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Gastrin — active participant or

bystander in gastric carcinogenesis?
Susan A. Watson, Anna M. Grabowska, Mohamad El-Zaatari and Arjun Takhar
Abstract | Gastrin is a pro-proliferative, anti-apoptotic hormone with a central role in
acid secretion in the gastric mucosa and a long-standing association with malignant
progression in transgenic mouse models. However, its exact role in human gastric
malignancy requires further validation. Gastrin expression is tightly regulated by two
closely associated hormones, somatostatin and gastrin-releasing peptide, and aspects of
their interaction may be deregulated during progression to gastric adenocarcinoma.
Furthermore, agonists and antagonists of the receptors for all three hormones have
shown modest clinical efficacy against gastric adenocarcinoma, which might provide
useful information on the future combined use of these agents.

Proton pump inhibitors

Agents that block acid
secretion in the stomach and
are used for the treatment of
stomach ulcers.
Enterochromaffin-like cell
A neuroendocrine cell, found
in the gastric mucosa, that
secretes histamine following
hormonal stimulation.
Antro-pyloric mucosa
The lower region of the
stomach spanning the antrum
and pylorus.
Academic Unit of Cancer
Studies, University of
Nottingham, Nottingham,
NG7 2UH, UK.
Correspondence to S.A.W.
e-mail: sue.watson@
nottingham.ac.uk
doi:10.1038/nrc2014
The polypeptide hormone gastrin induces gastric acid
secretion during the passage of food in the stomach,
thereby maintaining the appropriate acidic pH for the
function of gastric digestive enzymes. However, since
the mid-1980s, several research groups have focused on the
proposal that gastrin also increases gastrointestinal (GI)
carcinogenesis. Gastrin expression is commonly increased
through two factors: infection with Helicobacter pylori and
administration of proton pump inhibitors (PPIs), the former
being associated with gastric adenocarcinoma. However,
it is still unclear whether gastrin is a central player or a
secondary phenomenon in the development of gastric
adenocarcinoma. Nevertheless, gastrin can be regarded
as a pioneer in investigations to determine the multifunc-
tional role of gut hormones in both proximal and distal
GI carcinogenesis. The role of gastrin in human gastric
carcinogenesis will ultimately be determined in clinical
trials, but the field has been sustained by a progression
of new concepts over the past 20 years that have emerged
mainly from mouse models.
Hypergastrinaemia has been shown to promote
development of gastric adenocarcinoma in mice and
yet clinical conditions that are associated with hyper-
gastrinaemia in humans, such as the Zollinger–Ellison
syndrome, result in the development of hyperplasia of
enterochromaffin-like (ECL) cells and carcinoid tumours.
Here this discrepancy will be discussed by contrasting
pathological changes in transgenic mouse models with
those encountered in humans.
In the early 1980s the concept was simple: serum-
associated gastrin binds a cell-surface receptor and
induces a mitogenic stimulus. Blocking this receptor
would therefore represent a therapeutic modality for
gastrin-sensitive malignancies. However, we now know
that gastrin might also have a role in cell differentiation
and carcinogenesis, within both proximal and distal loca-
tions of the GI tract. Gastrin is a diverse transcriptional
activator, mediating gene expression that is associated
with cell division, invasion, angiogenesis and anti-apop-
totic activity, which are all pivotal in the gain of malig-
nant potential. Furthermore, the source of gastrin can
be either endocrine, through gastric mucosal secretion,
or of tumour origin, through de novo activation of the
gastrin gene following early mutational events, including
adenomatosis polyposis coli (APC) gene mutations, as
gastrin is a target of β-catenin-mediated transcription.
Importantly, gastrin expression is normally tightly regu-
lated by the positive regulator gastrin-releasing peptide
(GRP, the mammalian homologue of bombesin) and the
family of related hormones, acting together with a nega-
tive regulator, somatostatin. All have been independently
examined for their role in GI carcinogenesis, resulting in
the generation of potential therapeutic candidates.
This Review explores the emerging role of these hor-
mones in gastric carcinogenesis, with a focus on gastrin,
as, to date, information on how GRP and somatostatin
contribute to gastric malignancy is more limited. Where
possible, however, any findings have been included.
Normal roles of gastrin, somatostatin and GRP
The main site of gastrin synthesis is the G cell within the
antro-pyloric mucosa (FIG. 1a), a classic gut endocrine cell with
microvilli on the luminal surface that detect food within
the stomach. Gastrin is translated as a 101-amino-acid

