Gastrointestinal Surgical Pathobiology Research Group, Yale University School of Medicine and the West Haven Veterans Affairs Medical Center, New Haven, Connecticut 06520-8062
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ABSTRACT |
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We have previously demonstrated that in
Mastomys species proliferation of gastric
enterochromaffin-like (ECL) cells is predominantly regulated by gastrin
and by transforming growth factor- (TGF-
) in the naive and
neoplastic state, respectively. In this study we examined whether these
intracellular mitogenic responses are mediated by polyamines and
ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine
biosynthesis. An ECL cell preparation of high purity was used to
measure the effect of the polyamine derivatives putrescine, spermidine,
and spermine on DNA synthesis by bromodeoxyuridine uptake. Both
putrescine and spermidine augmented gastrin-stimulated, but not basal,
DNA synthesis in naive cells. This proliferative response correlated
with an increase in ODC activity that was partially inhibited (20%) by
difluoromethylornithine (DFMO), an inhibitor of ODC
(IC50, 30 pM). In
contrast, all polyamines increased both basal and TGF-
-stimulated
DNA synthesis as well as ODC activity in tumor ECL cells. DFMO
completely inhibited the proliferative response of TGF-
(IC50, 3 pM). Thus polyamine biosynthesis is involved in proliferation of ECL cells and in particular the mitogenesis of tumor cells, suggesting a role for this
pathway in the regulation of ECL cell transformation.
gastrin; ornithine decarboxylase; transforming growth factor-
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INTRODUCTION |
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THE AFRICAN RODENT Mastomys is genetically
susceptible to spontaneous gastric carcinoid (ECLoma) development and,
depending on the breeding strain, between 40 and 50% of the animals
have such lesions by 2 yr of age (16). Inhibition of parietal cell acid
secretion via irreversible H2
receptor blockade (loxtidine) results in an elevation in serum gastrin
levels which is sustained for the duration of the
treatment. Enterochromaffin-like (ECL) cell hyperplasia is
evident at 8 wk and neoplasia at 16 wk in ~80% of the animals (16,
17). Hypergastrinemia seems requisite for ECL cell hyperplasia, and
cell transformation is related both to the level and the duration of
hypergastrinemia (7, 13). However, cell growth subsequently becomes
autonomous of the gastrin stimulation. We have previously characterized
this gastrin-independent state as neoplasia or ECL cell transformation
(16, 17). In addition, we have demonstrated that transforming growth
factor- (TGF-
) becomes one of the regulatory mechanisms of
proliferation during cell transformation via an autocrine pathway (27).
This suggests that gastrin is important as an initiator of ECL cell replication, which is thereafter driven by a growth factor-mediated cascade.
In vitro studies with purified ECL cells isolated either from untreated
or loxtidine-treated (8 wk) animals indicate that gastrin is the most
potent activator of DNA synthesis in naive and hyperplastic cells. It
has little effect in transformed cells, whereas TGF- is most potent
in transformed cells, with minimal effect in naive cells (27). TGF-
mediates the mitogenic effect via a process that involves protein
tyrosine phosphorylation of the TGF-
epidermal growth factor
receptor, whereas gastrin activates the cellular second messenger
signal transduction system by activation of a receptor-linked
GTP-binding protein and subsequent protein phosphorylation. The
postreceptor events involved in the cascade of intracellular mechanisms
by which either gastrin or TGF-
activates ECL cell DNA synthesis are
unknown.
Polyamine biosynthesis is a tightly regulated, ubiquitous eukaryotic cellular phenomenon, which is responsible for mediating growth responses to most agents stimulating cell growth, including gastrin and growth factors (24). The rate-limiting enzyme in polyamine synthesis is ornithine decarboxylase (ODC), which catalyzes the formation of putrescine from ornithine via decarboxylation. Thereafter, spermidine and spermine, respectively, are derived from putrescine by a series of aminopropyltransferase steps. Polyamine homeostasis is a dynamic, nonlinear process which comprises synthesis, interconversion, and uptake from extracellular sources. Decreases in intracellular polyamine concentrations by the competitive addition of difluoromethylornithine (DFMO) result both in a decrease in DNA synthesis as well as in an increase in polyamine uptake (12, 29). An increase in polyamine uptake often, but not always, results in a decrease in ODC activity (18). Polyamines are especially evident in rapidly proliferating cells and tissues such as developing embryos and tumors, which have higher putrescine and spermidine concentrations than nongrowing tissues (24). These positively charged amines alter DNA conformation and catalyze nucleosome condensation, effects considered to be of importance in establishing the conditions necessary for DNA synthesis (1, 2). In addition, increases in ODC activity and polyamine synthesis are evident in cells in the G1 phase of the cell division cycle (24), further supporting the critical role for ODC activity in cell proliferation.
