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Translational Review |
1 Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
Abstract
The gastric epithelium is a complex structure formed into tubular branched gastric glands. The glands contain a wide variety of cell types concerned with the secretion of hydrochloric acid, proteases, mucus and a range of signalling molecules. All cell types originate from stem cells in the neck region of the gland, before migrating and differentiating to assume their characteristic positions and functions. Endocrine and local paracrine mediators are of crucial importance for maintaining structural and functional integrity of the epithelium, in the face of a hostile luminal environment. The first such mediator to be recognized, the hormone gastrin, was identified over a century ago and is now established as the major physiological stimulant of gastric acid secretion. Recent studies, including those using mice that overexpress or lack the gastrin gene, suggest a number of previously unrecognized roles for this hormone in the regulation of cellular proliferation, migration and differentiation. This review focuses on the identification of hitherto unsuspected gastrin-regulated genes and discusses the paracrine cascades that contribute to the maintenance of gastric epithelial architecture and secretory function. Helicobacter infection is also considered in cases where it shares targets and signalling mechanisms with gastrin.
(Received 6 March 2007;
accepted after revision 2 April 2007; first published online 5 April 2007)
Corresponding author R. Dimaline: Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK. Email: r.dimaline{at}liv.ac.uk
The stomach is lined by a complex epithelium, which is folded into numerous branching, tubular gastric glands that reach deep into the muscularis mucosa. Pluripotent stem cells occupy a niche in the isthmus or neck region of the gastric glands and ultimately give rise to all cells of the gastric epithelium. Proliferating cells migrate up or down the gland from the neck region and differentiate into a variety of cell types that differ markedly in function and lifespan. In the acid-secreting mucosa, surface mucous cells, mucous neck cells, acid-secreting parietal cells and pepsinogen-secreting chief cells all reside in characteristic locations. In addition, a range of enteroendocrine cells are scattered throughout the glandular epithelium, including histamine-secreting enterochromaffin-like (ECL) cells, somatostatin-secreting D-cells and ghrelin-secreting X-(or A-like) cells (Fig. 1). Gastric epithelial cells may survive for a matter of 2 or 3 days (surface mucous cells) up to several months (e.g. parietal cells), and their diverse range of functions is maintained in the face of a hostile luminal environment that can contain up to 150 mM HCl, aggressive proteases and a variety of pathogens.
Maintenance of gastric epithelial architecture and regulation of its secretory functions are achieved through endocrine and paracrine mediators. The first such mediator to be recognized, the hormone gastrin, was described as a stimulant of gastric acid secretion by Edkins over a century ago (Edkins, 1905), although the physiological status of gastrin and indeed its very existence were to remain controversial for decades (Gregory, 1974). Following the isolation and chemical characterization of gastrin (Gregory & Tracy, 1964), and the wide application of studies using radioimmunoassay, immunoneutralization and receptor antagonists, it is now firmly established as the principal physiological regulator of meal-stimulated gastric acid secretion (Walsh, 1994). In addition, however, several lines of evidence have emerged over the last few years, to suggest that the physiological functions of gastrin encompass far more than the regulation of acid secretion, and that it is a pivotal component in the organization and maintenance of the gastric epithelium. Experimental approaches to reveal the ‘new biology’ of gastrin include the use of genetically modified mice that lack the gastrin gene or overexpress it, studies on patients with hypergastrinaemic conditions and functional genomics methods to identify hitherto unrecognized targets of gastrin. In this review we discuss recent advances in our understanding of how gastrin contributes to the maintenance of the functional integrity of the gastric epithelium, and the consequences of hypersecretion. We focus on work from our own laboratory in identifying previously unrecognized targets of gastrin and in exploring how these might play a part in the maintenance of epithelial architecture. We also consider the gastric pathogen Helicobacter pylori (H. pylori), in cases where its targets and signalling mechanisms are shared with gastrin.
Gastrin and gastrin receptors
Gastrin was originally isolated from the mucosa of hog gastric antrum on the basis of its acid stimulatory properties, and characterized as a heptadecapeptide (G17) amidated at the carboxyl terminus (Gregory & Tracy, 1964). The C-terminal tetrapeptide amide was shown to be essential for stimulation of gastric acid and, subsequently, further active forms extended at the amino terminus (e.g. G34) were also identified (Gregory, 1974). The biosynthetic pathways leading to the production of amidated gastrins from the precursor, progastrin, are now well established (Varro & Ardill, 2003). A number of recent studies provide support for the idea that other products of the gastrin gene, hitherto considered to be inactive processing intermediates or precursors, are likely to have important biological functions in gastric epithelium and elsewhere (Dockray et al. 2001). However, consideration of these gene products is beyond the scope of this review, and here the term gastrin refers to amidated peptides capable of stimulating acid secretion.
Gastrin and the related hormone cholecystokinin (CCK) act through two G protein-coupled receptors designated CCK1 (formerly CCKA) and CCK2 (formerly CCKB). The CCK1R has high affinity for CCK whilst the CCK2R has high affinity for both peptides (Noble et al. 1999). The principal peripheral locations of the CCK2R are parietal and ECL cells of the gastric epithelium, where gastrin is likely to be the physiologically relevant ligand since it circulates in concentrations at least an order of magnitude higher than those of CCK.