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At a glance
• Coordinated activity between somatostatin and gastrin-releasing peptide (GRP)
regulates secretion of gastrin from G cells in a negative and positive manner,
respectively, to facilitate the release of gastric acid from parietal cells.
• In transgenic mouse models, hypergastrinaemia contributes to the development of
atrophy in the proximal gastric mucosa through the induction of parietal cell
apoptosis, leading to the development of gastric adenocarcinoma. This phenomenon
has not been confirmed in human gastric cancer.
• Infection with Helicobacter pylori is associated with increased gastrin levels in serum
and components of the bacterium might activate the gastrin promoter directly and
indirectly. Conversely, infection with H. pylori reduces somatostatin activity.
Furthermore, GRP, somatostatin and gastrin seem to modulate the inflammatory
response to the bacterium.
• Gastrin and GRP have well-documented pro-carcinogenic roles, particularly in animal
models, that affect proliferation, angiogenesis and apoptosis, whereas the potential
pro-apoptotic signal of somatostatin is lost during carcinogenesis owing to weak
expression of somatostatin receptor isoforms.
• Clinical agonists and antagonists of the three hormones have shown modest activity
in patients with gastrointestinal cancer, and rational combinations of these agents
might prove to be more clinically beneficial.
Oxyntic mucosa
precursor1 and undergoes sequential processing to the
The region within the amidated end-products gastrin 17 and gastrin 34 (REFS 2,3).
gastric mucosa that contains It is exocytosed from secretory granules along the
acid-secreting glands. baso-lateral border as a result of endocrine, paracrine,
neurocrine and local luminal factors4 and is transported
Parietal cells
Cells of the gastric mucosa to its site of action, the oxyntic mucosa (FIG. 1a), in an endo-
that produce gastric acid in crine manner. There, it interacts with the cholecystokinin 2
response to histamine, (CCK2) receptors on ECL cells, potentiating the release of
gastrin or stimulation by histamine, which induces gastric acid secretion by parietal
the vagal nerve.
cells5–8 (FIG. 1b). There have been some reports that gastrin
Fundus can directly stimulate acid release from parietal cells, which
The dome-shaped upper part are based on the observation that histamine antagonists are
of the stomach. unable to completely block acid secretion in patients, but
this is controversial9–11. The most convincing evidence for
Secretagogue
A molecule that stimulates the expression of CCK2 receptors in parietal cells comes
the secretion of gastric or from histological studies in the human stomach using
pancreatic peptides. immunohistochemistry and in situ reverse transcription
PCR. However, other studies have been unable to dem-
Lauren classification
A histological method for
onstrate the expression of CCK2 receptors in parietal cells
classifying gastric tumours into using a fluorescence-labelled CCK, which is similar to
intestinal or diffuse type. The gastrin, or a gastrin analogue. Expression of CCK2 recep-
intestinal type is characterized tors has been described in isolated parietal cells12–14 and
by the formation of cohesive
gastrin potentiated the action of histamine in these cells15
gland-like tubular structures,
whereas the diffuse type but, although these cell preparations were enriched for
involves infiltration and parietal cells, they might also have included ECL cells. In
thickening of the stomach other studies, gastrin only stimulated acid release when the
wall by individual cells. release of histamine was also stimulated16, and in histamine
Signet ring
receptor H2 (Hrh2) knockout mice neither histamine nor
A poorly differentiated diffuse gastrin was able to induce gastric acid secretion17.
type of gastric cancer in which However, the caveat to this is that canine parietal
the nuclei of glandular cells cells were used, indicating that there might be species
are pushed aside by mucin
differences in the receptor expression profiles5.
vacuoles within the cell, giving
them the appearance of a Gastrin release is controlled by somatostatin and
signet ring. GRP in a negative and positive manner, respectively
(FIG. 1a). Somatostatin, secreted by D cells in the antrum
Isthmus in response to luminal acid, inhibits gastrin release by
The region of the gastric
gland between the pit and
G cells; somatostatin is also able to inhibit upregulation of
neck that contains immature gastrin gene expression by G cells in response to external
progenitor cells. mediators, such as dibutyryl-cyclic-AMP, carbachol and
NATURE REVIEWS | CANCER
© 2006 Nature Publishing Group
REVIEWS
epidermal growth factor (EGF)18,19, but does not affect
basal transcription. In the fundus, the release of soma-
tostatin by D cells in response to neurohumoral agents
mediates direct inhibition of gastric acid secretion by the
parietal cell20 and indirect inhibition by reducing ECL-
cell histamine-release (FIG. 1b) through the somatostatin
receptor subtype 2 (SSTR2) (REFS 21,22).
Two forms of GRP (a 27-amino-acid peptide and a
carboxy-10-amino-acid peptide fragment23), released
from the neuronal fibres of the stomach, facilitate gas-
trin secretion by acting as secretagogues (FIG. 1a). Gastrin
release is also mediated by a GRP homologue, bombesin24.
However, in the fundic mucosa, GRP has a negative
effect, mediating somatostatin release by D cells25 and
reducing acid secretion.
Each of the hormones bind to G-protein-coupled
receptors, for which there are various functional isoforms
expressed within the gastric mucosa (TABLE 1).
Gastric cancer
Gastric cancer can be divided into two main categories,
diffuse and intestinal, which are based on the Lauren
classification. The diffuse, or signet ring, type, which is
more common in Western populations, is associated with
the proximal area of the stomach, and tumours tend to
be poorly differentiated. The intestinal type, which typi-
cally involves the distal stomach, is common in Asian and
elderly populations and is associated with the develop-
ment of intestinal-like glands26–28. Infection with H. pylori
is associated with 72% of antral gastric cancers and it
leads to a ninefold increase in gastric cancer risk29.
The gastric epithelium undergoes continuous renewal
of stem cells in the isthmus niche, which differentiate
into specialized cell types. The development of gastric
cancer is associated with deregulation of these prolif-
eration30 and differentiation processes31,32 that regulate
the renewal and specification of gastric stem cells into
specialized gastric epithelial cell types.
Roles of the hormones in cell differentiation
The glandular structure of the main body of the gastric
mucosa (fundus and corpus) consists of stem cells that
reside in the isthmus region, which migrate bidirec-
tionally to give rise to several differentiated cell types,
including mucous-secreting pit and neck cells, pepsino-
gen-secreting base cells, histamine-releasing ECL cells,
and acid-secreting parietal cells.
A potential mechanism by which gastrin might influ-
ence the gastric stem-cell niche is through the induction
of regenerating islet-derived 1α (REG1α), which is
upregulated in conditions of hypergastrinaemia and
in gastric adenocarcinoma 33, and seems to induce
stem-cell proliferation34,35. A transgenic mouse model
overexpressing Reg1 had significantly increased gas-
tric mucosal thickness and proliferation. Increased Reg1
expression also led to a roughly twofold increase in parietal
and zymogenic cell numbers. Therefore, Reg1 might have
a role in promoting proliferation of precursor cells and
differentiation into parietal and ECL cells36, and seems
to be important in mediating the effects of gastrin on
the proliferation and differentiation of ECL cells.
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a Oesophagus GRP receptor + Ach

GRP nerve Vagus
Luminal D cell
GRP

Pit cells
nerve
Cardia Fundus acid
Pit cell H+
Gastrin Capillary
Stomach receptors Stem cell Somatostatin bed

