CCK2 receptor antagonists: pharmacological tools to study the gastrin-ECL cell-parietal cell axis

Gastrin-recognizing CCK2 receptors are expressed in parietal cells and in so-called ECL cells in the acid-producing part of the stomach. ECL cells are endocrine/paracrine cells that produce and store histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. The ECL cells are the principal cellular transducer of the gastrin-acid signal. Activation of the CCK2 receptor results in mobilization of histamine (and pancreastatin) from the ECL cells with consequent activation of the parietal cell histamine H2 receptor. Thus, release of ECL-cell histamine is a key event in the process of gastrin-stimulated acid secretion. The oxyntic mucosal histidine decarboxylase (HDC) activity and the serum pancreastatin concentration are useful markers for the activity of the gastrin-ECL cell axis. Powerful and selective CCK2 receptor antagonits have been developed from a series of benzodiazepine compounds. These agents are useful tools to study how gastrin controls the ECL cells. Conversely, the close control of ECL cells by gastrin makes the gastrin-ECL cell axis well suited for evaluating the antagonistic potential of CCK2 receptor antagonists with the ECL-cell HDC activity as a notably sensitive and reliable parameter. The CCK2 receptor antagonists YF476, YM022, RP73870, JB93182 and AG041R were found to cause prompt inhibition of ECL-cell histamine and pancreastatin secretion and synthesis. The circulating pancreastatin concentration is raised, was lowered when the action of gastrin on the ECL cells was blocked by the CCK2 receptor antagonists. These effects were associated with inhibition of gastrin-stimulated acid secretion. In addition, sustained receptor blockade was manifested in permanently decreased oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and CGA mRNA concentrations. CCK2 receptor blockade also induced hypergastrinemia, which probably reflects the impaired gastric acid secretion (no acid feedback inhibition of gastrin release). Upon withdrawal of the CCK2 receptor antagonists, their effects on the ECL cells were readily reversible. In conclusion, gastrin mobilizes histamine from the ECL cells, thereby provoking the parietal cells to secrete acid. While CCK2 receptor blockade prevents gastrin from evoking acid secretion, it is without effect on basal and vagally stimulated acid secretion. We conclude that specific and potent CCK2 receptor antagonists represent powerful tools to explore the functional significance of the ECL cells.     

Physiological significance of ECL-cell histamine.

In the oxyntic mucosa of the mammalian stomach, histamine is stored in ECL cells and in mucosal mast cells. In the rat, at least 80 percent of oxyntic mucosal histamine resides in the ECL cells. Histamine is a key factor in the regulation of gastric acid secretion. Following depletion of ECL-cell histamine by treatment with alpha-fluoromethylhistidine (alpha-FMH), basal acid secretion was reduced, and gastrin-stimulated acid secretion was abolished. Vagally-induced acid secretion (by insulin injection or pylorus ligation) was unaffected by alpha-FMH treatment but inhibited by an H2 antagonist. These results suggest that gastrin stimulates acid secretion via release of ECL-cell histamine, whereas vagally-induced acid secretion--although histamine-dependent--does not rely on ECL-cell histamine. Gastrin is known to have a trophic effect on the oxyntic mucosa. By combining long-term hypergastrinemia with continuous infusion of alpha-FMH, we were able to show that gastrin-evoked trophic effects in the stomach do not depend on ECL-cell histamine.     

Differentiation of the gastric mucosa. I. Role of histamine in control of function and integrity of oxyntic mucosa: understanding gastric physiology through disruption of targeted genes

Many physiological functions of the stomach depend on an intact mucosal integrity; function reflects structure and vice versa. Histamine in the stomach is synthesized by histidine decarboxylase (HDC), stored in enterochromaffin-like (ECL) cells, and released in response to gastrin, acting on CCK(2) receptors on the ECL cells. Mobilized ECL cell histamine stimulates histamine H(2) receptors on the parietal cells, resulting in acid secretion. The parietal cells express H(2), M(3), and CCK(2) receptors and somatostatin sst(2) receptors. This review discusses the consequences of disrupting genes that are important for ECL cell histamine release and synthesis (HDC, gastrin, and CCK(2) receptor genes) and genes that are important for "cross-talk" between H(2) receptors and other receptors on the parietal cell (CCK(2), M(3), and sst(2) receptors). Such analysis may provide insight into the functional significance of gastric histamine.     