In the gastrointestinal tract, previous immunocytochemical studies of
gastric epithelia suggest that ODC is present in mucous neck cells and
is colocalized with mucus (6, 11). In contradistinction, polyamine
immunostaining indicates that the secretory granules of gastric chief
cells are most strongly reactive for polyamine antiserum (8). The
effect of gastrin on mucous cells appears to be partially mediated by
the polyamine pathway (15), but the role of this pathway in mediating
gastric endocrine ECL cell proliferation has not previously been
identified. We hypothesized that polyamines and ODC activity might
serve as a common intracellular mechanism in modulating the ECL cell
proliferative response mediated by gastrin or TGF-. To investigate
this we examined the effect of polyamine derivatives on DNA synthesis
and the correlation between ODC activity and cell proliferation in both
naive or transformed ECL cells.
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MATERIALS AND METHODS |
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Materials
All chemicals, including polyamine derivatives and experimental buffers, were obtained from Sigma Chemical (St. Louis, MO) or were of the highest quality available. Loxtidine, an irreversible H2 blocker, was a kind gift of Glaxo (Ware, UK), human gastrin-17 and rat TGF-Animals
All animals for these studies were bred from the Mastomys colony (Modlin/Yale) maintained at the West Haven Department of Veterans Affairs Medical Center. The animals were maintained in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Animals with equal sex distribution were randomly assigned to receive either water (control group) or loxtidine (1 mg · kgIsolation of ECL Cells
Naive Mastomys ECL cells were prepared by a recalibration of the method of Prinz et al. (20), as previously reported by us (27). For each preparation, 8-10 nonfasting Mastomys (80-100 g) were used (n = 1). Mastomys tumor ECL cells were prepared as previously described (27). From each loxtidine-treated Mastomys (n = 1), macroscopic carcinoids, mainly free of other gastric mucosal cells, were isolated and minced by hand, and individual cells released by Pronase (1 mg/ml) and collagenase (1 mg/ml) digestion. Cells were either immediately used in ODC assays or cultured in growth medium (DMEM and F-12, 2% FCS, 0.5 mg/ml insulin-transferrin-sodium selenite, 10 nM hydrocortisone, 0.1 mg/100 ml gentamicin, pH 7.4) at a final concentration of 105 cells/ml, 100 µl/well.Cell Proliferation Assay by BrdU Incorporation
After 24 h in culture (96-well collagen-I coated plate, 104 cells/well), medium was aspirated and replaced with culture medium containing BrdU [prediluted labeling reagent (1:200), Amersham] and the indicated agent as previously described (27). After incubation for an additional 24 h, the medium was removed and the cells were fixed at 4°C in 90% ethanol-5% acetic acid-5% water and then washed in 0.1% Tween 20 in PBS (11.5 mg/ml Na2HPO4, 3 mg/ml NaH2PO4, 5.8 mg/ml NaCl, pH 7.4). The wells were incubated with anti-BrdU antibody with nuclease (1:400, Amersham) for 60 min at room temperature and, after three washes, incubated with rabbit anti-mouse IgG conjugated to horseradish peroxidase (1:800, Amersham) for 30 min at 20°C. After a further three washes, wells were incubated with substrate (30 mg o-phenylenediamine dihydrochloride in citrate-phosphate buffer, pH 4.12), and optical density was determined at 405 nm by spectrophotometry (Bio-Rad microplate reader model 450). Results are expressed as optical density units (405 nm), and final results are expressed as the ratio of means ± SE to control.Evaluation of ODC Activity
Freshly isolated cells (105/100 µl culture medium) were incubated with or without gastrin (naive) or TGF-Experimental Design
Naive cells.