Isthmus
Preganglionic
Antrum Corpus CCK2R cholinergic
SSTR2 nicotinic
Pylorus nerves
Amino G cell
ECL cell
Base
acids, Gastrin
peptides
G cells Gastrin G cell
D cell
GRP
Duodenum GRP nerve
Mucous cell GRP receptor + Ach

Postganglionic cholinergic muscarinic nerves

b Oesophagus
–Ach + Ach
Vagus
D cell

Pit cells

GRP nerve nerve

+ Ach
Cardia Fundus GRP
Pit cell Ach
Gastrin
receptors ECL cell
+
Stomach Stem cell Somatostatin
Isthmus

Preganglionic
Antrum Corpus Parietal cell cholinergic
SSTR2 nicotinic
Neck

Pylorus nerves
Histamine
H+
Mucous cell H+ Parietal cell H+ HRH2
Base

G cells Gastrin ECL cell CCK2R Gastrin

D cell

Duodenum + Ach + Ach
Base cell

Postganglionic cholinergic muscarinic nerves

Figure 1 | The macroscopic and microscopic cellular interactions of the human gastric antro-pyloric and corpic/
fundic mucosa. a | The main site of gastrin synthesis is the gastrin-containing G cell within the antro-pyloric mucosa. A
representative gland is shown in the middle panel. The G cell is a classic gut endocrine cell with microvilli on the
luminal surface that mediate the detection of food within the stomach. Gastrin is released into the circulation from
secretory granules along the baso-lateral border (right panel), in close proximity to mucosal blood vessels4. Gastrin is
released by explosive exocytosis, an activity modulated by endocrine, paracrine, neurocrine and local luminal factors4.
Somatostatin, which is secreted by D cells, controls gastrin secretion by the G cell through modification of gastrin gene
transcription. Furthermore, gastrin-releasing peptide (GRP), present in the neuronal fibres innervating the antral
mucosa, facilitates gastrin secretion by acting as a secretagogue. b | Following exocytosis from the G cell, gastrin is
transported to its site of action, the oxyntic mucosa of the stomach, in an endocrine manner. Once there, it interacts
with the CCK2 receptor (CCK2R) on enterochromaffin-like (ECL) cells, potentiating the release of histamine, which
then interacts with the parietal cell to induce gastric acid secretion (right panel)5–8. Facilitation of this process is further
mediated by gastrin regulation of the expression and activity of histidine decarboxylase, which increases histamine
production159. D cells are also present within the oxyntic mucosa and somatostatin release can inhibit gastric acid
secretion by local diffusion through the intercellular space or the local mucosal circulation4. Fundic somatostatin works
in two ways, by inhibiting gastric acid secretion and by modulating the gastric acid response to gastrin4,160. GRP can
also have a negative regulatory role in the fundic mucosa by directly mediating the release of somatostatin by the D
cell25. Ach, acetylcholine; HRH2, histamine receptor H2; SSTR2, somatostatin receptor subtype 2. Right panels of a and
b are adapted with permission from REF. 4 © (1994) Balliere Tindall.

Corpus
The main body of the stomach.
Zymogenic cell
Also known as chief cells, these
secrete pepsinogen and are
characterized by spherical
zymogen granules. They
differentiate as they migrate
downwards from the isthmus to
the base of the gastric gland.
A second factor, sonic hedgehog (SHH), is required
for maintaining gastric mucosal development by control-
ling the processes of proliferation and apoptosis through
activation of the Gli family of transcription factors37–39.
Deregulation might have a role in early pre-malignant
change. Gastrin has been shown to indirectly induce SHH
mRNA expression (M.E.-Z., A.M.G. and S.A.W., unpub-
lished observations) and the proteolytic processing and
activation of SHH protein through acid secretion40. A rela-
tionship between gastric acid secretion and SHH expres-
sion has been confirmed in parietal cells41. For example,
the kinase PKB (also known as AKT) regulates gastric
acid secretion42 and is essential for SHH signalling43,44.
Gastrin, somatostatin and GRP therefore have the poten-
tial to regulate SHH transcription through gastric acid
secretion45, which warrants further investigation.
Gastrin and somatostatin mouse models
Perturbation of the gastrin–somatostatin axis has been
achieved in several transgenic mouse systems. The
transgenic mouse that overexpresses human gastrin
(InsGas mouse) develops corpus atrophy, intestinal-like

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Table 1 | CCK2 receptor, somatostatin and GRP isoforms associated with the gastric mucosa
Receptor isoform Characteristics or normal location Receptor function References
CCK2 receptor
Classical Expressed by ECL cells, parietal cells, Gastric acid secretion, 161–165
gastric stem cells and neuroendocrine histamine release and parietal
cells cell differentiation
Intron IV splice variant Gastric mucosa adjacent to gastric Not known in gastric setting 166
tumour
Truncated in N-terminal Expression with classical receptor in Not known 167
domain normal gastric mucosa
Truncated in extracellular Only in gastric and colorectal cancer Not known 168
and transmembrane domains (sporadic and hereditary)
Somatostatin receptors
SSTR2A G cells, ECL cells and nerve fibres Histamine release, 156,169–172
anti-proliferative
SSTR2B Parietal cells Pro-proliferative 172
SSTR3 Gastric mucosa Pro-apoptotic 115
GRP receptors
BB2 Gastric antrum G-cell secretagogue 114,173
BB2, bombesin; CCK2, cholecystokinin 2; ECL, enterochromaffin-like; GRP, gastrin-releasing peptide; SSTR, somatostatin receptor.

