Compared to the well-described proliferative actions of gastrin and CCK, their involvement in the regulation of apoptosis is, however, poorly understood. To date, whether gastrin and CCK exert apoptotic or anti-apoptotic effect is still of debate and might be dependent on the exact physiological and pathological conditions. The same group further showed AKT inhibits apoptosis through activation of the pro-apoptotic proteins BAD and caspase-9, and transcriptional inactivation of FOXO forkhead transcription factors In vitro study in human retinal pigment epithelial cells showed that CCK suppresses peroxynitrite-triggered cell apoptosis through inhibiting the expression of Fas, Fas-associated death domain FADD , caspase-8, and BAX In addition, the level of plasminogen activator inhibitor type 2 PAI-2 , a major gastrin-targeted gene implicated as an inhibitor for cell invasion and apoptosis , , was shown to be elevated in serum and stomach of hypergastrinemic patients and gastrin-treated media Despite the anti-apoptotic effects of gastrin and CCK discussed above, gastrin and CCK were also reported to stimulate apoptosis of various cell lines.
Similarly, gastrin-induced apoptosis was also demonstrated in gastric epithelial RGM-1 cells and cholangiocarcinoma Mz-ChA-1 cells , Although the ambivalent actions of gastrin were reported in a number of in vitro studies, the majority of evidence from in vivo studies suggested gastrin signaling through CCK2R stimulates gastric cell apoptosis. Moss and colleagues, using TUNEL technique, showed that Mastomys rodents treated with loxtidine, an irreversible H 2 receptor antagonist, for 8 weeks have a 1.
Nevertheless, the ratio of fundic mucosal proliferative to apoptotic cells also increases in the loxtidine-treated Mastomys rodents compared to that of the controls In addition, INS-GAS mice and gastrin-infused GAS-KO mice have significantly elevated apoptotic glandular parietal cells, extraglandular mesenchymal cells and infiltrating immune cells, along with increased expression of proapoptotic BAX and decreased expression of BCL-2 compared to the corresponding controls Sustained H.
Treatment of H. Similar results were observed in gastric corpus biopsies obtained from H. One possible mechanism by which gastrin-induced apoptosis results in gastrointestinal cancers was proposed by Houghton et al.
Subsequently, the bone marrow—derived cells progress through metaplasia and dysplasia to intraepithelial cancer since they are more susceptible to development of malignancy than the originally inhabited gastric epithelial stem cells In contrast, CCK has been shown to suppress neuronal apoptosis in several animal models. The pilot study of Sugaya et al. Similarly, in cultured rat cortical neurons, CCK was shown to inhibit glutamate-induced neuronal death in a dose-dependent manner at concentrations of 1— nM.
In addition, Reisi et al. Due to lack of evidence, the exact roles of gastrin and CCK in the regulation of apoptosis are still of debate. Further investigations are needed to elucidate gastrin- and CCK-induced effects in apoptosis in the context of cell types and animal models.
It has been well-recognized that both the expression of CCK2R and CCK1R are increased in numerous human NETs over the corresponding normal tissues, suggesting that both receptors might be utilized as molecular targets for localization of certain adenocarcinomas by radiopeptide imaging in vivo , and more recently, for treatment by peptide receptor radiation therapy , Indeed, inspired by somatostatin receptor scintigraphy, the diagnostic gold standard procedure for the detection of several tumor entities, Gotthardt et al.
By comparing different detection methods in 26 patients with metastasized MTC, it was shown that GRS combined with computed tomography is the most effective in MTC detection, with a tumor detection rate of In a patient cohort of carcinoids and other NETs the same group suggested that GRS should be performed in selected patients since it may provide additional information in NET patients with equivocal or absent somatostatin uptake In this scenario, the search of radiolabeled CCK2R ligands with good tumor-to-kidney pharmacodynamics is of great importance in clinical settings.
Accumulating evidence showed that gastrin signaling via CCK2R stimulates the growth of gastrointestinal cancer cells in vitro and in vivo , indicating blockade of CCK2R pathway might present a promising strategy for the treatment of gastrointestinal carcinoma.
Indeed, in xenografted nude mice transplanted with the mouse colon adenocarcinoma cell line MC, proglumide, a weak CCK2R inhibitor, suppresses growth of MC colon cancer and prolongs survival in tumor-bearing mice In addition, decreased mean tumor area, mean tumor weight, and tumor DNA and RNA contents were also observed in proglumide-treated group compared to the control group However, the beneficial effects of proglumide on survival from gastric carcinoma were abolished in a randomized, controlled study of proglumide in gastric tumor patients The authors proposed that more specific and potent CCK2R antagonists, in combination with agents that block gastrin secretion such as somatostatin analogs or prostaglandin analogs, might exert a greater benefit on survival in humans Furthermore, Watson et al.
The colon tumor-xenografted rats treated with G17DT were shown to have significantly reduced median cross-sectional tumor area and weights, and increased degree of necrosis compared to control rats Similar survival-promoting effects were observed in severe combined immune deficient mice xenografted with two human gastric cancer lines MGLVA1 cells and ST16 cells Due to the positive results of G17DT achieved in multiple gastrin-sensitive tumor models, the same group further investigated the therapeutic effectiveness of G17DT in clinical trials.