Gastric acid secretion
Although the status of gastrin as a physiological regulator of acid secretion is no longer in doubt, there has been considerable debate regarding its functional relationship with the other endogenous gastric acid secretagogues, histamine and acetylcholine, since receptors for all three are expressed on parietal cells. However, a number of lines of evidence, including quantitative pharmacological studies using histamine receptor antagonists, support the view that in vivo, gastrin acts mainly by releasing histamine from ECL cells, which in turn acts as a paracrine stimulant of parietal cells (Black & Shankley, 1987; Hersey & Sachs, 1995; Kitano et al. 2000; Dockray et al. 2001). Under normal circumstances, a variety of mechanisms, including mucus and bicarbonate secretion from surface mucous cells, are effective in protecting the gastric epithelium from the potentially damaging effects of luminal hydrochloric acid. The contribution of gastric acid to peptic ulcer disease has been exhaustively investigated for decades and extensively reviewed. The present view is that up to 80% of gastric and perhaps more than 90% of duodenal peptic ulcers are caused by infection with Helicobacter pylori. Thus, although secretion or hypersecretion of gastric acid may contribute to peptic ulcer disease, it is generally not the underlying cause. It is now becoming increasingly clear that a reduction or total loss of acid secretion can also contribute to disruption of epithelial integrity.
Enterochromaffin-like cells
Activation of CCK2 receptors on ECL cells stimulates release of histamine (Sandvik et al. 1987), activates the enzyme histidine decarboxylase (HDC, Sandvik et al. 1994) and upregulates the expression of genes involved in histamine synthesis and storage, namely HDC, vesicular monoamine transporter type 2 (VMAT2) and chromogranin A (CGA; Dimaline & Sandvik, 1991; Dimaline et al. 1993a; Dimaline & Struthers, 1996). Increased ECL cell expression of synaptotagmin V, which is involved in calcium-dependent exocytosis, has also been reported in response to elevated gastrin concentrations (Bjorkqvist et al. 1999). Gastrin also increases ECL cell numbers (Johnson, 1988), an effect that came into sharp focus during toxicological studies of profound inhibitors of acid secretion such as histamine H2 receptor antagonists and proton pump inhibitors (PPI), which remove the somatostatin-mediated negative feedback on the gastrin-secreting G-cell. Rats subjected to long-term acid inhibition (up to 2 years) developed ECL cell hyperplasia, which progressed to dysplasia and often resulted in ECL cell carcinoid tumours (Havu, 1986; Betton et al. 1988).
The natural concern that long-term use of high-dose PPIs in humans, for example during treatment for reflux oesophagitis, might also lead to ECL cell tumours seem largely to have been unfounded, although such patients may develop ECL cell hyperplasia (Klinkenberg-Knol et al. 2000; Rindi et al. 2005). In part this might be due to the fact that the increases in circulating gastrin concentrations in response to complete acid inhibition are generally smaller in humans than in rats, although there may well be other complicating factors (Ferrand & Wang, 2006). There are, however, human conditions, notably chronic atrophic gastritis (CAG), in which achlorhydria leads to chronic hypergastrinaemia that in 5–10% of patients eventually results in ECL cell tumours. For the most part these tumours are benign and therefore tend to be conservatively managed, although suppression of gastrin release by somatostatin analogues has been used to reverse ECL cell hyperplasia (Hirschowitz et al. 1992; Bordi et al. 1993; Ferraro et al. 1996), and surgical removal of the antrum to eliminate the source of gastrin was reported to completely resolve small ECL cell tumours (Hirschowitz et al. 1992). However, larger ECL cell tumours may undergo transformation, develop the capacity to metastasize and fail to regress after antrectomy, leading to suggestions that total gastrectomy should be performed where such larger tumours have been identified (Borch et al. 1985; Thomas et al. 1994). It would therefore be reasonable to suppose that only those tumours that remain responsive to gastrin are likely to regress after removal of the antrum.
Plainly, a marker of ECL function would facilitate the monitoring of progression of ECL cell hyperplasia and might enable identification of larger ECL cell tumours that remain responsive to gastrin and thereby amenable to regression following antrectomy, rather than total gastrectomy. Gene expression by the ECL cell is a potentially attractive marker since it responds rapidly to changes in circulating gastrin concentrations (Dimaline & Sandvik, 1991; Dimaline et al. 1993b), which in turn can be readily manipulated by somatostatin or its analogues (Bloom et al. 1974; Brand & Stone, 1988). In what was dubbed an ‘octreotide suppression test’, a patient with CAG and multiple ECL cell nodules received an infusion of the somatostatin analogue octreotide over 72 h, during which the circulating gastrin concentrations were monitored. Expression of HDC, VMAT2 and CGA in the nodules was monitored at the start and end of the infusion. The octreotide infusion temporarily reversed the hypergastrinaemia, and ECL cell gene expression was depressed by up to 97%, suggesting that nodule function was regulated by gastrin. Three months following a partial gastrectomy (antrectomy) the ECL cell nodules had resolved (Higham et al. 1998). Expression of HDC has been used to monitor ECL cell responses to octreotide infusion in a number of further patients with CAG and ECL cell nodules (Fig. 2) and in all cases antrectomy, when performed, resolved the nodules (R. Dimaline, A. Varro & D. M. Pritchard, unpublished observations).
