1 Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606 - 8507; and 2 Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371 - 8512, Japan
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ABSTRACT |
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Gastrin/CCK-B receptors (CCKB-Rs) are present on parietal and enterochromaffin-like cells in the gastric mucosa but not on pit cells in the proliferative zone. Because serum gastrin levels are well correlated with the growth of the gastric pit, we examined whether pit precursor cells express CCKB-Rs using hypergastrinemic transgenic mice and a mouse pit precursor cell line, GSM06. In situ hybridization indicated that CCKB-R mRNA was limited to the lower one-third of the mucosa in control mice, whereas it was faintly distributed along the mid- to low glandular region in the hypergastrinemic transgenic mouse mucosa. CCKB-R-positive midglandular cells appear to have a pit cell lineage; therefore, GSM06 cells were used for an [125I]gastrin binding study. [125I]gastrin bound to the membrane fraction of the GSM06 cells when precultured with gastrin. Gastrin dose dependently induced CCKB-R expression in GSM06 cells and stimulated their growth. Thus these findings suggest that gastrin directly stimulates the growth of the pit cell lineage by inducing its own receptor in pit cell precursors.
gastric mucosal growth; gastric surface mucous cell; gastrin/cholecystokinin-B receptor
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INTRODUCTION |
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GASTRIN CONTROLS THE GROWTH of gastric mucosa (14, 15). Hypertrophied gastric mucosa is observed in patients with gastrin-producing tumors and also in rats infused continuously with gastrin (5, 31). In contrast, hypotrophic or atrophic mucosa results from fasting in rats whose serum gastrin levels become low (35). The glandular cell components, which include parietal, chief, and enterochromaffin-like (ECL) cells, have relatively long lifespans of 3, 5, and 2 mo, respectively (17). Thus the atrophic change induced by fasting in rats appears to be due mainly to a shortage of pit/gastric surface mucous cells that survive only 3 days in rodents (18). It is not known, however, whether the pit cells and their precursors express gastrin receptors.
The physiological roles of gastrin in mucosal growth were recently
studied using hypergastrinemic animal models. Wang et al. (45) produced transgenic (TG) mice expressing gastrin
under the control of an insulin promoter, which resulted in gastrin production in pancreatic -cells. They reported that gastrin enhances gastric mucosal growth, whereas progastrin preferentially stimulates colonic mucosal growth. They further demonstrated that hypergastrinemic TG mice develop gastric atrophy and eventually gastric cancer (44) and postulated that the hyperplasia of the foveolar
pit cell region and the decrease in the parietal cell mass are due, at
least in part, to gastrin-stimulated upregulation of growth factors,
including heparin binding-epidermal growth factor-like growth factor
(HB-EGF) and transforming growth factor-
(TGF-
). Moreover,
infection with Helicobacter felis accelerates the formation of gastric cancer in a synergistic manner with hypergastrinemia in
hypergastrinemic TG mice (44).
We generated TG mice with hypergastrinemia by expressing a human
gastrin transgene (19). The gastric mucosa of these mice was hypertrophic and characterized by an elongated pit with an active
proliferative zone, whereas the glandular region containing parietal
cells was reduced in size. The pit cells contained fewer mucous
granules than those of control littermates and were not reactive to the
pit cell-specific cholera toxin -subunit (CTB) lectin. Pit cells
along the foveolar region and many mucous neck cells were Alcian blue
positive, suggesting the presence of sialomucin. Thus gastrin promotes
the growth of gastric mucosa, especially in the pit region, whereas
mucosal cells have less-differentiated features.
Gastrin, CCK, and CCK-related peptides comprise a hormone family
characterized by identical COOH-terminal pentapeptide amide structures
and bind to two receptor subtypes: CCK-A receptors (CCKA-Rs) and
gastrin/CCK-B receptors (CCKB-Rs). CCKA-Rs exhibit a 500- to 1,000-fold
higher affinity for sulfated analogs of CCK than for gastrin, whereas
CCKB-Rs have approximately equal affinity for both sulfated and
nonsulfated peptide analogs of CCK and gastrin (32, 34, 46,
47). CCKB-Rs are present in parietal, ECL, and probably
somatostatin cells (2, 4, 23, 27, 28, 41). It is unknown,
however, whether the pit cells express CCKB-Rs, although many
investigators have examined gastrin binding on pit cells. There are
specific binding sites for [125I]gastrin on parietal,
chief, and ECL cells (2, 28). Immunohistochemical studies
have also demonstrated the distribution of CCKB-R in the same cell
types (41). On the other hand, Matsuda et al.