Role of gastrin in the development of gastric mucosa,ECL cells and A-like cells in newborn and young rats

Histamine-producing ECL cells and ghrelin-producing A-like cells are endocrine/paracrine cell populations in the acid-producing part of the rat stomach. While the A-like cells operate independently of gastrin, the ECL cells respond to gastrin with mobilization of histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. Gastrin is often assumed to be the driving force behind the postnatal development of the gastric mucosa in general and the ECL cells in particular. We tested this assumption by examining the oxyntic mucosa (with ECL cells and A-like cells) in developing rats under the influence of YF476, a cholecystokinin-2 (CCK(2)) receptor antagonist. The drug was administered by weekly subcutaneous injections starting at birth. The body weight gain was not affected. Weaning occurred at days 15-22 in both YF476-treated and age-matched control rats. Circulating gastrin was low at birth and reached adult levels 2 weeks after birth. During and after weaning (but not before), YF476 greatly raised the serum gastrin concentration (because of abolished acid feedback inhibition of gastrin release). The weight of the stomach was unaffected by YF476 during the first 2-3 weeks after birth. From 4 to 5 weeks of age, the weight and thickness of the gastric mucosa were lower in YF476-treated rats than in controls. Pancreastatin-immunoreactive cells (i.e. all endocrine cells in the stomach) and ghrelin-immunoreactive cells (A-like cells) were few at birth and increased gradually in number until 6-8 weeks of age (control rats). At first, YF476 did not affect the development of the pancreastatin-immunoreactive cells, but a few weeks after weaning, the cells were fewer in the YF476 rats. The ECL-cell parameters (oxyntic mucosal histamine and pancreastatin concentrations, the histidine decarboxylase (HDC) activity, the HDC mRNA levels and serum pancreastatin concentration) increased slowly until weaning in both YF476-treated and control rats. From then on, there was a further increase in the ECL-cell parameters in control rats but not in YF476 rats. The postnatal development of the ghrelin cells (i.e. the A-like cells) and of the A-like cell parameters (the oxyntic mucosal ghrelin concentration and the serum ghrelin concentrations) was not affected by YF476 at any point.We conclude that gastrin affects neither the oxyntic mucosa nor the endocrine cells before weaning. After weaning, CCK(2) receptor blockade is associated with a somewhat impaired development of the oxyntic mucosa and the ECL cells. While gastrin stimulation is of crucial importance for the onset of acid secretion during weaning and for the activation of ECL-cell histamine formation and secretion, the mucosal and ECL-cell growth at this stage is only partly gastrin-dependent. In contrast, the development of the A-like cells is independent of gastrin at all stages.     

Effect of cholecystokinin-2 receptor blockade on rat stomach ECL cells

The ECL cells in the oxyntic mucosa of rat stomach produce histamine and chromogranin A-derived peptides such as pancreastatin. The cells respond to gastrin via cholecystokinin-2 (CCK2) receptors. A CCK2 receptor blockade was induced by treatment (for up to 8 weeks) with two receptor antagonists, YM022 and YF476. Changes in ECL-cell morphology were examined by immunocytochemistry and electron microscopy, while changes in ECL cell-related biochemical parameters were monitored by measuring serum pancreastatin and oxyntic mucosal pancreastatin, and histamine concentrations, and histidine decarboxylase (HDC) activity. The CCK2 receptor blockade reduced the ECL-cell density only marginally, if at all, but transformed the ECL cells from slender, elongated cells with prominent projections to small, spherical cells without projections. The Golgi complex and the rough endoplasmic reticulum were diminished. Secretory vesicles were greatly reduced in volume density in the trans Golgi area. Circulating pancreastatin concentration and oxyntic mucosal HDC activity were lowered within a few hours. Oxyntic mucosal histamine and pancreastatin concentrations were reduced only gradually. The CCK2 receptor blockade was found to prevent the effects of omeprazole-evoked hypergastrinaemia on the ECL-cell activity and density. In conclusion, gastrin, acting on CCK2 receptors, is needed to maintain the shape, size and activity of the ECL cells, but not for maintaining the ECL-cell population.     