Another ECL cell gene that is upregulated in hypergastrinaemia, but not directly associated with histamine synthesis or secretion, encodes the regenerating protein Reg 1A (Fukui et al. 1998; Higham et al. 1999), a member of the calcium-dependent lectin superfamily. Reg1A was originally identified as a gene upregulated during pancreatic islet regeneration (Terazono et al. 1988) and was subsequently shown to promote the growth of a number of gastric epithelial cell types, although not ECL cells (Fukui et al. 1998; Miyaoka et al. 2004). In patients with ECL cell tumours, mutations of Reg have been reported that disrupt the signal sequence and that are therefore predicted to prevent entry of Reg into the secretory pathway (Higham et al. 1999). The findings are consistent with the idea that Reg might act as an extracellular tumour suppressor, restraining the effects of hypergastrinaemia on ECL cell growth and contributing to the regulation of the proportions of epithelial cell types (Fig. 1).
Parietal cells
Parietal cells express functional CCK2 receptors, whose activation induces intracellular calcium signalling (Urushidani & Forte, 1997). However, this appears to have little or no effect on acid secretion, and gastrin alone is considered to be a relatively poor direct stimulant of acid secretion from parietal cells (Sachs et al. 1997; Takeuchi et al. 1997; Kinoshita et al. 1998). A number of recent studies on mice in which the gene encoding gastrin or its receptor is deleted suggest instead a role for the hormone in parietal cell maturation. Thus, although parietal cells are present in mice that lack the gastrin gene, the cells have an immature appearance and the animals have reduced basal acid secretion that is unresponsive to acute stimulation by gastrin, histamine or acetylcholine analogues (Koh et al. 1997; Friis-Hansen et al. 1998). Maturation of parietal cells and restoration of the acute response to acid secretagogues in the gastrin-deficient animals could, however, be achieved by chronic administration of gastrin (Friis-Hansen et al. 1998; Chen et al. 2000). During maturation, some parietal cells migrate upwards from the neck region, but the majority migrate downwards to reside in the lower one-third of the gland. It seems that gastrin might also be required for correct migration, since in gastrin-deficient mice, the rate of migration is significantly depressed (Kirton et al. 2002).
As well as direct effects on the parietal cell itself, it is now clear that gastrin also activates numerous paracrine signalling pathways that include shedding or induction of members of the epidermal growth factor (EGF) family (Miyazaki et al. 1999; Varro et al. 2002b), fibroblast growth factor-1 (Noble et al. 2003) interleukin-8 (IL-8 (Hiraoka et al. 2001) and activation of cyclooxygenase 2 (COX-2 (Guo et al. 2002; Komori et al. 2002; Slice et al. 2003).
Proliferation in gastric epithelium
It has been recognized for many years that long-term administration of high doses of gastrin induces gastric hypertrophy, and that patients with conditions leading to hypergastrinaemia may exhibit thickening of the acid-secreting mucosa (Johnson, 1988). A number of transgenic mouse strains have been developed that overexpress the gastrin gene and have raised plasma gastrin concentrations (Wang et al. 1996; Konda et al. 1999). In one such model, designated INS-GAS, in which gastrin expression is targeted to pancreatic β-cells, there is increased proliferation in gastric (and colonic) mucosa (Wang et al. 1996) and, initially, increased numbers of parietal cells and enhanced acid secretion. However, after about 4 months, parietal cells (and acid secretion) are progressively lost and a foveolar hyperplasia develops, similar to that seen in the human premalignant condition of CAG. Older INS-GAS mice are predisposed to develop gastric cancer, an occurrence that seems to be accelerated by infection with the gastric pathogen Helicobacter (H. felis, Wang et al. 2000). In humans, H. pylori infection of the gastric antrum is now recognized as the cause of most peptic ulcers; infection with H. pylori is also associated with gastric cancer (Uemura et al. 2001). There is little evidence to suggest that hypergastrinaemia alone predisposes to gastric atrophy in humans and it is not usually seen, for example, in patients with elevated gastrin owing to gastrin-secreting tumours (Jensen, 2002). The possibility arises, however, that hypergastrinaemia might exacerbate the effects of inflammatory conditions, such as infection with H. pylori, which itself is often associated with moderately elevated plasma gastrin concentrations (Calam et al. 1997).
Targets downstream of the CCK2 receptor
There is increasing evidence to suggest that activation of the gastric CCK2R evokes a range of biological responses far beyond the stimulation of gastric acid secretion. In addition to the proliferative effects outlined above, these include the stimulation of cell migration (Noble et al. 2003), invasion (Wroblewski et al. 2002), tubulogenesis (Pagliocca et al. 2002) and apoptosis (Todisco et al. 2001). Taken together, the available data suggest that circulating concentrations of gastrin within the physiological range are essential for maintenance of normal epithelial architecture, but that when elevated, particularly in conjunction with inflammation, epithelial structure and function may be disrupted. In this context, it is of interest that in some cases targets and signalling cascades may be shared between gastrin and H. pylori (Wroblewski et al. 2003; Mori et al. 2003; Varro et al. 2004).
Cells within the acid-secreting epithelium, other than parietal cells and ECL cells, are generally considered not normally to express the CCK2R, so many of the newly identified actions of gastrin are likely to result from paracrine cascades. In order to study paracrine signalling pathways stimulated by gastrin and to distinguish them from direct effects, we developed a co-culture system in which the gastric cancer cell line AGS, which does not express the CCK2R, is transfected with promoter–reporter constructs of genes of interest. When these transfected cells are co-cultured with non-transfected AGS cells that do, however, express the CCK2R (AGS-GR), and the co-cultures stimulated with gastrin, any response seen in the AGS cells must be indirect (Varro et al. 2002a; Khan et al. 2003; Fig. 3A).