(23) reported no specific binding of
[125I]gastrin to guinea pig gastric epithelial cells in
culture, most of which displayed periodic acid-Schiff (PAS)-positive
granules, characteristic of pit cells. In the study by Reubi et al.
(30), a high concentration of CCKB-Rs was detected in the
midglandular region of the human fundic mucosa, although
[125I]gastrin-bound cell types were not identified due to
low magnification. Therefore, it remains to be investigated whether
gastrin promotes mucosal cell growth directly by stimulating pit cell
precursors in the proliferative zone or indirectly by stimulating
CCKB-R-expressing parietal and ECL cells to produce HB-EGF, TGF-,
and regenerating gene (Reg), which then stimulate the growth
of the pit cell precursors.
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MATERIALS AND METHODS |
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Animals.
We used 30- to 35-wk-old hypergastrinemic TG mice (ICR strain) in which
mutated human gastrin cDNA was introduced under the control of the
-actin promoter as we previously reported (19). Briefly, TG mice were generated by inducing mutated human gastrin cDNA
for which the peptide product contains two mutations. One mutation is a
processing site at the NH2 terminus of gastrin: -Asp-Pro-4-Ser-3-Lys-2-Lys-1
(native) was changed to
-Asp-Arg-4-Arg-3-Lys-2-Arg-1
(mutant). This tetrabasic site was efficiently cleaved by furin, which
is distributed in many cell types (48). The other mutation is at the COOH terminus of gastrin after glycine: the progastrin sequence was terminated after the glycine position by inserting a stop
codon. With these modifications, the mutated progastrin was efficiently
cleaved and amidated even in nonneuroendocrine cells (11).
The gastrin titer of hypergastrinemic TG mice homozygously expressing
gastrin cDNA was 5- to 10-fold higher than that of control mice.
Hypergastrinemic TG mice did not have elevated glycine-extended gastrin
(G-Gly) or unprocessed progastrin (19).
Morphological studies.
Experimental procedures for removing stomachs followed the guidelines
for animal experiments of Kyoto University. Briefly, stomach tissues
were removed from TG mice with hypergastrinemia (>400 pg/ml) and fixed
in 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4. Small pieces
of the sample underwent saccharose replacement and were then frozen for
microtome sectioning. Immunostaining was performed as previously
described (19). Parietal cells were identified by staining
with a monoclonal antibody to the rabbit H,K-ATPase -subunit
(16). The proliferative zone of the mouse gastric mucosa
was confirmed by staining with proliferating cell nuclear antigen
(PCNA) using a mouse monoclonal anti-PCNA antibody (DAKO Japan, Kyoto,
Japan). An LSAB2/HRP staining kit (DAKO Japan) was used as the
secondary antibody reaction system. Gastric pit cells were
visualized using fluorescein-5-isothiocyanate-labeled CTB lectin
(Sigma, St Louis, MO) binding as previously reported (6,
7).
In situ hybridization. In situ hybridization for CCKB-Rs was performed using the RNA Color Kit (Amersham Pharmacia Biotech, Buckinghamshire, UK). To obtain template cDNAs, total RNA was isolated from mouse gastric mucosa using Trizol reagent (GIBCO, Grand Island, NY), and first-strand cDNA was prepared by reverse transcription. Then PCR was performed using 5'-TGACAGCGAGACCCAAAGCC-3' and 5'-ATTCGCACCACCCGCTTCTT-3' for the mouse CCKB-R (255 bp). cDNA fragments were subcloned into the pGEM-T easy vector (Promega, Madison, WI). RNA probes were prepared in a reaction mixture containing fluorescein-labeled UTP and other NTPs from the template cDNA with SP6 RNA polymerase for an antisense strand probe and T7 RNA polymerase for a sense-strand probe. The RNA probes were heat denatured before use.
Tissue sections were mounted on a glass slide and treated with 0.02 M HCl for 10 min, followed by 0.2% acetic acid for 5 min, and then air dried before hybridization. The sections were incubated with a hybridization solution containing sense- or antisense-strand cRNAs at a concentration of 500 ng/ml at 55°C overnight. The sections were washed several times after hybridization for the second reaction with an anti-fluorescein antibody complexed with alkaline phosphatase at a dilution of 1:1,000 for 1 h. RNA probes were visualized with an alkaline phosphatase reaction using 5-bromo-4-chloro-3-indolyl phosphate and 4-nitroblue tetrazolium chloride.Cell culture studies.
