Role of gastrin peptides in carcinogenesis

doi:10.1016/j.canlet.2007.06.017

Cancer Letters

Volume 257, Issue 1, 8 November 2007, Pages 1-15

https://doi.org/10.1016/j.canlet.2007.06.017 Get rights and content

Abstract

Gastrin gene expression is upregulated in a number of pre-malignant conditions and established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical CCK-2R receptor, CCK-2R isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion. Here we review this network of events, highlighting the importance of cellular context for interpreting the role of gastrin peptides and a possible role for gastrin in supporting the early stage of carcinogenesis.

Section snippets

General introduction

Novel, active peptides derived from the precursor peptide encoded by the gastrin gene have been purified [1] and variant isoforms of the classical gastrin/CCK-2 receptor (CCK-2R) [2], [3], [4], [5], [6] as well as potential gastrin receptors unrelated to CCK-2R [7], which bind one of more gastrin peptides or are constitutively active, have been identified. Binding to these receptors triggers signalling through a variety of intracellular pathways [8]. This review will focus on the factors

Expression of gastrin in pre-malignant lesions and cancer

The main physiological role of gastrin is in the control of acid release within the stomach. The main site of gastrin production is within G cells of the gastric antrum. Endocrine, paracrine, neurocrine and local luminal conditions stimulate release of gastrin from secretory granules within the G cells by explosive exocytosis, leading to release into the circulation from the baso-lateral border (reviewed in [9]). Exocytosis is positively regulated by gastrin-releasing peptide which is expressed

Factors influencing expression of the gastrin gene

Since gastrin expression is upregulated in pre-malignant tissues and adenocarcinomas, the mechanism involved provides a potential point of therapeutic intervention. The gastrin gene is located on chromosome 17 and consists of a 4-kb sequence encoding three exons and two introns giving rise to a 434-bp transcript expressed in the stomach antrum [28], [29]. However, an earlier report identified a smaller 0.7 kb unit lacking the first exon and the large 3 kb first intron, encoding a transcript

Array of expressed peptides derived from the gastrin precursor polypeptide

The initial translation product of the gastrin transcript is the gastrin precursor peptide, preprogastrin, a 101 amino acid polypeptide, encoded within two exons of the gastrin gene [30]. However, it includes an N-terminal signal peptide which is rapidly removed so that the full-length precursor is not detected under normal circumstances. Following cleavage of the signal peptide, progastrin is processed through a number of steps to generate further active biological forms [1]. These steps

Gastrin receptors

The array of gastrin-derived peptides is thought to act through different receptors, triggering a variety of signalling cascades (reviewed in [8]). The wild-type gastrin receptor, CCK-2R, has the classical structure of a G protein-coupled receptor (GPCR) characterised by an extracellular N-terminus, three extracellular loops, three intracellular loops and an intracellular C-terminus [66]. CCK-2R couples to the effector phospholipase C, via a pertussis toxin (PTX)-insensitive G protein of the Gα_q

Growth

One of the normal physiological roles for gastrin is in regulating the proliferation of gastric mucosal cells [89] which led to the initial investigations into its potential role in stimulating tumour cell growth. There is a large body of evidence showing that exogenously applied gastrin, including G17, Gly-G17 and progastrin, promotes growth of a range of GI cancer cell lines in vitro and in vivo[84], [85], [90], [91], [92] and endogenously-produced gastrin can also act through the autocrine

Downstream targets of gastrin

Many of gastrin’s biological effects are mediated through upregulation of transcriptional targets. Some of its targets have recently been profiled in parietal cells and the mouse stomach through the use of microarray technology [131]. Gastrin knockout led to changes in expression of molecules involved in acid secretion, potassium and water channels, energy consumption, cytoskeletal structure, signalling and inflammation [131]. These may include specific targets of gastrin but may also be due to

Conclusions

Gastrin plays a multi-functional role in supporting the carcinogenic process. Further information is needed about the factors involved in upregulation of the gastrin gene in tumour cells and how the elevated levels of the individual gastrin peptides regulate expression of downstream genes leading to their subsequent biological effects. Perhaps the most exciting recent data point to a possible role for gastrin in supporting the carcinogenic process at an early stage.