In an attempt to identify genes involved in the broad biology of gastrin, we applied a functional genomic approach that included gene arrays, mRNA differential display and proteomics. In array studies using the human gastric cancer cell line AGS, expressing the CCK2R, gastrin upregulated expression of a range of genes involved in proteolysis, proliferation, differentiation and migration, consistent with a role in the maintenance and remodelling of epithelial architecture (Table 1). For example, plasminogen activator inhibitor type 2 (PAI-2), a component of the urokinase-type plasminogen activator (uPA) system, was identified as a hitherto unrecognized major target of gastrin that showed a 50-fold increase in expression (Varro et al. 2002a). Elements of the uPA system, including PAI-2, have attracted attention as potential prognostic indicators in a range of cancers. The relevance in vivo of the array data was shown by demonstrating increased concentrations of PAI-2 in gastric tissue and in the circulation of patients who were hypergastrinaemic as a result of pernicious anaemia (PA) or multiple endocrine neoplasia type 1 (MEN1; Varro et al. 2002a). Expression of PAI-2 was also increased in patients infected with H. pylori but who had normal circulating gastrin concentrations; in the case of H. pylori infection, hypergastrinaemia increased PAI-2 still further (Varro et al. 2004). Both gastrin and H. pylori could also indirectly induce PAI-2 expression in adjacent cells via paracrine mediators that in both cases included IL-8 and products of COX-2 activation (Varro et al. 2004; Fig. 3B). Since its signal sequence is relatively inefficient, a proportion of PAI-2 is retained within the cell, where one of its effects is to depress apoptosis; secreted PAI-2 is presumed to inhibit fibrinolysis and thereby reduce cell invasion. Expression of PAI-2 has been reported in gastric cancers, although there is uncertainty regarding its relationship to disease progression, which in part may reflect the relative balance between its intracellular and extracellular actions. Thus, intracellular inhibition of apoptosis could be oncogenic by preserving cells that had suffered DNA damage, whilst extracellular inhibition of fibrinolysis in areas of mucosal damage might reduce cell invasion (Varro et al. 2004).
Other genes involved in tissue remodelling, initially identified as targets of gastrin by DNA array, include members of the matrix metalloproteinase (MMP) family and their inhibitors (Table 1). Following its identification as a gastrin-sensitive gene, MMP-9 was shown to be elevated in patients with MEN-1, and gastrin, acting via MMP-9, stimulated invasiveness in a gastric cancer cell line (Wroblewski et al. 2002). The increase in MMP-9 expression was mediated by both PKC-independent and -dependent pathways via Ras, Raf and the MAP kinase pathway (Wroblewski et al. 2002). A second family member, MMP-7, was also shown to be upregulated in hypergastrinaemic conditions and by infection with H. pylori. In this case, stimulation of MMP-7 expression involved the small GTPases, RhoA and Rac, which differentially activated the transcription factors NF
B and AP1 (Wroblewski et al. 2003; Varro et al. 2007). Increased MMP-7 plays an important role in migration of primary human gastric epithelial cells (Fig. 4; Wroblewski et al. 2003), and signalling between epithelial and mesenchymal cells (see section on Epithelial–mesenchymal interactions below; McCaig et al. 2006; Varro et al. 2007).
In a complementary approach to array technology, mRNA differential display was applied to the gastric mucosa of wild-type and gastrin-deficient mice, and revealed a number of novel targets of gastrin. Of particular interest was the identification of trefoil family factor 1 (TFF1; Khan et al. 2003) and ezrin (Pagliocca et al. 2003), since both are known to have important functions in the gastric epithelium yet had not previously been linked to gastrin.
Trefoil family factor 1 is a member of the trefoil family of small protease-resistant proteins expressed in mucous cells of the gastric epithelium (TFF1 and TFF2) and goblet cells of the intestinal epithelium (TFF3). The trefoil factors are secreted in association with mucus and are important in restitution and repair of the epithelium; their expression is rapidly upregulated in response to injury (Sands & Podolsky, 1996). The notion that TFF1 is a target of gastrin was confirmed by showing that the depressed expression in gastrin-deficient mice could be rescued by chronic administration of gastrin (Khan et al. 2003). Since TFF1 is normally confined for the most part to gastric surface mucous cells, which seem not to express the CCK2R, it seems that activation in vivo is likely to be indirect. Support for this idea comes from co-culture studies using cell lines. Thus, TFF1 promoter-reporter constructs transfected into AGS cells lacking the CCK2R could be activated by co-culture with non-transfected AGS cells expressing the CCK2R (AGS-GR; Fig. 3A) and stimulation with gastrin (Khan et al. 2003).
In response to ulcerative damage of the gastric mucosa, expression of TFF1 extends deeper into the gastric glands, in closer association with cells that express the CCK2R (Saitoh et al. 2000; Ulaganathan et al. 2001; Khan et al. 2003). These findings are consistent with the idea that the indirect activation of TFF1 by gastrin might augment its expression in response to mucosal injury and thus enhance wound healing. However, in addition to promoting wound healing, there is evidence to suggest that TFF1 might act to suppress proliferation and promote cellular differentiation (Bossenmeyer-Pourie et al. 2002). Expression and activation of TFF1 via the CCK2R might therefore be important in limiting uncontrolled growth during the healing process. Mice deficient in TFF1 are prone to develop tumours of the gastric antrum, suggesting that it may be a gastric-specific tumour suppressor (Lefebvre et al. 1996); moreover, deletion or mutation of TFF1 is fairly common in human gastric cancers (Park et al. 2000). It seems then that activation of TFF1 by gastrin might counteract the proliferative effects of the hormone and thus influence the delicate balance of proliferation and differentiation required in the reparative response to mucosal injury.