An isolated, purified preparation of naive Mastomys ECL
cells was used in all experiments (27). To evaluate an effect on DNA
synthesis, we incubated cells with either gastrin, putrescine, spermidine, or spermine alone
(1012-10
6
M), or with a combination of each polyamine
(10
12-10
6
M) and a maximal concentration of gastrin
(10
8 M) for 24 h. To
examine whether the combined effect of polyamines and gastrin was
mediated via ODC, we next investigated the effect of the irreversible
ODC inhibitor DFMO on gastrin
(10
8 M)-stimulated DNA
synthesis. Thereafter we determined the effect of gastrin
(10
10-10
6
M) on the activity of this enzyme using a radiometric technique to
measure the formation of
14CO2
from [14C]ornithine.
Tumor cells.
An isolated, purified preparation of Mastomys tumor ECL
cells was used in all experiments (27). To evaluate an effect on DNA
synthesis, we incubated cells with either TGF-, putrescine, spermidine, or spermine alone
(10
12-10
6
M) or with a combination of each polyamine
(10
12-10
6
M) and a maximal concentration of TGF-
(10
9 M) for 24 h. To
examine whether the effect of polyamines and TGF-
was mediated via
ODC, we next evaluated the effect of DFMO on TGF-
(10
9 M)-stimulated DNA
synthesis. Thereafter we evaluated the effect of TGF-
(10
13-10
9
M) on the activity of this enzyme using a radiometric technique. In
addition, to examine whether gastrin had an effect on tumor cells we
evaluated the ability of this agent
(10
11-10
7
M) to alter ODC activity.
Statistical Evaluation
Results are expressed as means ± SE. The number of ECL cell preparations is indicated by n. Statistical analysis was performed using the two-tailed Student's t-test for paired values as appropriate, and P < 0.05 were considered significant. ![]() |
RESULTS |
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Naive ECL Cells
Effect of polyamines on DNA synthesis.
We initially undertook to measure the effect of putrescine, spermidine,
and spermine on basal and stimulated ECL cell DNA synthesis. None of
the polyamines alone (up to 1 µM) significantly altered basal DNA
synthesis over the 24-h experimental period (Fig.
1). However, both putrescine and spermidine
augmented the stimulatory effect of gastrin
(108 M), with estimated
EC50 values of 8 × 10
10 M and 2 × 10
9 M, respectively (Fig.
1). In contrast, spermine had no detectable effect.
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Effect of DFMO on DNA synthesis.
We next measured the effect of the irreversible ("suicide") ODC
inhibitor DFMO on basal and stimulated DNA synthesis. As in previous
experiments, incubation with gastrin
(108 M) significantly
(P < 0.01) stimulated DNA synthesis.
DFMO alone did not significantly alter basal DNA synthesis at
concentrations up to 1 µM (Fig. 2).
Pretreatment of the cells for 30 min with this agent resulted in a
partial inhibition (~20%) of gastrin-stimulated DNA synthesis. This
effect, albeit biphasic, was significant between concentrations of
10
9 and
10
6 M
(P < 0.05).
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Gastrin stimulation of DNA synthesis and ODC activity.
To evaluate the relationship between gastrin-altered ECL cell DNA
synthesis and ODC activity we measured the effect of this mitogen both
in cultured cells and in acutely isolated naive ECL cells. Gastrin
stimulated DNA synthesis over 24 h, with an estimated EC50 of 5 × 1011 M and a maximal
response of 2.6 ± 0.4 of the control value. Similarly, gastrin
stimulated ODC activity with an estimated
EC50 of 3 × 10
10 M and a maximal
response of 1.55 ± 0.03 of the control value (P < 0.01; Fig.
3). The specificity of the
gastrin-stimulated ODC activity response was determined when
preincubation of cells with DFMO
(10
8 M) for 30 min reversed
the stimulatory effect of this agent
(10
9 M; data not shown).
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Tumor ECL Cells
Effect of polyamines on DNA synthesis.
We initially undertook to measure the effect of putrescine, spermidine,
and spermine on basal and stimulated ECL cell DNA synthesis. All of the
polyamines significantly increased (~30%) basal DNA synthesis over
the 24-h experimental period (Fig.
4A). The estimated EC50 values were 3 × 1012 M for
putrescine and 2 × 10
10 M for spermidine and
spermine, respectively. In addition, all of the polyamines
significantly augmented (~40%) the stimulatory effect of TGF-
(10
9 M; Fig.
4B). The estimated
EC50 values were 2 × 10
11 M for putrescine, 2 × 10
10 M for
spermidine, and 3 × 10
10 M for spermine,
respectively
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Effect of DFMO on DNA synthesis.