Explosive exocytosis
The rapid release of the
contents of cellular vesicles at
the cell surface.
Corpus atrophy
Loss of glandular structure
within the corpus mucosa
which is possibly accompanied
by fibrosis, thinning of the
lamina propria and
replacement of gastric
epithelium by intestinal
metaplastic epithelium.
Helicobacter felis
A strain of Helicobacter that
was originally isolated from a
cat and is also able to colonize
mice and dogs.
metaplastic lesions, dysplasia and ultimately gastric
adenocarcinoma within 20 months46. Conversely, in a
gastrin-deficient mouse model, parietal cells are lost
and antral inflammation is increased, resulting in antral
atrophy, intestinal metaplasia and antral tumours47.
Gastrin overexpression facilitates cancer development,
which is based on an amplified mitogenic effect, whereas
gastrin loss potentially leads to loss of gastric acid secretion
and bacterial overgrowth in the stomach, which can
also result in cancer development. Somatostatin-
deficient mice have hyperplastic fundi and increased
parietal cell numbers but do not develop tumours47.
These transgenic models confirm that deregulation of
gastrin is a crucial factor in mouse gastric carcinogenesis
and, where there is development of corpus atrophy,
G cells are maintained but parietal cells are lost. The
resulting hypergastrinaemia can contribute to malig-
nant progression through several downstream signalling
pathways that will be described in later sections.
Infection with H. pylori
Helicobacter pylori (BOX 1) is an important risk factor
for cancer of the distal stomach 48. Infection with
H. pylori downregulates SHH expression, resulting in
the loss of morphogenic differentiation, the disruption
of glandular structure and the gain of a more intestinal
phenotype by upregulation of intestine-related genes,
such as CDX2, MUC2 and villin47. The development of
pre-malignant lesions such as intestinal metaplasia pre-
dispose to gastric cancer.
During H. pylori-induced inflammation, cytokines
such as IL8, IL1β and TNFα have been implicated in
increasing gastrin production from G cells49,50. Gastrin
and IL1β have been shown to synergistically increase
the expression of the heparin-binding EGF-like growth
factor (HB-EGF) and amphiregulin from parietal cells51.
This effect might be important in modifying the prolif-
eration and survival of cells within the gastric isthmus,
which seem to be sensitive to EGF receptor ligands52,53.
Interferon-γ production also suppresses somatostatin
expression levels and this affects the production of the
T helper cell type 2 (T H 2) cytokine IL4, which is
stimulated by somatostatin54 and has a role in reversing
H. pylori-induced gastritis.
Somatostatin has also been shown to inhibit dendritic
cell (DC) responsiveness to H. pylori55, reducing the
severity of gastritis through the stimulation of IL4
production. Preliminary work by our group supports
a hormonal influence of gastrin on DC maturation56.
Recently, Makarenkova et al.57 described how GRP and
bombesin lead to dose-dependent inhibition of DC
maturation. Based on the above, coordinated action of
the three hormones might help to regulate DC function,
and deregulation of hormone expression levels might
affect DC-mediated immune surveillance.
In addition, H. pylori has been shown to activate the
gastrin promoter through a mechanism involving the type
IV secretory system (T4SS) (REF. 58) that, following
adherence of H. pylori, translocates the pathogenicity
factor protein CagA into epithelial cells where it under-
goes tyrosine phosphorylation and affects the phospho-
rylation of host proteins2,59–62 In a human gastric cancer
cell line, MKN45, gastrin and CCK2 receptor expression
were increased following incubation with a pathogenic
form of H. pylori to a greater extent than with a less
pathogenic strain63,64. The synergy of gastrin expression
and Helicobacter infection in the progression of gastric
adenocarcinoma was further demonstrated by the infec-
tion of InsGas transgenic mice with Helicobacter felis,
which decreased the development time of the malignant
phenotype from 20 to 9 months46. Alongside inflamma-
tory changes, mouse gastrin levels were increased46,
owing in part to the loss of parietal cells and the
acid-secretory activity of the gastric mucosa.