A further gene defined by differential display and also by proteomics as gastrin sensitive is the cytoskeleton–membrane linker protein, ezrin (Pagliocca et al. 2003). Within the gastric epithelium, ezrin is largely confined to parietal cells. It is of crucial importance in the morphological transformation that results in the formation of extensive secretory canaliculi prior to acid secretion, and ezrin-deficient mice are achlorhydric (Yao & Forte, 2003; Tamura et al. 2005). Initial studies indicated that gastrin was able to reverse the depression of ezrin expression seen in gastrin-deficient mice and to modulate the subcellular distribution of ezrin in cultured parietal cells (Pagliocca et al. 2003). Plainly, further investigation is warranted to determine whether gastrin and ezrin are functionally linked in the process of parietal cell maturation.
Epithelial–mesenchymal interactions
The paracrine signalling cascades considered so far have been primarily concerned with communication between epithelial cells. There are, however, important signalling pathways between epithelial and other cell types. Two-way interactions between epithelial cells and mesenchymal cells are a critical determinant of normal mucosal organization and occur during development and wound healing and in the progression to cancer. These interactions are, for example, probably important in determining the niche occupied by the stem cell, and dysfunction of this system is likely to be a contributor to the process by which epithelial tumours arise on a background of chronic tissue injury or inflammation. Cogent examples are provided by the development of both gastric cancer and ECL cell carcinoid tumours in patients infected with H. pylori or subjected to prolonged hypergastrinaemia due to PA or gastrin-producing tumours. The progression in both cases involves remodelling of the epithelium and includes loss of some cell types and increases in others. The mechanisms that redefine these changes are still largely unknown but include altered expression of growth factors, cytokines, extracellular proteases and protease inhibitors. Myofibroblasts are considered to be a key mesenchymal cell type because they produce a number of epithelial growth factors and they are located in close proximity to epithelial cells. We have recently shown that both in H. pylori infection and in prolonged hypergastrinaemia there are increases in myofibroblast numbers and stimulation of functions such as proliferation and migration, owing to increased production and release from the epithelial cells of a matrix metalloproteinase, MMP-7 (McCaig et al. 2006; Varro et al. 2007). In turn, MMP-7 acts by liberating a growth factor, insulin-like growth factor II (IGF-II), secreted by the myofibroblasts. The bioavailability of insulin-like growth factors is controlled by a family of IGF binding proteins, at least one of which, IGFBP-5 is expressed by myofibroblasts. Increased MMP-7 release from the epithelial cells cleaves IGFBP-5, thereby increasing local concentrations of IGF-II. Interestingly, IGF-II then acts not only on the myofibroblasts themselves, but also on the epithelial cells, to increase proliferation, providing an insight into two-way interactions within a complex epithelium and its microenvironment (Fig. 5). These mechanisms in general might play an important role in altering the niche that favours premalignant changes in the gastric epithelium and also in the maintenance of stroma in both epithelial adenocarcinomas and ECL cell tumours (McCaig et al. 2006; Varro et al. 2007).
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Betton GR, Dormer CS, Wells T, Pert P, Price CA & Buckley P (1988). Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole. Toxicol Pathol 16, 288–298.[Medline]
Bjorkqvist M, Lindstrom E, Norlen P, Groenborg M, Hakanson R & Gammeltoft S (1999). Gastrin-induced gene expression in oxyntic mucosa and ECL cells of rat stomach. Regul Pept 84, 29–35.[CrossRef][Medline]
Black JW & Shankley NP (1987). How does gastrin act to stimulate oxyntic cell secretion? TIPS 8, 486–490.
Bloom SR, Mortimer CH, Thorner MO, Besser GM, Hall R, Gomez-Pan A, Roy VM, Russell RC, Coy DH, Kastin AJ & Schally AV (1974). Inhibition of gastrin and gastric-acid secretion by growth-hormone release-inhibiting hormone. Lancet 2, 1106–1109.[Medline]
Borch K, Renvall H & Liedberg G (1985). Gastric endocrine cell hyperplasia and carcinoid tumors in pernicious anemia. Gastroenterology 88, 638–648.[Medline]
Bordi C, Azzoni C, Pilato FP, Robutti F, D'Ambra G, Caruana P, Rindi G, Corleto VD, Annibale B & Delle FG (1993). Morphometry of gastric endocrine cells in hypergastrinemic patients treated with the somatostatin analogue octreotide. Regul Pept 47, 307–318.[CrossRef][Medline]
Bossenmeyer-Pourie C, Kannan R, Ribieras S, Wendling C, Stoll I, Thim L, Tomasetto C & Rio MC (2002). The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1–S phase transition and reducing apoptosis. J Cell Biol 157, 761–770.