References (157)

J.F. Rehfeld et al.
Naming progastrin-derived peptides
Regul. Pept.
(2004)
M.R. Hellmich et al.
Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth
J. Biol. Chem.
(2000)
L. Laghi et al.
Frameshift mutations of human gastrin receptor gene (hGARE) in gastrointestinal cancers with microsatellite instability
Lab. Invest.
(2002)
A. Miyake
A truncated isoform of human CCK-B/gastrin receptor generated by alternative usage of a novel exon
Biochem. Biophys. Res. Commun.
(1995)
C.M. Thorburn et al.
Gastrin and colorectal cancer: a prospective study
Gastroenterology
(1998)
T.C. Wang et al.
Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer
Gastroenterology
(2000)
T.C. Wang et al.
Islet cell-specific regulatory domain in the gastrin promoter contains adjacent positive and negative DNA elements
J. Biol. Chem.
(1990)
B. Simon et al.
RAP1-like binding activity in islet cells corresponds to members of the Sp1 family of transcription factors
FEBS Lett.
(1997)
J.L. Merchant et al.
Epidermal growth factor stimulation of the human gastrin promoter requires Sp1
J. Biol. Chem.
(1995)
J.L. Merchant et al.
Sp1 phosphorylation by Erk 2 stimulates DNA binding
Biochem. Biophys. Res. Commun.
(1999)

T. Taniuchi et al.

Overexpression of ZBP-89, a zinc finger DNA binding protein, in gastric cancer

Biochem. Biophys. Res. Commun.

(1997)

L.G. Tillotson

RIN ZF, a novel zinc finger gene, encodes proteins that bind to the CACC element of the gastrin promoter

J. Biol. Chem.

(1999)

J.-P. Spano et al.

Impact of EGFR expression on colorectal cancer patient prognosis and survival

Ann. Oncol.

(2005)

I.L. Beales

Gastrin and interleukin-1 beta stimulate growth factor secretion from cultured rabbit gastric parietal cells

Life Sci.

(2004)

G. Rieder et al.

Helicobacter pylori cag-type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils

Gastroenterology

(2005)

A. Chakladar et al.

Synergistic activation of the murine gastrin promoter by oncogenic Ras and beta-catenin involves SMAD recruitment

Biochem. Biophys. Res. Commun.

(2005)

H. Nakata et al.

Oncogenic ras induces gastrin gene expression in colon cancer

Gastroenterology

(1998)

K.A. Smith et al.

Production, secretion, and biological activity of the C-terminal flanking peptide of human progastrin

Gastroenterology

(2006)

J.F. Rehfeld et al.

The tumor biology of gastrin and cholecystokinin

Adv. Cancer Res.

(1994)

W.W. van Solinge et al.

Expression but incomplete maturation of progastrin in colorectal carcinomas

Gastroenterology

(1993)

G.D. Ciccotosto et al.

Expression, processing, and secretion of gastrin in patients with colorectal carcinoma

Gastroenterology

(1995)

T.H. Ji et al.

G protein-coupled receptors. I. Diversity of receptor–ligand interactions

J. Biol. Chem.

(1998)

S. Roche et al.

Involvement of a pertussis toxin-sensitive G protein in the action of gastrin on gastric parietal cells

Biochim. Biophys. Acta

(1990)

F. Noble et al.

CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology

Prog. Neurobiol.

(1999)

H. Hori et al.

Oncogenic ras induces gastrin/CCKB receptor gene expression in human colon cancer cell lines LoVo and Colo320HSR

J. Lab. Clin. Med.

(2003)

C.H. Yang et al.

Identification of a 70-kDa gastrin-binding protein on DLD-1 human colorectal carcinoma cells

Int. J. Biochem. Cell Biol.

(2001)

S. Ahmed et al.

High and low affinity receptors mediate growth effects of gastrin and gastrin-Gly on DLD-1 human colonic carcinoma cells

FEBS Lett.

(2004)

S. Ahmed et al.

Importance of N- and C-terminal regions of gastrin-Gly for preferential binding to high and low affinity gastrin-Gly receptors

Peptides

(2005)

G.S. Baldwin et al.

Biologically active recombinant human progastrin(6–80) contains a tightly bound calcium ion

J. Biol. Chem.

(2001)

J.P. Smith et al.

Functional significance of gastrin gene expression in human cancer cells

Regul. Pept.

(2004)

H.R. Luttichau et al.

Developmental expression of the gastrin and cholecystokinin genes in rat colon

Gastroenterology

(1993)

S. Muerkoster et al.

Gastrin suppresses growth of CCK2 receptor expressing colon cancer cells by inducing apoptosis in vitro and in vivo

Gastroenterology

(2005)

J.J. Zhou et al.

Coexpression of cholecystokinin-B/gastrin receptor and gastrin gene in human gastric tissues and gastric cancer cell line

World J. Gastroenterol.

