on the parietal cell. Scand J Gastroenterol. 2001;36:1128-1133.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Tanaka S, Hamada K, Yamada N, Sugita Y, Tonai S, Hunyady B, Palkovits M, Falus A, Watanabe T, Okabe S. Gastric acid secretion in L-histidine decarboxylase-deficient mice. Gastroenterology. 2002;122:145-155.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Kobayashi T, Tonai S, Ishihara Y, Koga R, Okabe S, Watanabe T. Abnormal functional and morphological regulation of the gastric mucosa in histamine H2 receptor-deficient mice. J Clin Invest. 2000;105:1741-1749.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Crean GP, Marshall MW, Rumsey RD. Parietal cell hyperplasia induced by the administration of pentagastrin (ICI 50,123) to rats. Gastroenterology. 1969;57:147-155.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Poynter D, Pick CR, Harcourt RA, Selway SA, Ainge G, Harman IW, Spurling NW, Fluck PA, Cook JL. Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut. 1985;26:1284-1295.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Havu N. Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion. 1986;35 Suppl 1:42-55.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Havu N, Mattsson H, Ekman L, Carlsson E. Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine. Digestion. 1990;45:189-195.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Larsson H, Carlsson E, Mattsson H, Lundell L, Sundler F, Sundell G, Wallmark B, Watanabe T, Hakanson R. Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology. 1986;90:391-399.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Sundler F, Hakanson R, Carlsson E, Larsson H, Mattsson H. Hypergastrinemia after blockade of acid secretion in the rat: trophic effects. Digestion. 1986;35 Suppl 1:56-69.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Hakanson R, Blom H, Carlsson E, Larsson H, Ryberg B, Sundler F. Hypergastrinaemia produces trophic effects in stomach but not in pancreas and intestines. Regul Pept. 1986;13:225-233.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Ryberg B, Tielemans Y, Axelson J, Carlsson E, Hakanson R, Mattson H, Sundler F, Willems G. Gastrin stimulates the self-replication rate of enterochromaffinlike cells in the rat stomach. Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats. Gastroenterology. 1990;99:935-942.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Tielemans Y, Axelson J, Sundler F, Willems G, Hakanson R. Serum gastrin concentration affects the self replication rate of the enterochromaffin like cells in the rat stomach. Gut. 1990;31:274-278.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Tielemans Y, Hakanson R, Sundler F, Willems G. Proliferation of enterochromaffinlike cells in omeprazole-treated hypergastrinemic rats. Gastroenterology. 1989;96:723-729.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Mattsson H, Havu N, Brautigam J, Carlsson K, Lundell L, Carlsson E. Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffinlike-cell carcinoids in the rat. Gastroenterology. 1991;100:311-319.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Spencer AJ, Barbolt TA, Henry DC, Eason CT, Sauerschell RJ, Bonner FW. Gastric morphological changes including carcinoid tumors in animals treated with a potent hypolipidemic agent, ciprofibrate. Toxicol Pathol. 1989;17:7-15.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Martinsen TC, Nesjan N, Ronning K, Sandvik AK, Waldum HL. The peroxisome-proliferator ciprofibrate induces hypergastrinemia without raising gastric pH. Carcinogenesis. 1996;17:2153-2155.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Waldum HL, Kvetnoi IM, Sylte R, Schulze B, Martinsen TC, Sandvik AK. The effect of the peroxisome proliferator ciprofibrate on the gastric mucosa and particularly the gastrin cell. J Mol Endocrinol. 1998;20:111-117.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Poynter D, Selway SA, Papworth SA, Riches SR. Changes in the gastric mucosa of the mouse associated with long lasting unsurmountable histamine H2 blockade. Gut. 1986;27:1338-1346.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Waldum HL, Brenna E, Martinsen TC. Safety of proton pump inhibitors. Aliment Pharmacol Ther. 2000;14:1537-1538.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Wang TC, Dangler CA, Chen D, Goldenring JR, Koh T, Raychowdhury R, Coffey RJ, Ito S, Varro A, Dockray GJ. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology. 2000;118:36-47.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Takaishi S, Cui G, Frederick DM, Carlson JE, Houghton J, Varro A, Dockray GJ, Ge Z, Whary MT, Rogers AB. Synergistic inhibitory effects of gastrin and histamine receptor antagonists on Helicobacter-induced gastric cancer. Gastroenterology. 2005;128:1965-1983.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Kidd M, Miu K, Tang LH, Perez-Perez GI, Blaser MJ, Sandor A, Modlin IM. Helicobacter pylori lipopolysaccharide stimulates histamine release and DNA synthesis in rat enterochromaffin-like cells. Gastroenterology. 