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Box 1 | Helicobacter pylori
Helicobacter pylori is a spiral shaped, Gram-negative bacteria that colonizes the mucous
pit layer of the gastric mucosa. It is acquired during childhood and persists throughout
life if not treated with antibiotics. Infection is thought to be associated with cancer
development, as it slowly induces gastric atrophy, which is known to be a precursor
lesion to intestinal metaplasia.
Gastric atrophy in response to infection with H. pylori develops slowly over a long
period of 20 to 40 years158. In 1993, The World Health Organization (WHO) and the
International Agency for Research on Cancer (IARC) performed an extensive literature
review and concluded that there is a clear
association between H. pylori and the
development of gastric cancer. Therefore,
H. pylori was designated as a group 1
carcinogen. Helicobacter pylori infects 40%
of the population in developed countries
by the age of 50, with a much higher
prevalence in developing countries.
However, only ~0.4% of the infected
population develop gastric cancer.
Image courtesy of David Kelly, University of Sheffield.
Infection with H. pylori in Mongolian gerbils is asso-
ciated with the loss of somatostatin receptor expression
and reduced somatostatin levels in the gastric mucosa65.
Furthermore, lipopolysaccharide from H. pylori inhibits
the binding of somatostatin to its receptor in the gastric
mucosa66. The receptor subtype has not been described,
but if SSTR2A was involved, this might potentially
reverse the inhibition mediated by SSTR2B on parietal
cells. Furthermore, as SSTR2A has been shown to induce
apoptosis67, inhibition might have profound effects on
the architecture and cellular composition of the gastric
unit. Additional factors released following infection
with H. pylori, such as platelet-activating factor, increase
GRP-induced gastrin release68, although the mechanism
for this activity is not clearly delineated.
Recent data have shown that acute Helicobacter
infection resulted in an influx of bone-marrow-derived
stem cells (BMDCs) in C57/Bl mice69. By 30 weeks,
entire glands were repopulated by BMDCs, which,
after 12 months, gave rise to intraepithelial dysplasia
and invasive neoplastic glands. This finding indicates a
new mechanism for the development of pre-malignant
gastric lesions and has implications for potential che-
moprophylactic modalities. The role of gastrin in this
process is unknown, but as bacterial infection might
have created a hypergastrinaemic environment, it would
be interesting to evaluate whether CCK2 receptors are
expressed in the BMDCs that repopulated the gastric
glands, as seen in the proliferative gastric component
of a hypergastrinaemic mouse70.
Hypergastrinaemia and gastric carcinogenesis
This is a controversial area with many confounding fac-
tors to address, making interpretation of the literature
Pseudo-pyloric gland difficult. However, recent reviews have helped to clarify
metaplasia certain conflicting issues71,72.
Gastric metaplasia in which Hypergastrinaemia in the InsGas mouse results in
gastric glands disappear and
are replaced by tubules that
gastric adenocarcinoma and is not accompanied by ECL
closely resemble normal cell hyperplasia46, whereas in the rat hypergastrinaemia
pyloric glands. results in the development of ECL cell carcinoids73–75.
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In human conditions with sustained tenfold elevations
in hypergastrinaemia, such as Zollinger–Ellison syn-
drome or pernicious anaemia, ECL cell hyperplasia
might develop but rarely leads to carcinoids. There have
been various explanations for these differing phenomena
including increased ECL cell numbers in the rat76,77 and
a net increase in glycine-extended gastrin levels in the
mouse when compared with rats and humans 78–81;
the significance of the latter being that glycine-extended
gastrin might help to prevent the loss of parietal cells82.
However, the key issue is the role of hypergastrinaemia
that is secondary to H. pylori infection, particularly in
infected patients that are treated with PPIs.
In patients with H. pylori infection who are treated
with PPIs there seems to be a shift in the location of
associated gastritis from the antrum to the corpus83,84,
which is significant in that the development of corpus-
predominant gastritis is associated with an increased
risk for gastric adenocarcinoma85. This has led to the
recommendation by some clinicians that H. pylori
should be eradicated before treatment with PPIs86.
Intriguingly, although patients with pernicious anae-
mia rarely develop carcinoma, those with pre-existing
corpus-associated gastric atrophy or gastritis have an
increased risk of developing gastric cancer87–89. Studies
of patients with Zollinger–Ellison are also difficult to
interpret as H. pylori infection in this patient group has
been found to be relatively low, as is the development
of gastric atrophy90–94.
Helicobacter pylori might increase serum gastrin
two to threefold, but this does not always lead to malig-
nancy as it is dependent on a variety of factors, including
expression of pathogenicity elements, such as CagA, and
associated inflammatory events. Therefore, in humans,
gastrin might not lead to cancer development in its own
right, but we speculate that it is an important cofactor
once pre-malignant changes are triggered. However, the
contribution made by hypergastrinaemia to the loca-
tion shift of atrophy in patients infected with H. pylori
and to the clinical outcomes from these pre-malignant
phenotypes is currently unknown71.
Roles of the hormones in pre-malignant changes
Infection with H. pylori is associated with 40% of gastric
atrophy cases and results in a reduction of G cells and
extension of antral type glands (pseudo-pyloric gland
metaplasia) into the corpus95. However, pseudo-pyloric
glandular ducts that arise within the fundic area are still
associated with gastrin-expressing G cells (1.03% of total
cell types within each duct) in 31.63% of cases, leading
to maintained expression of gastrin96. A larger subset of
individuals infected with H. pylori have corpus mucosal
atrophy with loss of parietal cells97. In corpus atrophy,
G cells within the pyloric glands of the antrum remain,
and therefore gastrin is overexpressed in response to pari-
etal cell loss in either intestinal metaplasia or in a mixed
gastric and intestinal metaplastic phenotype96.
CCK2 receptor expression has been shown to be