We next measured the effect of DFMO on basal and stimulated DNA
synthesis. As in previous experiments incubation with TGF- (10
9 M) significantly (1.58 ± 0.02, P < 0.01) stimulated DNA
synthesis (Fig. 5). DFMO alone did not have
a substantial inhibitory effect on basal DNA synthesis (Fig. 5), but
pretreatment of the cells for 30 min with this agent dose dependently
inhibited TGF-
(10
9
M)-stimulated DNA synthesis with an
IC50 of ~3 × 10
12 M and a maximal
inhibition of ~90% at
10
9 M (1.07 ± 0.15, P < 0.05 vs. TGF-
).
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TGF- stimulation of DNA synthesis and ODC activity.
We then measured the effect of TGF-
on DNA synthesis and ODC
activity in ECL tumor cells. TGF-
stimulated DNA synthesis over 24 h
with an estimated EC50 of 5 × 10
12 M and a
maximal concentration of
10
10 M (1.92 ± 0.14, P < 0.01, Fig.
6). TGF-
stimulated ODC activity with an
estimated EC50 of 3 × 10
12 M and a maximal
concentration of 10
11 M
(1.5 ± 0.08, P < 0.01).
Pretreatment of the cells for 30 min with DFMO
(10
8 M) reversed the
stimulatory effect of TGF-
(10
11 M) on ODC activity
(1.17 ± 0.07, P < 0.05 vs.
TGF-
alone; data not shown). Gastrin had no effect on tumor ECL cell
ODC activity (data not shown). This is consistent with our previous
observation that the effect of gastrin on tumor cell DNA synthesis is
negligible (27).
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DISCUSSION |
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The gastric endocrine ECL cell plays a critical role in the regulation
of gastric exocrine function. Of particular pathological significance
is the self-replicative nature of ECL cells under long-term
hypergastrinemia in Mastomys and rats (27). Gastrin as a
physiological hormone promotes cell proliferation, and sustained hypergastrinemia may culminate in ECL cell hyperplasia and neoplasia (7, 27). The loss of gastrin "control" is associated with the
involvement of alternative growth regulatory mechanisms, such as a
TGF- autocrine pathway (27). Although gastrin and TGF-
activate
different postreceptor second messenger systems, it is not known
whether they share a common downstream intracellular denominator which
is involved in activation of DNA synthesis process.
Consistent with our hypothesis, we have demonstrated for the first time
that polyamine biosynthesis is involved in both gastrin and
TGF--mediated cell proliferative response in a purified gastric endocrine ECL cell population, and in addition we have delineated the
relationship between DNA synthesis and ODC activity and these stimuli.
Previous investigations attempted to measure ODC activity in whole
mucosal homogenates to stimuli which activate ECL cells (omeprazole,
antrectomy, gastrin infusion). Unfortunately these studies cannot
identify the precise cell source (3, 15). Indeed, because the ECL cell
is only ±1% of the total mucosal mass, it is possible that these
studies would not reliably detect changes in this cell population.
Addition of polyamines to a population of purified naive ECL cells had no effect on DNA synthesis. Naive ECL cells have a relatively long dividing time in vivo, ~60 days in the mouse (28), and in vitro, gastrin typically activates only ±20% of cells to take up and incorporate BrdU over a 24-h period (20). The combination of these observations suggests that there are relatively few mitogenic-sensitive cells in the late G1 phase. The lack of effect of polyamines on basal DNA synthesis may reflect either no uptake of these agents or a minimal mitogenic effect which is not detectable by the method of BrdU uptake. In contrast, cells stimulated by gastrin were responsive to polyamines. Thus both putrescine and spermidine amplified the effect of gastrin on BrdU incorporation by ~40%. The lack of effect of spermine may reflect the fact that it is an intracellular end-derivative of polyamines and poorly taken up by cells (21). We then explored the relationship between ODC activity and DNA synthesis in ECL cells. As might be predicted gastrin stimulated ODC activity as well as DNA synthesis in naive ECL cells. The effect of gastrin on BrdU uptake was biphasic, as has been previously demonstrated (20, 27). The nonparallel relationship between DNA synthesis and ODC activation suggests that additional mechanisms are, however, involved in gastrin-stimulated DNA synthesis. The partial inhibition of gastrin-stimulated DNA synthesis by DFMO, an ODC inhibitor, would seem to confirm that the trophic effect of this agent is only partly mediated via a polyamine-regulated pathway. However, it is possible that at high concentrations, DFMO perturbs other cellular events or, alternatively, that compensatory polyamine uptake occurs which may account for the partial inhibitory effect of this agent in naive cells.