1997;113:1110-1117.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Fox JG, Rogers AB, Ihrig M, Taylor NS, Whary MT, Dockray G, Varro A, Wang TC. Helicobacter pylori-associated gastric cancer in INS-GAS mice is gender specific. Cancer Res. 2003;63:942-950.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Franic TV, Judd LM, Robinson D, Barrett SP, Scarff KL, Gleeson PA, Samuelson LC, Van Driel IR. Regulation of gastric epithelial cell development revealed in H(+)/K(+)-ATPase beta-subunit- and gastrin-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2001;281:G1502-G1511.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Scarff KL, Judd LM, Toh BH, Gleeson PA, Van Driel IR. Gastric H(+),K(+)-adenosine triphosphatase beta subunit is required for normal function, development, and membrane structure of mouse parietal cells. Gastroenterology. 1999;117:605-618.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Friis-Hansen L, Sundler F, Li Y, Gillespie PJ, Saunders TL, Greenson JK, Owyang C, Rehfeld JF, Samuelson LC. Impaired gastric acid secretion in gastrin-deficient mice. Am J Physiol. 1998;274:G561-G568.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Friis-Hansen L, Rieneck K, Nilsson HO, Wadstrom T, Rehfeld JF. Gastric inflammation, metaplasia, and tumor development in gastrin-deficient mice. Gastroenterology. 2006;131:246-258.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Friis-Hansen L. Achlorhydria is associated with gastric microbial overgrowth and development of cancer: lessons learned from the gastrin knockout mouse. Scand J Clin Lab Invest. 2006;66:607-621.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Friis-Hansen L. Lessons from the gastrin knockout mice. Regul Pept. 2007;139:5-22.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Willems G, Vansteenkiste Y, Limbosch JM. Stimulating effect of gastrin on cell proliferation kinetics in canine fundic mucosa. Gastroenterology. 1972;62:583-589.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Waldum HL, Brenna E, Sandvik AK, Petersen H. Trophic effect of histamine on the stomach. Scand J Gastroenterol Suppl. 1991;180:137-142.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Watson SA, Wilkinson LJ, Robertson JF, Hardcastle JD. Effect of histamine on the growth of human gastrointestinal tumours: reversal by cimetidine. Gut. 1993;34:1091-1096.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Waldum HL, Lehy T, Brenna E, Sandvik AK, Petersen H, Sognen BS, Bonfils S, Lewin MJ. Effect of the histamine-1 antagonist astemizole alone or with omeprazole on rat gastric mucosa. Scand J Gastroenterol. 1991;26:23-35.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Brenna E, Tielemans Y, Kleveland PM, Sandvik AK, Willems G, Waldum HL. Effect of the histamine-2 agonist impromidine on stem cell proliferation of rat oxyntic mucosa. Scand J Gastroenterol. 1995;30:311-314.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, Tochino Y, Okamoto H. A novel gene activated in regenerating islets. J Biol Chem. 1988;263:2111-2114.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Asahara M, Mushiake S, Shimada S, Fukui H, Kinoshita Y, Kawanami C, Watanabe T, Tanaka S, Ichikawa A, Uchiyama Y. Reg gene expression is increased in rat gastric enterochromaffin-like cells following water immersion stress. Gastroenterology. 1996;111:45-55.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Fukui H, Kinoshita Y, Maekawa T, Okada A, Waki S, Hassan S, Okamoto H, Chiba T. Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology. 1998;115:1483-1493.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Kawanami C, Fukui H, Kinoshita Y, Nakata H, Asahara M, Matsushima Y, Kishi K, Chiba T. Regenerating gene expression in normal gastric mucosa and indomethacin-induced mucosal lesions of the rat. J Gastroenterol. 1997;32:12-18.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Kazumori H, Ishihara S, Fukuda R, Kinoshita Y. Localization of Reg receptor in rat fundic mucosa. J Lab Clin Med. 2002;139:101-108.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Steele IA, Dimaline R, Pritchard DM, Peek RM Jr, Wang TC, Dockray GJ, Varro A. Helicobacter and gastrin stimulate Reg1 expression in gastric epithelial cells through distinct promoter elements. Am J Physiol Gastrointest Liver Physiol. 2007;293:G347-G354.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Dhar DK, Udagawa J, Ishihara S, Otani H, Kinoshita Y, Takasawa S, Okamoto H, Kubota H, Fujii T, Tachibana M. Expression of regenerating gene I in gastric adenocarcinomas: correlation with tumor differentiation status and patient survival. Cancer. 2004;100:1130-1136.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Sekikawa A, Fukui H, Fujii S, Takeda J, Nanakin A, Hisatsune H, Seno H, Takasawa S, Okamoto H, Fujimori T. REG Ialpha protein may function as a trophic and/or anti-apoptotic factor in the development of gastric cancer. Gastroenterology. 