maintained in early pre-malignant changes within
the gastric mucosa. For example, in atrophic gastritis,
despite the loss of parietal and ECL cells, CCK2 receptors
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are still expressed at low levels (around 4% of the cell
population)98. CCK2 receptor expression increased to
8.5% of the cell population in intestinal metaplasia. In
dysplasic gastric mucosa there was the greatest change
in CCK2 receptor expression between moderate dys-
plasia (12%) and severe dysplasia (29%) with 33.5%
of adenocarcinoma cells expressing the receptor98.
Expression levels of the CCK2 receptor were not related
to serum gastrin levels, but it is possible that increased
receptor occupancy could have been responsible
for the upregulation. Expression did not seem to be
restricted to classical CCK2 receptor-expressing cells,
although co-staining would be needed to confirm this98.
Interestingly in the InsGas mouse model, work within
our laboratory has confirmed a sequential upregulation
of CCK2 receptors in samples of increasing malignant
potential (M.E.-Z., unpublished observations).
In a study on human samples, D-cell numbers were
reduced, potentially reducing somatostatin levels,
within mixed gastric and intestinal metaplasia of the
fundus and the antrum. D cells are almost absent in full
intestinal metaplasia but they are retained in pseudo-
pyloric gland metaplasia within the fundus96. A recent
study examining the gastric phenotype in a somatosta-
tin-deficient transgenic mouse model suggested that
parietal cell numbers were increased47. This is interest-
ing based on the recent observation that in the InsGas
mouse model corpus atrophy is due to gastrin-induced
apoptosis of parietal cells31. Furthermore, in the InsGas
model, a histamine receptor H2 antagonist reversed
parietal cell loss and atrophy development, leading
the authors to suggest that gastrin-induced histamine
overexpression might have contributed to parietal cell
apoptosis. Somatostatin expression was not examined
in this model but if the findings in the somatostatin
knockout mice were extrapolated to these observations,
it might be speculated that overexpression of somato-
statin in response to hypergastrinaemia might have also
played a part.
Deregulation of hormone expression
The gastrin gene is expressed de novo in non-endocrine
epithelial cells within gastric adenocarcinoma, unlike
in normal mucosa in which the expression is restricted
to G cells, and tumour-associated gastrin peptides
can participate in autocrine–paracrine pathways99.
Furthermore, the gastrin gene has been confirmed as
a target of β-catenin-mediated transcription100. Placing
these findings in a clinical context, co-expression
of gastrin and the CCK2 receptor is prognostic in terms of
survival in diffuse types of gastric adenocarcinoma101.
EGF receptor (EGFR) ligands induce gastrin gene
transcription in a human gastric cancer cell line,
through an EGF response element (gERE) that has
been mapped to the gastrin promoter102. In the gastric
mucosa, sources of EGF family ligands include the
parietal cell46,103,and the related ligand, transforming
growth factor-α (TGFα), is secreted by inflammatory
cells, such as macrophages104. The SP1 and SP3 tran-
scription factors are the predominant factors that bind
to the gERE element, and EGF might increase gastrin
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REVIEWS
gene transcription through enhancing SP1 levels within
the cell102 or by increasing the phosphorylation of SP1,
thereby maximizing the affinity of SP1 for the gastrin
promoter105. A protein–protein interaction between
SP1 and JUN further mediates EGF activation of the
gastrin gene and might explain the inhibitory effect of
somatostatin on this process as somatostatin inhibits
JUN transcriptional activation 106. Furthermore, a
helix–loop–helix cis-regulatory element on the gas-
trin promoter mediates somatostatin’s inhibition of
EGF-stimulated gastrin gene transcription107.
Further transacting factors that interact with the
gastrin promoter and might affect gastric carcinogen-
esis include the zinc-finger transcription factor, ZBP89
(REF. 108), which represses the induction of gastrin gene
expression109. ZBP89 might link gastrin gene transcrip-
tion to TP53 mutations as ZBP89 also binds to and sta-
bilizes p53 (REFS 110,111). Gastrin transcription is also
linked to the β-catenin pathway by a binding site for the
transcription factor TCF4 in the gastrin promoter112.
Expression of somatostatin in non-endocrine cells of
gastric adenocarcinomas seems undefined, with just one
report describing mRNA expression in poorly differenti-
ated gastric carcinomas113. Somatostatin expression lev-
els in endocrine cells within antral and fundic atrophy,
however, seem to follow the same pattern as gastrin96,
and D-cell production of somatostatin might still inter-
act with cell types within gastric adenocarcinoma if they
express the relevant SSTR isoforms.
GRP does not seem to be expressed in gastric adeno-
carcinomas. However, GRP expressed by normal cells
within the gastric mucosa might affect gastrin produc-
tion by the epithelial cells of gastric adenocarcinoma
through appropriate receptor isoform expression by the
cancer cells114.
CCK2 receptor deregulation in gastric adeno-
carcinoma has been reported in several studies with
contrasting results. Some data indicate that receptor
expression might correlate with differentiation sta-
tus and is higher in intestinal compared with diffuse
type gastric cancer101. However, the data in different
studies are highly variable, probably owing to low
levels of receptor expression and to the use of different
methodologies.
Somatostatin receptors are weakly expressed in
gastric adenocarcinoma. For example, SSTR3 showed
reduced expression both in gastric adenocarcinoma,
compared with normal mucosa, and in poorly differen-
tiated cancers, compared with more well-differentiated
cancers. Interestingly, when SSTR3 was expressed in a
gastric cancer cell line, administration of the somatosta-
tin analogue octreotide induced apoptosis115, indicating
that downregulation of the receptor in tumours could
contribute to the anti-apoptotic phenotype. In the rat,
SSTR2A expressed on ECL cells was anti-proliferative
whereas SSTR2B was pro-proliferative. We speculate that
SSTR2B might be preferentially expressed in tumours
because these receptors can induce pro-proliferative
signalling pathways.
GRP receptors have been found to be expressed