(2004)

M. Ito et al.

Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene

Cell Growth Differ.

(1994)

P. Singh et al.

and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells

Oncogene

(2006)

A. Ferrand et al.

Gastrin and cancer: a review

Cancer Lett.

(2005)

S.A. Watson et al.

Gastrin – active participant or bystander in gastric carcinogenesis?

Nat. Rev. Cancer

(2006)

E. Lindstrom et al.

Control of gastric acid secretion: the gastrin–ECL cell–parietal cell axis

Comp. Biochem. Physiol. A Mol. Integr. Physiol.

(2001)

H. Koop et al.

Serum gastrin levels during long-term omeprazole treatment

Aliment. Pharmacol. Ther.

(1990)

I.L. Beales et al.

Helicobacter pylori increases gastrin release from cultured canine antral G-cells

Eur. J. Gastroenterol. Hepatol.

(2000)

P.C. Konturek et al.

Cancerogenesis in Helicobacter pylori infected stomach – role of growth factors, apoptosis and cyclooxygenases

Med. Sci. Monit.

(2001)

R.T. Jensen

Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas

Basic Clin. Pharmacol. Toxicol.

(2006)

S.A. Watson et al.

Hypergastrinemia promotes adenoma progression in the APC(Min−/+) mouse model of familial adenomatous polyposis

Cancer Res.

(2001)

G. Bombski et al.

Elevated plasma gastrin, CEA, and CA 19-9 levels decrease after colorectal cancer resection

Int. J. Colorectal Dis.

(2003)

M. Kameyama et al.

Level of serum gastrin as a predictor of liver metastasis from colorectal cancer

Dis. Colon Rectum

(1993)

K. Mukawa et al.

Analysis of K-ras mutations and expression of cyclooxygenase-2 and gastrin protein in laterally spreading tumors

J. Gastroenterol. Hepatol.

(2005)

K. Hur et al.

Expression of gastrin and its receptor in human gastric cancer tissues

J. Cancer Res. Clin. Oncol.

(2006)

J.P. Goetze et al.

Closing the gastrin loop in pancreatic carcinoma: coexpression of gastrin and its receptor in solid human pancreatic adenocarcinoma

Cancer

(2000)

W.W. van Solinge et al.

Ovarian cancers express and process progastrin

Cancer Res.

(1993)

J.F. Rehfeld et al.

Gastrin in human bronchogenic carcinomas: constant expression but variable processing of progastrin

Cancer Res.

(1989)