We used a gastric surface mucous cell line, GSM06, derived from the pit
cells of mice expressing the temperature-sensitive SV40 large T-antigen
transgene (37). The cells grew to confluence at the
T-antigen-active temperature (33°C), whereas at the
T-antigen-inactive temperature (39°C), the cells ceased growing and
displayed differentiated features such as PAS-positive material,
secretory granules, and TGF- (20). Even if this cell
line is differentiated at 39°C and under high cell density
conditions, its features appear to be in a prepit cell stage, according
to the classification by Karam and Leblond (18). The cells
were cultured in DMEM/Ham's F-12 medium (GIBCO) containing 10% fetal
bovine serum (FBS; GIBCO) at 33°C in 5% CO2 on a
collagen type I-coated plastic plate (Iwaki, Tokyo, Japan) as
previously described (20).
RT-PCR. Expression of mouse CCKB-R mRNA was assessed by RT-PCR (Super Script Preamplification System, GIBCO) using 5'-CTTTGATGGTGATAATGACAGCGA-3' and 5'-GCACGTAGCAGCCATCACTGT-3' by amplifying the 155-bp DNA for the mRNA encoding a part of the third loop of CCKB-R (12, 46, 47). These primers also amplify the 349-bp genomic DNA for the same region including the 194-bp intron, which was used as a control. An amplified 155-bp DNA fragment underwent direct DNA sequencing for confirmation using the ABI PRISM Dye Terminator Cycle Sequencing FS Ready Reaction Kit (Perkin-Elmer, Norwalk, CT).
Receptor binding study.
To perform the in vitro gastrin binding experiment, we isolated the
membrane fraction from GSM06 cells preincubated in the presence or
absence of various peptides for 2 days at 33°C by homogenization and
centrifugation at 42,000 g for 15 min as reported previously
(27). The membrane fraction (1 mg) was labeled for 2 h at 24°C with 50 pM [125I]gastrin in the presence of
varying concentrations (1011 to 10
6 M) of
nonlabeled gastrin, CCK-8, or G-Gly.
Cell growth study.
GSM06 cells were inoculated on a 96-well plastic plate (Iwaki, Tokyo,
Japan) at a seeding density of 1,000 cells/well. Cells were incubated
for 24 h in DMEM/Ham's F-12 medium containing 10% FBS, followed
by 24 h culture in DMEM/Ham's F-12 medium containing 1% FBS.
Incubation was continued for 72 h with varying concentrations (1011 to 10
6 M) of gastrin, G-Gly, or CCK-8
in the presence or absence of the CCKB-R-specific antagonist S-0509
(10
8, 10
6, or 10
4 M; kindly
provided by Shionogi Pharmaceutical, Osaka, Japan). S-0509 has a
specific antagonizing effect on CCKB-R (1, 10, 33, 39).
Cell counting kit-8 (Dojindo Laboratory, Kumamoto, Japan) was used to
count cells based on the action of
2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-[2H]tetrazolium
monosodium salt, and the cell number was evaluated by measuring the
optical density at an absorbance of 450 nm (20).
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RESULTS |
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Characterization of the hypertrophied gastric mucosa in
hypergastrinemic TG mice.
The hypertrophic gastric mucosa of hypergastrinemic TG mice was
recently characterized, and the pit cells in the elongated pit were
found to have less-differentiated immature features (19). The present study further investigated the expression of CCKB-R. Immunostaining revealed that in control mice, PCNA-stained cells had a
scattered distribution approximately one-third of the way down the
gastric surface (Fig. 1A),
whereas they were densely located at the base of the elongated pit of
the hypergastrinemic TG mouse gastric glands (Fig. 1D). We
assessed the degree of differentiation of gastric surface pit cells
using gastric surface pit cell-specific binding lectin, CTB lectin.
There was positive staining for CTB lectin along the foveolar-facing
membrane of gastric pit cells in control mice (Fig. 1C). In
contrast, elongated pits of hypergastrinemic TG mice were only slightly
stained for CTB lectin, and the presence of lectin-positive pit cells
was limited to the top of the foveolar region. The PCNA-positive
elongated pits were negative for CTB lectin staining (Fig.
1F).
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Binding of [125I]gastrin in GSM06 cells.