on around 50% of gastric adenocarcinomas 116. In a
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REVIEWS
study that specifically evaluated non-antral gastric
adenocarcinomas, 8 out of 20 cancers expressed the GRP
receptor117. Some expressed mutated forms of the receptor,
which were either non-functional or showed constitu-
tive activity. However, functional receptor expression
was not related to prognosis, which might be due to
the low number of cases investigated and unknown
co-expression of other factors. It is possible that co-
expression of gastrin might also be necessary for a
prognostic relationship to be attained.
Hormone functions in gastric cancer
Gastrin, GRP and somatostatin can influence carcino-
genesis through several pathways (FIG. 2). The origin
of gastrin for these effects might be either serum-
associated endocrine gastrin or autocrine gastrin that is
endogenously produced by tumour cells.
Apoptosis. Gastrin induces the expression and function
of anti-apoptotic proteins, which seems to be poten-
tiated by GRP, whereas somatostatin induces pro-
apoptotic proteins. An initial report confirmed that
gastrin inhibits apoptosis of a rat pancreatic tumour
cell line, AR42J, by activating PKB/AKT42 through
a phosphatidylinositol 3-kinase (PI3K)-dependent,
mitogen-activated protein kinase (MAPK)-independent
pathway. AKT activation promotes survival by phos-
phorylating the pro-apoptotic protein BAD and
inhibiting the transcription of forkhead transcription
factors118. Furthermore, gastrin mediates the activa-
tion of AKT through degradation of IκBα in a protein
kinase C (PKC)-dependent fashion in human gastric
cancer and oesophageal cell lines119,120. Gastrin has
also been linked to an increase in expression of the
anti-apoptotic protein X-linked inhibitor of apoptosis
(XIAP) in a gastro-oesophageal cell line121.
In the large intestine there is reciprocal activity of
somatostatin and gastrin on pro- and anti-apoptotic
proteins, respectively, with high gastrin and low
somatostatin expression being related to increased
expression of the anti-apoptotic protein BCL2 and,
conversely, high somatostatin and low gastrin expres-
sion being related to increased expression of the
pro-apoptotic protein BAX122. Somatostatin receptor
isoforms SSTR1, SSTR4 and SSTR5 are associated
with cell-cycle arrest, whereas SSTR3 and SSTR2 seem
mostly linked to triggering apoptosis, although this
is dependent on the cell type involved123. Activation
of SSTR3 causes a conformational change in p53 and
induces BAX expression, both of which result in the
onset of apoptosis, whereas SSTR2-induced apoptosis
is p53-independent124. Interestingly, in a pituitary cell
line somatostatin has been shown to induce the expres-
sion of the tumour suppressor ZAC1, which induces
cell-cycle arrest and apoptosis, possibly through
dephosphorylation of PKB/AKT125, however, it is not
clear whether this mechanism is relevant in gastric
tumours. GRP might further potentiate gastrin’s effect
on PKB/AKT as it can downregulate the expression of
the tumour suppressor protein PTEN, which blocks
PKB/AKT signalling126.
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© 2006 Nature Publishing Group
Proliferation. Gastrin increases proliferation of gastric
mucosal cells through transcriptional activation of a
series of genes. One well-characterized pro-proliferative
gene, the expression of which is induced by gastrin stim-
ulation of ECL cells as previously described, is REG1α,
which affects the proliferation status of the stem-cell
niche and is also overexpressed in gastric cancer127.
Reg1 gene expression is upregulated through
H. pylori-induced increases in serum gastrin levels in the
Mongolian gerbil model of gastric neoplasia128.
Gastrin also promotes proliferation by activating the
transcription of cyclin D1 in gastric cancer cells through
a mechanism involving both β-catenin and the tran-
scription factor CREB pathways129, which correlates with
the finding that gastrin, as well as being a downstream
target of β-catenin, also stabilizes the expression of
β-catenin and activates β-catenin-dependent transcrip-
tion130. Interestingly, infection with H. pylori, possibly
through CagA, also increases the nuclear expression of
β-catenin131. In colorectal cancer, gastrin increases the
expression of cyclins D1, E, A and B1, whereas soma-
tostatin expression is inversely related to the expression
of these cell-cycle proteins132, which further confirms
the opposing activities of these hormones, although
somatostatin activities, as always, are dependent on
appropriate receptor expression. The GRP homologue,
bombesin, has been shown to have a direct effect on
cyclin D1 expression through the upregulation of the
early growth response protein 1 (EGR1) (REF. 133) and
so it could interact in an additive manner with gastrin,
increasing transit through the cell cycle.
Gastrin increases the expression of the EGFR ligands
amphiregulin and EGF, and is linked to increased TGFα
expression134,135. The activation of EGFR has an impor-
tant role in increasing cell proliferation, angiogenesis and
metastasis, and reducing apoptosis24, and the presence of
EGFR ligands in human gastric cancer correlates with
the degree of invasion and lymph node metastasis and a
worse 5-year survival rate136. Many of these growth fac-
tors remain tethered to the cell membrane in an inactive
form and, interestingly, GRP receptor activation results
in EGF ligand release137, which might act synergistically
with gastrin to generate active EGF ligands and maxi-
mize EGF ligand-mediated gastrin gene transcription
through the gERE.
Angiogenesis. Gastrin induces tubule formation of the
human endothelial cell line HUVEC through the tran-
scriptional activation of HB-EGF138. The clinical sig-
nificance of this effect was determined by showing that
in GI cancer patients with hypergastrinaemia, micro-
vessel density was increased at the tumour margin138.
Furthermore, the angiogenic activity of gastrin might be
indirectly mediated through its ability to transcription-
ally upregulate cyclooxygenase 2 (COX2) (REFS 139–141),
particularly as COX2 expression in gastric cancer speci-
mens correlates with microvessel density and is related to
tumour invasion and lymph node metastasis142.
SSTR2 has been shown to be upregulated during the
angiogenic switch from resting to proliferating endothe-
lium143, whereas SSTR3 has been proposed to show
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 REVIEWS