Brand SJ, Stone D (1988). Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria. J Clin Invest 82, 1059–1066.[Medline]
Calam J, Gibbons A, Healey ZV, Bliss P & Arebi N (1997). How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology 113, S43–S49.[Medline]
Chen D, Zhao CM, Dockray GJ, Varro A, Van Hoek A, Sinclair NF, Wang TC & Koh TJ (2000). Glycine-extended gastrin synergizes with gastrin 17 to stimulate acid secretion in gastrin-deficient mice. Gastroenterology 119, 756–765.[CrossRef][Medline]
Dimaline R, Evans D, Forster ER, Sandvik AK & Dockray GJ (1993a). Control of gastric corpus chromogranin A messenger RNA abundance in the rat. Am J Physiol Gastrointest Liver Physiol 264, G583–G588.
Dimaline R & Sandvik AK (1991). Histidine decarboxylase gene expression in rat fundus is regulated by gastrin. FEBS Lett 281, 20–22.[CrossRef][Medline]
Dimaline R, Sandvik AK, Evans D, Forster ER & Dockray GJ (1993b). Food stimulation of histidine decarboxylase messenger RNA abundance in rat gastric fundus. J Physiol 465, 449–458.
Dimaline R & Struthers J (1996). Expression and regulation of a vesicular monoamine transporter (VMAT2) in rat stomach: a putative histamine transporter. J Physiol 490, 249–256.[Medline]
Dockray GJ, Varro A, Dimaline R & Wang T (2001). The gastrins: their production and biological activities. Annu Rev Physiol 63, 119–139.[CrossRef][Medline]
Edkins JS (1905). On the chemical mechanism of gastric secretion. Proc Roy Soc Series B Biol Sci 76, 376.
Ferrand A & Wang TC (2006). Gastrin and cancer: a review. Cancer Lett 238, 15–29.[CrossRef][Medline]
Ferraro G, Annibale B, Marignani M, Azzoni C, D'Adda T, D'Ambra G, Bordi C & Delle FG (1996). Effectiveness of octreotide in controlling fasting hypergastrinemia and related enterochromaffin-like cell growth. J Clin Endocrinol Metab 81, 677–683.[Abstract]
Friis-Hansen L, Sundler F, Li Y, Gillespie PJ, Saunders TL, Greenson JK, Owyang C, Rehfeld JF & Samuelson LC (1998). Impaired gastric acid secretion in gastrin-deficient mice. Am J Physiol Gastrointest Liver Physiol 274, G561–G568.
Fukui H, Kinoshita Y, Maekawa T, Okada A, Waki S, Hassan S, Okamoto H & Chiba T (1998). Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology 115, 1483–1493.[CrossRef][Medline]
Gregory RA (1974). The Bayliss–Starling lecture 1973. The gastrointestinal hormones: a review of recent advances. J Physiol 241, 1–32.
Gregory RA & Tracy HJ (1964). The constitution and properties of two gastrins extracted from hog antral mucosa. Gut 5, 103–114.
Guo YS, Cheng JZ, Jin GF, Gutkind JS, Hellmich MR & Townsend CM Jr (2002). Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor. J Biol Chem 277, 48755–48763.
Havu N (1986). Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 35 (Suppl. 1), 42–55.[CrossRef][Medline]
Hersey SJ & Sachs G (1995). Gastric acid secretion. Physiol Rev 75, 155–189.
Higham AD, Bishop LA, Dimaline R, Blackmore CG, Dobbins AC, Varro A, Thompson DG & Dockray GJ (1999). Mutations of RegI
are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia. Gastroenterology 116, 1310–1318.[CrossRef][Medline]
Higham AD, Dimaline R, Varro A, Attwood S, Armstrong G, Dockray GJ & Thompson DG (1998). Octreotide suppression test predicts beneficial outcome from antrectomy in a patient with gastric carcinoid tumor. Gastroenterology 114, 817–822.[CrossRef][Medline]
Hiraoka S, Miyazaki Y, Kitamura S, Toyota M, Kiyohara T, Shinomura Y, Mukaida N & Matsuzawa Y (2001). Gastrin induces CXC chemokine expression in gastric epithelial cells through activation of NF-B. Am J Physiol Gastrointest Liver Physiol 281, G735–G742.
Hirschowitz BI, Griffith J, Pellegrin D & Cummings OW (1992). Rapid regression of enterochromaffinlike cell gastric carcinoids in pernicious anemia after antrectomy. Gastroenterology 102, 1409–1418.[Medline]
Jensen RT (2002). Involvement of cholecystokinin/gastrin-related peptides and their receptors in clinical gastrointestinal disorders. Pharmacol Toxicol 91, 333–350.[CrossRef][Medline]
Johnson LR (1988). Regulation of gastrointestinal mucosal growth. Physiol Rev 68, 456–502.
Khan ZE, Wang TC, Cui G, Chi AL & Dimaline R (2003). Transcriptional regulation of the human trefoil factor, TFF1, by gastrin1. Gastroenterology 125, 510–521.[CrossRef][Medline]
Kinoshita Y, Nakata H, Kishi K, Kawanami C, Sawada M & Chiba T (1998). Comparison of the signal transduction pathways activated by gastrin in enterochromaffin-like and parietal cells. Gastroenterology 115, 93–100.[CrossRef][Medline]
Kirton CM, Wang T & Dockray GJ (2002). Regulation of parietal cell migration by gastrin in the mouse. Am J Physiol Gastrointest Liver Physiol 283, G787–G793.