G17DT was shown to elicit functional antibodies against gastrin with safe and well-tolerated profile in 52 patients with gastric carcinomas, with the exception that two patients suffered significant adverse reactions In another open-label, multinational, and multicenter phase II study, sixty-five of 94 advanced gastric cancer patients were successfully vaccinated with G17DT in terms of anti-gastrin antibody production and showed longer time-to-progression and median survival compared to control patients A further international multicenter randomized controlled Phase III clinical trial consisting of patients 79 G17DT and 75 placebo with advanced pancreatic cancer confirmed improved survival of patients in the G17DT group through an intention-to-treat analysis Therefore, G17DT represents a promising therapeutic option for gastrointestinal malignancy.
Since the discovery of gastrin and CCK a century ago as digestion-related gastrointestinal peptides, our understanding of these peptides have considerably improved. Extensive investigations have demonstrated the expression of gastrin, CCK, and their receptors in a variety of tumor cells and tissues and their involvement in the regulation of cell proliferation and apoptosis, as well as the pathogenesis of cancer.
However, it should be noted that the CCK2R- and CCK1R-mediated signal transduction varies in the context of cell types, suggesting that cautions should be taken in future investigations attempting to target the gastrin and CCK system for the treatment of certain types of cancer.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Gastrointestinal endocrinology. Scand J Gastroenterol. Johnson LR, Gastrointestinal hormones and their functions.
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The 4. It should be noted that the numbering system of critical amino acid residues involved in peptide cleavage and post-translational modifications of gastrin varies within the scientific literature. There are no known mutations in the gastrin gene causing a pathologic entity. Gastrinomas are neuroendocrine tumors that can arise from the stomach, duodenum or pancreas. Gastric carcinogenesis is a multistep process that arises from superficial gastritis, chronic atrophic gastritis, progressing to intestinal metaplasia, dysplasia, and finally carcinoma.
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Gastrin mediated cholecystokinin-2 receptor activation induces loss of cell adhesion and scattering in epithelial MDCK cells. Modulation of the cleavage of the gastrin precursor by prohormone phosphorylation.
Molecular cloning of human gastrin cDNA: evidence for evolution of gastrin by gene duplication. Effect of cholecystokinin and gastrin on human peripheral blood lymphocyte functions, implication of cyclic AMP and interleukin 2.
IL1B promoter polymorphism regulates the expression of gastric acid stimulating hormone gastrin. Acute responses of rat stomach enterochromaffinlike cells to gastrin: secretory activation and adaptation. Glycine-extended gastrin synergizes with gastrin 17 to stimulate acid secretion in gastrin-deficient mice. Gastrin induction of histamine release from primary cultures of canine oxyntic mucosal cells. Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E2 production.
Specificity of prohormone convertase endoproteolysis of progastrin in AtT cells. Food stimulation of histidine decarboxylase messenger RNA abundance in rat gastric fundus. The calcium-sensing receptor acts as a modulator of gastric acid secretion in freshly isolated human gastric glands.
Gastrin response to candidate messengers in intact conscious rats monitored by antrum microdialysis. Role of gastrin heptadecapeptide in the acid secretory response to amino acids in man. Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion.
EGF receptor activation stimulates endogenous gastrin gene expression in canine G cells and human gastric cell cultures. Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor. Effects of fundic vagotomy and cholinergic replacement on pentagastrin dose responsive gastric acid and pepsin secretion in man.
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Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells. Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastrin is a major mediator of the gastric phase of acid secretion in dogs: proof by monoclonal antibody neutralization.
Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Mononuclear cells and cytokines stimulate gastrin release from canine antral cells in primary culture. The genes for human gastrin and cholecystokinin are located on different chromosomes. Role of acetylcholine and gastrin-releasing peptide GRP in gastrin secretion.
Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor. Gastrin suppresses growth of CCK2 receptor expressing colon cancer cells by inducing apoptosis in vitro and in vivo. Gastrin stimulates the growth of gastric pit cell precursors by inducing its own receptors. Vagal regulation of GRP, gastric somatostatin, and gastrin secretion in vitro. Agonist-independent activation of Src tyrosine kinase by a cholecystokinin-2 CCK2 receptor splice variant.
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Effects of inhibition of gastric secretion on antral gastrin and somatostatin gene expression in rats. Studies of regulation of gastrin synthesis and post-translational processing by molecular biology approaches. Free journal version : [ pdf ] [ DOI ]. GAST GAST gastrin. GAST - 17q Gene Expression Viewer FireBrowse. P [Sequence] [Exons] [Medical] [Publications]. Gastrin PF CATH Classification of proteins structures. P Human Protein Atlas [tissue]. Gastric acid secretion.
P [protein]. R-HSA [pathway]. The gastrin receptor is also one of the receptors that bind cholecystokinin, and is known as the CCK-B receptor. It is a member of the G protein-coupled receptor family. The primary stimulus for secretion of gastrin is the presence of certain foodstuffs, especially peptides, certain amino acids and calcium, in the gastric lumen.
Also, as yet unidentified compounds in coffee, wine and beer are potent stimulants for gastrin secretion. Secretion of this hormone is inhibited when the lumenal pH of the stomach becomes very low less than about 3.
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