We postulated that CCKB-R-positive cells over the proliferative zone of
the hypergastrinemic TG mouse mucosa are prepit cells and/or pit cell
precursors. Because immature pit cells do not have characteristic
features (18), it is difficult to identify those cell
types as a pit cell lineage. To circumvent this difficulty, we used the
mouse gastric mucous/pit cell-derived cell line GSM06 for
[125I]gastrin binding studies. Initially,
[125I]gastrin did not specifically bind to the membrane
fraction at either 33°C (a growing state) or 39°C (a growth arrest
state). When the cells were cultured at 33°C in the presence of
107 M gastrin for 48 h before the binding study,
[125I]gastrin bound specifically to the membrane
fraction. The binding of [125I]gastrin was competitively
inhibited by the addition of unlabeled gastrin in a dose-dependent
manner with a half-maximum inhibition obtained at approximately
10
8 M (Fig. 3). This
binding was similarly inhibited by CCK-8, indicating that this receptor
is shared by both gastrin and CCK. In contrast, G-Gly displaced the
specific binding only at 10
6 M. Thus gastrin upregulated
the expression of its own receptor in GSM06 cells (14).
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Detection of CCKB-R mRNA by RT-PCR in GSM06 cells.
The presence of CCKB-R mRNA in the cells was confirmed using RT-PCR.
One band with a predicted size of 155 bp was detected, which increased
in density with incubation with 107 M gastrin for up to
48 h, whereas the genomic DNA-derived 349-bp band remained
constant (Fig. 4A). By
analyzing the DNA sequence of the 155-bp transcript, we obtained a
mouse amino acid sequence homologous, with only minor differences, to
receptors of the rat, Mastomys, and human (Fig. 4B)
(12). This partial sequence completely matched the mouse
receptor sequence deposited in the GenBank (accession #AF019371).
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Growth stimulatory effect of gastrin on GSM06 cells.
We then examined the effect of gastrin on the growth of GSM06 cells.
Both gastrin and CCK-8 dose dependently increased the growth of the
cells (Fig. 5A). G-Gly had no
effect on growth, which is consistent with the results shown in Fig. 3.
The growth effect of gastrin on GSM06 cells was completely abolished by
the CCKB-R-specific antagonist S0509 (Fig. 5B).
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DISCUSSION |
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We previously demonstrated that the hypertrophic gastric mucosa of hypergastrinemic TG mice comprised an elongated pit with an active proliferative zone and that the glandular region containing parietal cells was relatively reduced in size (19). In the elongated pit, pit cells displayed less-differentiated features. For example, they showed less binding to pit cell-specific CTB lectin, although the pit region was extensively elongated. In previous studies, CCKB-Rs were localized in parietal, chief, and ECL cells (28, 41). Thus the CCKB-R-positive cells in the lower glands in control mice appear to be a mixture of these cells. In contrast, CCKB-R-positive cells were prominent in the midglandular region of the hypergastrinemic TG mouse mucosa, where PCNA-positive cells were most abundant. In our previous study, electron microscopy revealed that these cells contain various sizes of granules and enlarged endoplasmic reticulums, which actively produce secretory proteins. Moreover, morphological study with a light microscope indicated that these cells are oval in shape and smaller than parietal cells (19). Thus, although these cells were negative for staining with pit cell-specific CTB lectin, the CCKB-R-positive and PCNA-positive cells in the midglandular region of hypergastrinemic TG mice in our present study appear to be prepit cells.
To examine CCKB-R expression in the pit cell lineage, we used the
GSM06 cell line as a pit cell line model in vitro. The GSM06 cell line
is derived from the gastric surface mucous cells of a TG mouse that was
transformed with the temperature-sensitive SV40 T antigen DNA
(37). Morphologically, GSM06 cells are rounded or
polyhedral, as is typical of primary cultured gastric surface mucous
cells (3, 8, 24, 42). Electron microscopy revealed that
the cells contain a small number of secretory granules (20, 38). Immunologic studies indicate that the GSM06 cells are
positive for PAS and class I concanavalin A but negative for H,K-ATPase and class III concanavalin A (37). These morphological and
immunologic studies revealed that GSM06 cells display features similar
to immature pit cells, perhaps corresponding to those at a prepit stage
(18, 37). We initially failed to detect specific
[125I]gastrin binding to the membrane fraction of GSM06
cells. Because Johnson (14) and Takeuchi et al.
(40) reported that gastrin stimulation increases the
expression of its own receptor, we precultured the cells with
107 M gastrin for 48 h, then performed an
[125I]gastrin binding study. With this gastrin
pretreatment, we detected specific binding of
[125I]gastrin on GSM06 cell membranes, which was
competitively inhibited by an increase in exogenous gastrin and CCK-8.
Furthermore, we confirmed the increase of CCKB-R expression by gastrin
stimulation using RT-PCR (Fig. 4A). Takeuchi et al.