Gastric submucosal microdialysis: a method to study gastrin- and food-evoked mobilization of ECL-cell histamine in conscious rats

Rat stomach ECL cells are rich in histamine and chromogranin A-derived peptides, such as pancreastatin. Gastrin causes the parietal cells to secrete acid by flooding them with histamine from the ECL cells. In the past, gastric histamine release has been studied using anaesthetized, surgically manipulated animals or isolated gastric mucosa, glands or ECL cells. We monitored gastric histamine mobilization in intact conscious rats by subjecting them to gastric submucosal microdialysis. A microdialysis probe was implanted into the submucosa of the acid-producing part of the stomach (day 1). The rats had access to food and water or were deprived of food (48 h), starting on day 2 after implantation of the probe. On day 4, the rats received food or gastrin (intravenous infusion), and sampling of microdialysate commenced. Samples (flow rate 1.2 microl min(-1)) were collected every 20 or 60 min, and the histamine and pancreastatin concentrations were determined. The serum gastrin concentration was determined in tail vein blood. Exogenous gastrin (4-h infusion) raised microdialysate histamine and pancreastatin dose-dependently. This effect was prevented by gastrin receptor blockade (YM022). Depletion of ECL-cell histamine by alpha-fluoromethylhistidine, an irreversible inhibitor of the histamine-forming enzyme, suppressed the gastrin-evoked release of histamine but not that of pancreastatin. Fasting lowered serum gastrin and microdialysate histamine by 50%, while refeeding raised serum gastrin and microdialysate histamine and pancreastatin 3-fold. We conclude that histamine mobilized by gastrin and food intake derives from ECL cells because: 1) Histamine and pancreastatin were released concomitantly, 2) histamine mobilization following gastrin or food intake was prevented by gastrin receptor blockade, and 3) mobilization of histamine (but not pancreastatin) was abolished by alpha-fluoromethylhistidine. Hence, gastric submucosal microdialysis allows us to monitor the mobilization of ECL-cell histamine in intact conscious rats under various experimental conditions not previously accessible to study. While gastrin receptor blockade lowered post-prandial release of ECL-cell histamine by about 80%, unilateral vagotomy reduced post-prandial mobilization of ECL-cell histamine by about 50%. Hence, both gastrin and vagal excitation contribute to the post-prandial release of ECL-cell histamine.     

Physiology of the ECL cells.

The enterochromaffin-like (ECL) cells of the oxyntic mucosa (fundus) of the stomach produce, store and secrete histamine, chromogranin A-derived peptides such as pancreastatin, and an unanticipated but as yet unidentified peptide hormone. The cells are stimulated by gastrin and pituitary adenylate cyclase activating peptide and suppressed by somatostatin and galanin. Choline esters and histamine seem to be without effect on ECL cell secretion. The existence of a gastrin-ECL cell axis not only explains how gastrin stimulates acid secretion but also may help to explore the functional significance of the ECL cells with respect to the nature and bioactivity of its peptide hormone. From the results of studies of gastrectomized/fundectomized and gastrin-treated rats, it has been speculated that the anticipated ECL-cell peptide hormone acts on bone metabolism.     