Somatostatin pathway, which involved the phosphorylation of focal

Gastrin
GRP GRP
adhesion kinase (FAK)148. Gastrin also induced branch-
ing morphogenesis in a human gastric cancer cell line
Serum Autocrine that overexpressed the CCK2 receptor149. In terms of
hypergastrinaemia gastrin cell invasion, a human gastric epithelial cell line was
CCK2R shown to express matrix metalloproteinase 9 (MMP9) in
Helicobacter pylori Signalling pathways
Proton pump inhibitors • PKB/AKT
response to stimulation with gastrin through a PKC–Raf
• ERK/MAPK pathway 150, which increased invasion through an artifi-
• PKC cial basement membrane. This finding might be clini-
Somatostatin Somatostatin cally relevant as patients with serum hypergastrinaemia
GRP have increased MMP9 in their stomach150.

Cell proliferation Promotion of
• Cyclins angiogenesis
• HB-EGF
Circumvention • COX 2
Increased invasive of apoptosis
GRP enzyme expression • PKB/AKT
Cell migration/
• MMPs • NF-κB Somatostatin
adhesion
• Integrins
Somatostatin • FAK GRP
Figure 2 | Gastrin-mediated carcinogenic pathways. Gastrin is a diverse
transcriptional activator, mediating gene expression that is associated with cell division,
invasion, angiogenesis and anti-apoptotic activity, which are all pivotal in the gain of
malignant potential. Furthermore, the source of gastrin can be either endocrine in nature
through gastric mucosal secretion, or of tumour origin through de novo activation of the
gastrin gene following early mutational events (for example, mutation of the
adenomatosis polyposis coli (APC) gene in GI carcinogenesis). Importantly, gastrin
functions are regulated by the positive regulator, gastrin-releasing peptide (GRP; the
mammalian homologue of bombesin) and the family of related hormones, and a negative
regulator, somatostatin. CCK2R, CCK2 receptor; COX2, cyclooxygenase 2; ERK,
extracellular signal-regulated kinase; FAK, focal adhesion kinase; HB-EGF, heparin-
binding EGF-like growth factor; MAPK, mitogen-activated protein kinase; MMPs, matrix
metalloproteinases; NF-κB, nuclear factor κB; PKB, protein kinase B.
anti-angiogenic activity144. Interestingly, SSTR2 has been
detected in the peri-tumoral vessels of gastric tumours145.
The function of such receptors might be associated with
vasoconstriction, resulting in tumour hypoxia and
necrosis145. Furthermore, in hypoxic conditions, gastrin
might upregulate the expression of the transcription
factor hypoxia-inducible factor-1α (HIF1α), a phenom-
enon recently shown in our laboratory (E. Royal, A.M.G.
and S.A.W., unpublished observations). The gastrin-
mediated upregulation of HIF1α might increase
angiogenesis partially by inducing vascular endothelial
growth factor (VEGF), and perhaps by counteracting
somatostatin vasoconstriction.
The GRP homologue bombesin has been shown to
increase VEGF transcription through an NF-κB-mediated
pathway in prostate cancer cells146. However, this finding
has not been confirmed in gastric cancer.
Motility and invasion. Gastrin can modify the cell–cell adhe-
sion molecules p120, α- and β-catenins and E-cadherin,
resulting in loss of adhesion and increased cell motility
in intestinal epithelial-cell-culture systems147. A glycine-
extended version of gastrin, known to mediate autocrine
growth pathways in GI cancer cells99, was shown to
stimulate the migration of a mouse gastric epithelial cell
line through a Rho and ROCK (Rho kinase)-dependent
Hormone-targeted therapies
Several agents targeting gastrin have been evaluated
clinically, including CCK2 receptor antagonists and a
gastrin vaccine. The CCK2 receptor antagonist gastra-
zole (JB5008) was evaluated in a randomized, blind trial
in patients with advanced pancreatic cancer. Gastrazole
significantly increased median survival when compared
with a placebo (7.9 versus 4.5 months median survival,
P = 0.02) with a 1-year survival of 33% versus 11%
(P = 0.02) (REF. 151). In a second trial, no significant dif-
ference was observed when gastrazole was compared with
5-fluorouracil (median survival 3.6 versus 4.2 months)151.
No toxicity was shown for gastrazole, so it could
potentially be used in combination with cytotoxic drugs.
A gastrin vaccine, G17DT, has been evaluated in
several clinical trials. The immunogen induces anti-
gastrin antibodies that neutralize the amidated and
glycine-extended forms of gastrin 17 (REF. 152). In a
Phase II study in patients with gastric cancer, G17DT
was well tolerated and antibodies were functional in that
they prevented gastrin from binding to CCK2 receptors
in a competitive ex vivo ligand binding assay 153. In a
larger, open-label study in advanced gastric and gastro-
oesophageal cancer, G17DT vaccination combined with
5-fluorouracil and leucovorin correlated with longer
time to progression and increased median survival154.
In addition, anti-gastrin response was an independent
prognostic factor for overall survival154.
The GRP receptor antagonist RC-3095 was used in a
25-patient Phase I trial in advanced solid malignancies,
including gastric cancer155. There was no objective tumour
response as the dose escalation procedure could not be
undertaken owing to local toxicity. It was therefore proposed
that new formulations would be required to progress to
Phase II, and improved formulations with more favourable
pharmacokinetics are currently being investigated.
One trial of 107 patients with advanced GI cancer,
including 15 patients with advanced gastric cancer, has
been performed with the somatostatin analogue
octreotide. Octreotide extended survival in the treated
patients (median of 20 versus 11 weeks, P < 0.0001).
Although this result was encouraging, this therapeutic
approach has not been pursued for gastric adenocar-
cinomas, perhaps owing to low somatostatin receptor
expression in this cancer type115,156.
Based on the SSTR and GRP expression levels in
gastric cancer and their interrelationship with gastrin and
CCK2 receptor expression, combined therapies might be
synergistic. GRP antagonists could be used to prevent

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© 2006 Nature Publishing Group
REVIEWS

constitutive secretion of precursor forms of gastrin from Conclusion

malignant epithelial cells, which have biological activity but
no defined receptor157. This approach might complement
G17DT therapy, which blocks amidated and glycine-
extended gastrin, and the use of CCK2 receptor antagonists,
which are likely to be more efficacious against serum-
associated amidated gastrin forms. Additionally, if gastrin
suppresses SSTR expression in tumour cells, these receptors
might be re-expressed when gastrin expression is reduced.
This indicates that the efficacy of a somatostatin analogue
could be increased if used as an adjunct to anti-gastrin treat-
ment. Also, following eradication of H. pylori, SSTR might
reappear on pre-malignant lesions, which could be targeted
with ligands such as octreotide.
The interwoven network between gastrin, somatostatin
and GRP, which exists in the normal gastric environment,
has been exploited in gastric carcinogenesis and data pre-
sented in this Review reinforces the complexity and vari-
ability in pathological outcome of pre-malignant gastric
lesions arising within different mucosal areas within the
stomach. This in itself is a simplistic scenario consider-
ing the vast array of additional GI hormones that have an
effect on these pathways. However, it has highlighted areas
ripe for future investigation, and further analysis of the
inter-relationships of these hormones in gastric tumours
will enable investigators to define the optimal combination
of clinical candidates to target this hormone trio.

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Acknowledgements
The authors would like to acknowledge J. McClelland from
the Academic Unit of Cancer Studies for her input into the
diagrams within this article and E. Royal for the personal
communication regarding her ongoing studies.
Competing interests statement
The authors declare competing finantial interests: see Web
version for details.
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
APC | β-catenin | CCK2 | CDX2 | COX2 | EGF | EGFR | EGR1 |
Hrh2 | HB-EGF | MUC2 | PKB | REG1α | SHH | SSTR2 | TGFα |
TP53 | ZBP89
Entrez Protein: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=protein
gastrin | GRP | somatostatin
FURTHER INFORMATION
Wolfson Digestive Diseases Centre:
http://www.nottingham.ac.uk/wddc
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