(40) suggested two possible mechanisms for the increase in
CCKB-R expression by gastrin. First, gastrin might stabilize
its receptors, preventing receptor degradation. Second, gastrin
stimulates the synthesis of its own receptors (40).
Consistent with the binding studies, both gastrin and CCK-8 dose
dependently increased the growth of GSM06 cells, which was abolished by
a CCKB-R-specific antagonist S0509. Thus gastrin enhanced expression of
its own receptors in GSM06 cells, leading to augmented cell growth by
gastrin. Our in vitro data are consistent with our in vivo experiments,
in which long-lasting hypergastrinemia induced CCKB-R expression in the
midglandular region in association with increased proliferative
activity in the hypergastrinemic TG mouse gastric mucosa. Although we
did not detect CCKB-R expression in the proliferative zone of the
control mice, the cells in the proliferative zone might also express a
small amount of CCKB-Rs and their growth might normally be regulated by gastrin.
In our study, the growth curve induced by gastrin reached its peak at a relatively high concentration of gastrin and the displacement curve indicates a high Kd value compared with previous reports (22, 29, 36). Iwase et al. (13) reported almost the same displacement curve for labeled gastrin as ours using gastric mucosal cell lines AGS and SIIA. Although the precise reason for the difference in binding characteristics remains unknown at present, it might be due to differences in cell character.
CCKB-R expression is evident in parietal cells and ECL cells;
therefore, gastrin-induced mucosal cell growth is thought to be
mediated by parietal cells and/or ECL cells (9, 25, 26, 43). Parietal cells produce HB-EGF (26), and
recently, Miyazaki et al. (25) demonstrated that gastrin
induces the expression of HB-EGF mRNA and the secretion of a mature
form of HB-EGF into the culture medium using a rat pit cell line RGM-1
when CCKB-R was expressed in this cell line. Therefore, they
hypothesized that the gastrin-induced growth of gastric mucosa is
mediated by parietal cells, which possess CCKB-R and produce HB-EGF.
Fukui et al. (9) demonstrated that gastrin stimulates the
production of Reg protein from ECL cells. Reg protein has been isolated
from regenerating rat pancreatic islets (43) and
stimulates the growth of cultured rat gastric epithelial cells
(9). Recently, Wang et al. (44) reported that
human gastrin-expressing TG mice had initial mild hypergastrinemia with
an increased number of parietal cells, then later had a decreased
parietal cell mass in association with increased expression of HB-EGF
and TGF- in the hypertrophied mucosa. At 20 mo of age, the mice
exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric
cancer. Interestingly, Helicobacter felis infection
accelerated the size and invasiveness of gastric cancer. Wang et al.
(44) hypothesized that hypergastrinemia eventually induces
gastric atrophy and enhances the production of HB-EGF and TGF-
,
which, in turn, induce a malignant change in the atrophic gastric
mucosa. These data suggest that gastrin-induced growth of gastric
mucosa is mediated by gastrin-stimulated growth factors such as HB-EGF,
TGF-
, and Reg protein. As demonstrated in our previous and present
studies, the gastric mucosa of the TG mice with long-lasting
hypergastrinemia contains a reduced number of parietal cells and ECL
cells, and the CCKB-R expression in these cells is considerably
reduced. Thus it is possible that long-lasting hypergastrinemia
upregulates the CCKB-R expression in prepit cells and/or pit cell
precursors, eventually leading to the elongation of gastric pits with
less-differentiated features directly through its receptors on those cells.
Hypergastrinemia is frequently associated with both types A and B atrophic gastritis. Gastric cancer usually develops from atrophied mucosa, which leads to the hypotheses that atrophic gastritis is a precancerous lesion and that elevated gastrin induces the initiation of gastric cancer (44). This hypothesis is supported by the fact that the mucosal cells of atrophic gastritis exhibit more mitotic activity than those in healthy individuals (21). An important question is whether these mitotic cells are derived from a CCKB-R-expressing pit cell lineage.
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ACKNOWLEDGEMENTS |
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We are grateful to E. Hamana for secretarial assistance.
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FOOTNOTES |
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This work is supported by the grant-in-aid for scientific research from the Ministry of Education, Science, Culture, and Sports of Japan and the grant-in-aid for research for the future program from the Japanese Society for the Promotion of Science (JSPS-RFTF97100201).
Address for reprint requests and other correspondence: T. Takeuchi, Dept. of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma Univ., 3-39-15, Showa-machi, Maebashi 371-8512, Japan (E-mail tstake{at}showa.gunma-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00117.2001
Received 21 March 2001; accepted in final form 24 September 2001.
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