Time-dependent gastrin-stimulated ODC activity has previously been reported both in the pancreatic cell line AR42J (22, 26) and colonic mucosal explants (14). Activation of the gastrin receptor in these cells is coupled to ODC activity via protein kinase C (26). In colonic cells, the effect of gastrin on ODC was preceded by an initial increase in tyrosine kinase activity which could be abolished by genistein, a protein tyrosine kinase inhibitor (30). These results indicate that gastrin activation of ODC is mediated via upstream protein phosphorylation. The mechanism by which gastrin mediates ODC activity in ECL cells is unknown but may involve at least the tyrosine kinase pathway, given that genistein has been demonstrated to abolish the effect of gastrin on DNA synthesis (23).
Polyamines are typically overexpressed by most types of cancer (24),
and alterations in polyamine homeostasis (by the addition of DFMO) have
previously been demonstrated to result in growth inhibition of a
pancreatic "carcinoid" cell line (BON) (4). Because addition of
polyamines to carcinoid tumor ECL cells resulted in stimulation of
basal DNA synthesis (~30%) it seems probable that polyamines have a
direct mitogenic effect on tumor ECL cells. Interestingly, in contrast
to naive cells, spermine stimulated tumor cell DNA synthesis,
suggesting that either direct uptake of this agent occurs in tumor
cells or an alternative biochemical pathway is operative. Of particular
interest was the observation that the mitogenic effect of TGF- was
significantly augmented by all tested polyamines. This is consistent
with previous observations that growth factors increase both polyamine
uptake, as well as intracellular polyamine concentrations and DNA
synthesis (5, 19, 25). The effect of polyamines both on stimulated
naive cells and tumor cells appears to be comparable. In contrast to naive cells, preincubation with DFMO completely inhibited
TGF-
-stimulated DNA synthesis. This suggests that the
TGF-
-mediated pathway is largely driven via ODC activity and
polyamine biosynthesis and may be a reflection that tumor cells,
because of their high proliferative rate, are more dependent on
polyamine biosynthesis than their normal counterparts. This is
consistent with our observations that inhibition of ODC activity by
DFMO culminates in virtual abolition of DNA synthesis in transformed
ECL cells, but only a partial inhibition of nontransforming ECL cell
proliferation. This observation is similar to reports that quiescent
fibroblasts, fibroblast growth factor, and platelet-derived growth
factor all stimulate ODC activity through at least one pathway
involving protein kinase C (9). It was unexpected that DFMO had no
effect over 24 h on basal DNA synthesis. This may reflect the fact that ECL cells are well differentiated and are not rapidly proliferating.
In addition, TGF- stimulated tumor ECL cell ODC activity with an
EC50 of 3 × 10
12 M, a value consistent
with that of the effect on tumor cell DNA synthesis
(5 × 10
12 M). This supports
the conclusion that the proliferative effect of TGF-
is mediated
almost exclusively by this pathway in ECL tumor cells. This proposal is
further strengthened by the observation that DFMO completely inhibits
TGF-
-stimulated DNA synthesis.
In summary, we have demonstrated that the activity of the dominant
trophic factor of the naive ECL cell, gastrin, appears to be only
partially mediated by polyamine biosynthesis. In contrast, TGF--regulated proliferation of the transformed ECL cells appears to
be significantly mediated via the ODC pathway. Although the primary
mechanism by which gastrin mediates cell proliferation requires further
investigation, the observation that polyamine homeostasis is
substantially involved in tumor ECL cell proliferation, while not being
unexpected, suggests a major role for growth factor-dependent tyrosine
kinases in the regulation of ECL cell transformation.
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ACKNOWLEDGEMENTS |
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This work was supported by Veterans Administration Merit Award to I. M. Modlin and the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-48820 to L. H. Tang.
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FOOTNOTES |
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Address for reprint requests: I. M. Modlin, Yale Univ. School of Medicine, 333 Cedar St., PO Box 208062, New Haven, CT 06520-8062.
Received 25 August 1997; accepted in final form 14 April 1998.
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