Kitano M, Norlen P & Hakanson R (2000). Gastric submucosal microdialysis: a method to study gas. Regul Pept 86, 113–123.[CrossRef][Medline]
Klinkenberg-Knol EC, Nelis F, Dent J, Snel P, Mitchell B, Prichard P, Lloyd D, Havu N, Frame MH & Roman J (2000). Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 118, 661–669.[CrossRef][Medline]
Koh TJ, Goldenring JR, Ito S, Mashimo H, Kopin AS, Varro A, Dockray GJ & Wang TC (1997). Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology 113, 1015–1025.[CrossRef][Medline]
Komori M, Tsuji S, Sun WH, Tsujii M, Kawai N, Yasumaru M, Kakiuchi Y, Kimura A, Sasaki Y, Higashiyama S, Kawano S & Hori M (2002). Gastrin enhances gastric mucosal integrity through cyclooxygenase-2 upregulation in rats. Am J Physiol Gastrointest Liver Physiol 283, G1368–G1378.
Konda Y, Kamimura H, Yokota H, Hayashi N, Sugano K & Takeuchi T (1999). Gastrin stimulates the growth of gastric pit with less-differentiated features. Am J Physiol Gastrointest Liver Physiol 277, G773–G784.
Lefebvre O, Chenard MP, Masson R, Linares J, Dierich A, LeMeur M, Wendling C, Tomasetto C, Chambon P & Rio MC (1996). Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. Science 274, 259–262.
McCaig C, Duval C, Hemers E, Steele I, Pritchard DM, Przemeck S, Dimaline R, Ahmed S, Bodger K, Kerrigan DD, Wang TC, Dockray GJ & Varro A (2006). The role of matrix metalloproteinase-7 in redefining the gastric microenvironment in response to Helicobacter pylori. Gastroenterology 130, 1754–1763.[CrossRef][Medline]
Miyaoka Y, Kadowaki Y, Ishihara S, Ose T, Fukuhara H, Kazumori H, Takasawa S, Okamoto H, Chiba T & Kinoshita Y (2004). Transgenic overexpression of Reg protein caused gastric cell proliferation and differentiation along parietal cell and chief cell lineages. Oncogene 23, 3572–3579.[CrossRef][Medline]
Miyazaki Y, Shinomura Y, Tsutsui S, Zushi S, Higashimoto Y, Kanayama S, Higashiyama S, Taniguchi N & Matsuzawa Y (1999). Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor. Gastroenterology 116, 78–89.[CrossRef][Medline]
Mori N, Sato H, Hayashibara T, Senba M, Geleziunas R, Wada A, Hirayama T & Yamamoto N (2003). Helicobacter pylori induces matrix metalloproteinase-9 through activation of nuclear factor B. Gastroenterology 124, 983–992.[CrossRef][Medline]
Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon M & Roques BP (1999). International Union of Pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev 51, 745–781.
Noble PJ, Wilde G, White MR, Pennington SR, Dockray GJ & Varro A (2003). Stimulation of gastrin-CCKB receptor promotes migration of gastric AGS cells via multiple paracrine pathways. Am J Physiol Gastrointest Liver Physiol 284, G75–G84.
Pagliocca A, Khan ZE, Hemers E, Pennington SR, Dimaline R, Varro A & Dockray GJ (2003). Gastrin regulates parietal cell maturation: identificaton of ezrin as a novel target. Gastroenterology 124, A-22.
Pagliocca A, Wroblewski LE, Ashcroft FJ, Noble PJ, Dockray GJ & Varro A (2002). Stimulation of the gastrin-cholecystokininB receptor promotes branching morphogenesis in gastric AGS cells. Am J Physiol Gastrointest Liver Physiol 283, G292–G299.
Park WS, Oh RR, Park JY, Lee JH, Shin MS, Kim HS, Lee HK, Kim YS, Kim SY, Lee SH, Yoo NJ & Lee JY (2000). Somatic mutations of the trefoil factor family 1 gene in gastric cancer. Gastroenterology 119, 691–698.[CrossRef][Medline]
Rindi G, Fiocca R, Morocutti A, Jacobs A, Miller N & Thjodleifsson B (2005). Effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa. Eur J Gastroenterol Hepatol 17, 559–566.[CrossRef][Medline]
Sachs G, Zeng N & Prinz C (1997). Physiology of isolated gastric endocrine cells. Annu Rev Physiol 59, 243–256.[CrossRef][Medline]
Saitoh T, Mochizuki T, Suda T, Aoyagi Y, Tsukada Y, Narisawa R & Asakura H (2000). Elevation of TFF1 gene expression during healing of gastric ulcer at non-ulcerated sites in the stomach: semiquantification using the single tube method of polymerase chain reaction. J Gastroenterol Hepatol 15, 604–609.[CrossRef][Medline]
Sands BE & Podolsky DK (1996). The trefoil peptide family. Annu Rev Physiol 58, 253–273.[CrossRef][Medline]
Sandvik AK, Dimaline R, Marvik R, Brenna E & Waldum HL (1994). Gastrin regulates histidine decarboxylase activity and mRNA abundance in rat oxyntic mucosa. Am J Physiol Gastrointest Liver Physiol 267, G254–G258.
Sandvik AK, Waldum HL, Kleveland PM & Sognen BS (1987). Gastrin produces an immediate and dose-dependent histamine release preceding acid secretion in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 22, 803–808.[Medline]
Slice LW, Hodikian R & Zhukova E (2003). Gastrin and EGF synergistically induce cyclooxygenase-2 expression in Swiss 3T3 fibroblasts that express the CCK2 receptor. J Cell Physiol 196, 454–463.[CrossRef][Medline]
Takeuchi Y, Yamada J, Yamada T & Todisco A (1997). Functional role of extracellular signal-regulated protein kinases in gastric acid secretion. Am J Physiol Gastrointest Liver Physiol 273, G1263–G1272.