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Citation Excerpt :
However, in 15%–25% of patients, it leads to tissue necrosis and infection with severe complications including endocrine and exocrine pancreatic insufficiency, organ failure, fistulae, bleeding, and death.1 The gastrointestinal peptide cholecystokinin (CCK) acts physiologically on CCK receptors2-4 initiating various intracellular signaling pathways, which in turn result in enzyme/acid secretion, cellular proliferation and anti-apoptosis, and cell migration.5,6 Intracellular signaling pathways activated involve the hydrolysis of phosphatidylinositol bisphosphate by phospholipase C to generate inositol trisphosphate and diacylglycerol, which subsequently induce calcium mobilization and activation of protein kinase C.7 Several of these pathways involve activation or cross talk with tyrosine kinase receptors and proliferative pathways associated with cell growth including mammalian target of rapamycin, Akt, and extracellular signal-regulated kinases.2
Acute pancreatitis is an inflammatory process of the pancreas and a leading cause of hospitalization amongst gastrointestinal disorders. Previously, cholecystokinin (CCK) has been described to play a role in regeneration of pancreas. The aim of this study was to analyse the function of cholecystokinin octapeptide (CCK-8) during induced pancreatitis in an animal model.
Overall acute pancreatitis was induced in 38 pigs. After the induction of acute pancreatitis, half of the animals were treated with CCK-8. Intraoperative clinical data, postoperative blood parameters, ‘Porcine Well-being’ (PWB) and fitness score and post-mortal histopathological data were analysed.
At baseline, physiologically parameters of the pigs of both groups were comparable. No differences were observed regarding the overall survival of animals (p = 0.97). Postoperative PWB score were significantly enhanced in animals treated with CCK-8 as compared to the control group (p = 0.029). Moreover, histopathological analysis of the pancreatic tissue revealed that acinar necrosis and edema were significant reduced in the CCK-8 group in comparison to the control group (p = 0.016 and p = 0.019).
In conclusion, we found that CCK-8 treatment reduces acinar necrosis and edema of pancreatic tissue after induction of an acute pancreatitis in pigs.
Gastrin and Gastric Cancer
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The end result of CCK-BR signaling involves motility,58 secretion,59 and migration,60 as well as growth and proliferation.26 In addition, gastrin has shown angiogenesis and anti-apoptotic characteristics in several malignancies including gastric cancer.61–63 Unlike the normal expression of gastrin in G cells of the stomach,64 the gastrin gene also becomes overexpressed de novo in nonendocrine epithelial cells of gastric cancer65 and, likewise, the CCK-B receptor becomes overexpressed in cancer cells.40
Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review the role of gastrin and its pathway in gastric cancer and its potential as a therapeutic target in the management of gastric cancer. In the normal adult stomach, gastrin is synthesized in the G cells of the antrum; however, gastrin expression also is found in many gastric adenocarcinomas of the stomach corpus. Gastrin’s actions are mediated through the G-protein–coupled receptor cholecystokinin-B (CCK-B) on parietal and enterochromaffin cells of the gastric body. Gastrin blood levels are increased in subjects with type A atrophic gastritis and in those taking high doses of daily proton pump inhibitors for acid reflux disease. In experimental models, proton pump inhibitor–induced hypergastrinemia and infection with Helicobacter pylori increase the risk of gastric cancer. Understanding the gastrin:CCK-B signaling pathway has led to therapeutic strategies to treat gastric cancer by either targeting the CCK-B receptor with small-molecule antagonists or targeting the peptide with immune-based therapies. In this review, we discuss the role of gastrin in gastric adenocarcinoma, and strategies to block its effects to treat those with unresectable gastric cancer.
The HER2 amplicon in breast cancer: Topoisomerase IIA and beyond
2013, Biochimica et Biophysica Acta - Reviews on Cancer
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This initial product is first processed into progastrin and then into multiple alternative active gastrin peptides [171]. GAST is frequently co-amplified in HER2-amplified gastric cancer of the intestinal type [172] and is overexpressed in most cancers of the gastro-intestinal track [173,174]. However, little is known about GAST amplification in breast cancer.
HER2 gene amplification is observed in about 15% of breast cancers. The subgroup of HER2-positive breast cancers appears to be heterogeneous and presents complex patterns of gene amplification at the locus on chromosome 17q12-21. The molecular variations within the chromosome 17q amplicon and their clinical implications remain largely unknown. Besides the well-known TOP2A gene encoding Topoisomerase IIA, other genes might also be amplified and could play functional roles in breast cancer development and progression. This review will focus on the current knowledge concerning the HER2 amplicon heterogeneity, its clinical and biological impact and the pitfalls associated with the evaluation of gene amplifications at this locus, with particular attention to TOP2A and the link between TOP2A and anthracycline benefit. In addition it will discuss the clinical and biological implications of the amplification of ten other genes at this locus (MED1, STARD3, GRB7, THRA, RARA, IGFPB4, CCR7, KRT20, KRT19 and GAST) in breast cancer.
Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer
2012, Surgical Oncology
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Expressions of Gs gene and its receptor are closely related to the development, progression and invasion of cancer cells [37,38]. A recent study revealed that the intracellular signalling pathway involved in the activation of the CCK2R/GR can lead to carcinogenesis [39]. Thereby, the CCK2R/GR plays a vital role in initiating events leading to the development of preneoplastic lesions and cancer.
Cholecystokinin and Gastrin are amongst the first gastrointestinal hormone discovered. In addition to classical actions (contraction of gallbladder, growth and secretion in the stomach and pancreas), these also act as growth stimulants for gastrointestinal malignancies and cell lines. Growth of these tumours is inhibited by antagonists of the cholecystokinin and gastrin receptors. These receptors provides most promising approach in clinical oncology and several specific radiolabelled ligands have been synthesized for specific tumour targeting and therapy of tumours overexpressing these receptors. Therefore, definition of the molecular structure of the receptor involved in the autocrine/paracrine loop may contribute to novel therapies for gastrointestinal cancer. Hence, this review tries to focus on the role and distribution of these hormones and their receptors in gastrointestinal cancer with a brief talk about the clinical trial using available agonist and antagonist in gastrointestinal cancers.
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CCK-2/gastrin receptor signaling pathway is significant for gemcitabine-induced gene expression of VEGF in pancreatic carcinoma cells
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As activation and overexpression of the cholecystokinin-2 (CCK-2)/gastrin receptor can lead to carcinogenesis, it has been explored as a therapeutic target in pancreatic cancer. We demonstrated that Z-360, a CCK-2/gastrin receptor antagonist, combined with gemcitabine prolonged survival and reduced gemcitabine-induced vascular endothelial growth factor (VEGF) expression in a pancreatic carcinoma orthotopic xenograft mouse. In this study, we investigated the role of the CCK-2/gastrin signaling pathway on gemcitabine-induced VEGF expression in PANC-1 human pancreatic carcinoma cells.
In PANC-1 cells treated with Z-360, anti-gastrin IgG or kinase inhibitors, the gene expression levels were analyzed by quantitative real-time RT-PCR, and the protein levels of Akt and phosphorylated Akt (p-Akt) in cellular extracts were measured by ELISA.
Gemcitabine-induced expression of VEGF and hypoxia-inducible factor-1 alpha (HIF-1 alpha) were suppressed by the treatment with an anti-gastrin antibody. In addition, VEGF and HIF-1 alpha gene expression was inhibited by treatment with an inhibitor of phosphatidylinositol 3-kinase (PI3K), which is involved in the downstream signaling pathway of the CCK-2/gastrin receptor, and was also suppressed by treatment with Z-360. Moreover, although Akt phosphorylation was increased by treatment with gemcitabine, this elevation was partially, but significantly, inhibited by an exposure of Z-360.
Gemcitabine might induce gene expression of VEGF via the PI3K/Akt signaling pathway in the downstream of the CCK-2/gastrin receptor. The suppression of the CCK-2/gastrin signaling pathway by treatment with Z-360 could be a useful approach for potentiating prolonged survival of pancreatic cancer patients receiving gemcitabine therapy.