2005;128:642-653.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Kawase S, Ishikura H. Female-predominant occurrence of spontaneous gastric adenocarcinoma in cotton rats. Lab Anim Sci. 1995;45:244-248.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Waldum HL, Rorvik H, Falkmer S, Kawase S. Neuroendocrine (ECL cell) differentiation of spontaneous gastric carcinomas of cotton rats (Sigmodon hispidus). Lab Anim Sci. 1999;49:241-247.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Martinsen TC, Kawase S, Hakanson R, Torp SH, Fossmark R, Qvigstad G, Sandvik AK, Waldum HL. Spontaneous ECL cell carcinomas in cotton rats: natural course and prevention by a gastrin receptor antagonist. Carcinogenesis. 2003;24:1887-1896.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Fossmark R, Martinsen TC, Torp SH, Kawase S, Sandvik AK, Waldum HL. Spontaneous enterochromaffin-like cell carcinomas in cotton rats (Sigmodon hispidus) are prevented by a somatostatin analogue. Endocr Relat Cancer. 2004;11:149-160.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Fossmark R, Zhao CM, Martinsen TC, Kawase S, Chen D, Waldum HL. Dedifferentiation of enterochromaffin-like cells in gastric cancer of hypergastrinemic cotton rats. APMIS. 2005;113:436-449.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Fossmark R, Martinsen TC, Bakkelund KE, Kawase S, Waldum HL. ECL-cell derived gastric cancer in male cotton rats dosed with the H2-blocker loxtidine. Cancer Res. 2004;64:3687-3693.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Fossmark R, Martinsen TC, Bakkelund KE, Kawase S, Torp SH, Waldum HL. Hypergastrinaemia induced by partial corpectomy results in development of enterochromaffin-like cell carcinoma in male Japanese cotton rats. Scand J Gastroenterol. 2004;39:919-926.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Modlin IM, Himi K, Bilchik AJ, Nilsson O, Esterline WJ, Goldenring JR.  Pathobiology of enterochromaffin-like cell tumor induction in mastomys. In Hakanson R, Sundler F. The stomach as an endocrine organ. Amsterdam: Elsevier 1991; 499-514.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Schaffer K, McBride EW, Beinborn M, Kopin AS. Interspecies polymorphisms confer constitutive activity to the Mastomys cholecystokinin-B/gastrin receptor. J Biol Chem. 1998;273:28779-28784.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Bilchik AJ, Nilsson O, Modlin IM, Sussman J, Zucker KA, Adrian TE. H2-receptor blockade induces peptide YY and enteroglucagon-secreting gastric carcinoids in mastomys. Surgery. 1989;106:1119-1126; discussion 1026-1027.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Nilsson O, Wangberg B, Johansson L, Modlin IM, Ahlman H. Praomys (Mastomys) natalensis: a model for gastric carcinoid formation. Yale J Biol Med. 1992;65:741-751; discussion 827-829.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Chiba T, Kinoshita Y, Sawada M, Kishi K, Baba A, Hoshino E. The role of endogenous gastrin in the development of enterochromaffin-like cell carcinoid tumors in Mastomys natalensis: a study with the specific gastrin receptor antagonist AG-041R. Yale J Biol Med. 1998;71:247-255.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Modlin IM, Kumar R, Nangia A, Soroka CJ, Pasikhov D, Goldenring JR. Gastrin-dependent inhibitory effects of octreotide on the genesis of gastric ECLomas. Surgery. 1992;112:1048-1056; discussion 1056-1058.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Honda S, Fujioka T, Tokieda M, Satoh R, Nishizono A, Nasu M. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Cancer Res. 1998;58:4255-4259.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Hirayama F, Takagi S, Iwao E, Yokoyama Y, Haga K, Hanada S. Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils. J Gastroenterol. 1999;34:450-454.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Kagawa J, Honda S, Kodama M, Sato R, Murakami K, Fujioka T. Enterocromaffin-like cell tumor induced by Helicobacter pylori infection in Mongolian gerbils. Helicobacter. 2002;7:390-397.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Nozaki K, Shimizu N, Tsukamoto T, Inada K, Cao X, Ikehara Y, Kaminishi M, Sugiyama A, Tatematsu M. Reversibility of heterotopic proliferative glands in glandular stomach of Helicobacter pylori-infected Mongolian gerbils on eradication. Jpn J Cancer Res. 2002;93:374-381.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Fukui H, Franceschi F, Penland RL, Sakai T, Sepulveda AR, Fujimori T, Terano A, Chiba T, Genta RM. Effects of Helicobacter pylori infection on the link between regenerating gene expression and serum gastrin levels in Mongolian gerbils. Lab Invest. 2003;83:1777-1786.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Safholm C, Havu N, Forssell H, Sundell G, Mattsson H. Effect of 7 years' daily oral administration of omeprazole to beagle dogs. Digestion. 1994;55:139-147.  [PubMed]  [DOI]  [Cited in This Article: ]