Tamura A, Kikuchi S, Hata M, Katsuno T, Matsui T, Hayashi H, Suzuki Y, Noda T, Tsukita S & Tsukita S (2005). Achlorhydria by ezrin knockdown: defects in the formation/expansion of apical canaliculi in gastric parietal cells. J Cell Biol 169, 21–28.
Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, Tochino Y & Okamoto H (1988). A novel gene activated in regenerating islets. J Biol Chem 263, 2111–2114.
Thomas RM, Baybick JH, Elsayed AM & Sobin LH (1994). Gastric carcinoids. An immunohistochemical and clinicopathologic study of 104 patients. Cancer 73, 2053–2058.[CrossRef][Medline]
Todisco A, Ramamoorthy S, Witham T, Pausawasdi N, Srinivasan S, Dickinson CJ, Askari FK & Krametter D (2001). Molecular mechanisms for the antiapoptotic action of gastrin. Am J Physiol Gastrointest Liver Physiol 280, G298–G307.
Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N & Schlemper RJ (2001). Helicobacter pylori infection and the development of gastric cancer. New Engl J Med 345, 829–832.
Ulaganathan M, Familari M, Yeomans ND, Giraud AS & Cook GA (2001). Spatio-temporal expression of trefoil peptide following severe gastric ulceration in the rat implicates it in late-stage repair processes. J Gastroenterol Hepatol 16, 506–512.[CrossRef][Medline]
Urushidani T & Forte JG (1997). Signal transduction and activation of acid secretion in the parietal cell. J Membr Biol 159, 99–111.[CrossRef][Medline]
Varro A & Ardill JE (2003). Gastrin: and analytical review. Ann Clin Biochem 40, 472–480.[CrossRef][Medline]
Varro A, Hemers E, Archer D, Pagliocca A, Haigh C, Ahmed S, Dimaline R & Dockray GJ (2002a). Identification of plasminogen activator inhibitor-2 as a gastrin-regulated gene: role of Rho GTPase and menin. Gastroenterology 123, 271–280.[CrossRef][Medline]
Varro A, Kenny S, Hemers E, McCaig C, Przemeck S, Wang TC, Bodger K & Pritchard DM (2007). Increased gastric expression of MMP-7 in hypergastrinemia and significance for epithelial-mesenchymal signaling. Am J Physiol Gastrointest Liver Physiol 292, G1133–G1140.
Varro A, Noble PJ, Pritchard DM, Kennedy S, Hart CA, Dimaline R & Dockray GJ (2004). Helicobacter pylori induces plasminogen activator inhibitor 2 (PAI-2) in gastric epithelial cells through NF-B and RhoA: implications for invasion and apoptosis. Cancer Res 64, 1695–1702.
Varro A, Noble PJ, Wroblewski LE, Bishop L & Dockray GJ (2002b). Gastrin-cholecystokininB receptor expression in AGS cells is associated with direct inhibition and indirect stimulation of cell proliferation via paracrine activation of the epidermal growth factor receptor. Gut 50, 827–833.
Walsh JH (1994). Gastrin. In Gut Peptides, ed. Walsh JH & Dockray GJ, pp. 75–121. Raven Press, New York.
Wang TC, Dangler CA, Chen D, Goldenring JR, Koh T, Raychowdhury R, Coffey RJ, Ito S, Varro A, Dockray GJ & Fox JG (2000). Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 118, 36–47.[CrossRef][Medline]
Wang TC, Koh TJ, Varro A, Cahill RJ, Dangler CA, Fox JG & Dockray GJ (1996). Processing and proliferative effects of human progastrin in transgenic mice. J Clin Invest 98, 1918–1929.[Medline]
Wroblewski LE, Noble PJ, Pagliocca A, Pritchard DM, Hart CA, Campbell F, Dodson AR, Dockray GJ & Varro A (2003). Stimulation of MMP-7 (matrilysin) by Helicobacter pylori in human gastric epithelial cells: role in epithelial cell migration. J Cell Sci 116, 3017–3026.
Wroblewski LE, Pritchard DM, Carter S & Varro A (2002). Gastrin-stimulated gastric epithelial cell invasion: the role and mechanism of increased matrix metalloproteinase 9 expression. Biochem J 365, 873–879.[CrossRef][Medline]
Yao X & Forte JG (2003). Cell biology of acid secretion by the parietal cell. Annu Rev Physiol 65, 103–131.[CrossRef][Medline]
Zavros Y, Fleming WR, Hardy KJ & Shulkes A (1998). Regulation of fundic and antral somatostatin secretion by CCK and gastrin. Am J Physiol Gastrointest Liver Physiol 274, G742–G750.
Acknowledgements
The authors gratefully acknowledge funding support from the Medical Research Council, the Wellcome Trust, and the North-west Cancer Research Fund.
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100 pM). Upper panel indicates HDC mRNA, determined by Northern blot in endoscopic biopsies of ECL cell nodules taken before (left side) or after octreotide infusion (right side). Membranes were rehybridized for GAPDH. mRNA sizes (kilobases) are indicated to the left of the blot.