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Mini-reviewRole of gastrin peptides in carcinogenesis

Abstract

Section snippets

General introduction

Expression of gastrin in pre-malignant lesions and cancer

Factors influencing expression of the gastrin gene

Array of expressed peptides derived from the gastrin precursor polypeptide

Gastrin receptors

Growth

Downstream targets of gastrin

Conclusions

Regul. Pept.

J. Biol. Chem.

Lab. Invest.

Biochem. Biophys. Res. Commun.

Gastroenterology

Gastroenterology

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Ann. Oncol.

Life Sci.

Gastroenterology

Biochem. Biophys. Res. Commun.

Gastroenterology

Gastroenterology

Adv. Cancer Res.

Gastroenterology

Gastroenterology

J. Biol. Chem.

Biochim. Biophys. Acta

Prog. Neurobiol.

J. Lab. Clin. Med.

Int. J. Biochem. Cell Biol.

FEBS Lett.

Peptides

J. Biol. Chem.

Regul. Pept.

Gastroenterology

Gastroenterology

Coexpression of cholecystokinin-B/gastrin receptor and gastrin gene in human gastric tissues and gastric cancer cell line

World J. Gastroenterol.

Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: a preferential splice donor site in the human receptor gene

Cell Growth Differ.

and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells

Oncogene

Gastrin and cancer: a review

Cancer Lett.

Gastrin – active participant or bystander in gastric carcinogenesis?

Nat. Rev. Cancer

Control of gastric acid secretion: the gastrin–ECL cell–parietal cell axis

Comp. Biochem. Physiol. A Mol. Integr. Physiol.

Serum gastrin levels during long-term omeprazole treatment

Aliment. Pharmacol. Ther.

Helicobacter pylori increases gastrin release from cultured canine antral G-cells

Eur. J. Gastroenterol. Hepatol.

Cancerogenesis in Helicobacter pylori infected stomach – role of growth factors, apoptosis and cyclooxygenases

Med. Sci. Monit.

Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas

Basic Clin. Pharmacol. Toxicol.

Hypergastrinemia promotes adenoma progression in the APC(Min−/+) mouse model of familial adenomatous polyposis

Cancer Res.

Elevated plasma gastrin, CEA, and CA 19-9 levels decrease after colorectal cancer resection

Int. J. Colorectal Dis.

Level of serum gastrin as a predictor of liver metastasis from colorectal cancer

Dis. Colon Rectum

Analysis of K-ras mutations and expression of cyclooxygenase-2 and gastrin protein in laterally spreading tumors

J. Gastroenterol. Hepatol.

Expression of gastrin and its receptor in human gastric cancer tissues

J. Cancer Res. Clin. Oncol.

Closing the gastrin loop in pancreatic carcinoma: coexpression of gastrin and its receptor in solid human pancreatic adenocarcinoma

Cancer

Ovarian cancers express and process progastrin

Cancer Res.

Gastrin in human bronchogenic carcinomas: constant expression but variable processing of progastrin

Cancer Res.

Mini-review
Role of gastrin peptides in carcinogenesis