Serum gastrin and gastric enterochromaffin-like cells during estrous cycle, pregnancy and lactation, and in response to estrogen-like agents in rats

Histamine-containing enterochromaffin-like (ECL) cells are numerous in the gastric mucosa. They operate under the control of gastrin. ECL-cell tumors (gastric carcinoids) may arise as a consequence of sustained hypergastrinemia. For reasons unknown, such tumors have a female preponderance both in laboratory animals and humans. The present study consisted of four experiments exploring the possibility that gender-related factors might affect rat ECL cells. 1) A gender difference in terms of serum gastrin concentration and oxyntic mucosal histidine decarboxylase (HDC) activity appeared in Sprague-Dawley but not Wistar rats. Ultrastructural appearance of the ECL cells did not differ between genders. 2) During the different phases of the estrous cycle, the serum gastrin concentration, HDC activity and histamine concentration did not change. 3) During pregnancy, the serum gastrin concentration was suppressed, while it was increased during lactation. The HDC activity and the histamine concentration of the oxyntic mucosa were correlated with the levels of circulating gastrin. 4) Twelve-month treatment with estrogen-like agents, dieldrin and/or toxaphene (alone or in combination) was without any effect on the ECL cells neither in male nor in female rats. In conclusion, the ECL cells are under the control of gastrin, but probably not hormones that involve in the estrous cycle and pregnancy and lactation in rats. Possible gender-related factors behind the female preponderance of ECL-cell tumors remain unknown.     

The mechanism of histamine secretion from gastric enterochromaffin-like cells

Enterochromaffin-like (ECL) cells play a pivotal role in theperipheral regulation of gastric acid secretion as they respond to thefunctionally important gastrointestinal hormones gastrin andsomatostatin and neural mediators such as pituitary adenylate cyclase-activating peptide and galanin. Gastrin is the keystimulus of histamine release from ECL cells in vivo and in vitro.Voltage-gated K⁺ andCa²⁺ channels have been detectedon isolated ECL cells. Exocytosis of histamine following gastrinstimulation and Ca²⁺ entry acrossthe plasma membrane is catalyzed by synaptobrevin andsynaptosomal-associated protein of 25 kDa, both characterized as asoluble N-ethylmaleimide-sensitivefactor attachment protein receptor protein. Histamine release occursfrom different cellular pools: preexisting vacuolar histamineimmediately released by Ca²⁺ entryor newly synthesized histamine following induction of histidine decarboxylase (HDC) by gastrin stimulation. Histamine is synthesized bycytoplasmic HDC and accumulated in secretory vesicles byproton-histamine countertransport via the vesicular monoaminetransporter subtype 2 (VMAT-2). The promoter region of HDC containsCa²⁺-, cAMP-, and protein kinaseC-responsive elements. The gene promoter for VMAT-2, however, lacksTATA boxes but contains regulatory elements for the hormones glucagonand somatostatin. Histamine secretion from ECL cells is thereby under acomplex regulation of hormonal signals and can be targeted at severalsteps during the process of exocytosis.

     

Altered influence of CCK-B/gastrin receptors on HDC expression in ECL cells after neoplastic transformation

Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell endocrine function and growth. Long-standing hypergastrinemia may give rise to ECL cell carcinoids in the gastric corpus in man and in experimental models. We have analysed the expression and function of CCK-B/gastrin receptors in normal ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa. This increase was significantly and dose-dependently reversed by selective CCK-B/gastrin receptor blockade (YM022). Long-term (12 months) hypergastrinemia, induced by histamine2-receptor blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK-B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was eight-fold elevated in ECL cell carcinoids and was not influenced by CCK-B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.     

PACAP and gastrin regulate the histidine decarboxylase promoter via distinct mechanisms

The enterochromaffin-like (ECL) cell controls gastric acid secretion via histamine, generated by l-histidine decarboxylase (HDC). HDC expression is regulated by gastrin. However, gastrin is not alone in controlling ECL cell function. For example, the neural peptide pituitary adenylate cyclase-activating polypeptide (PACAP) also increases ECL cell proliferation. To investigate a potential role of PACAP in regulating HDC expression, we generated a series of HDC promoter-luciferase reporter constructs and transiently transfected them into PC12 cells (stably expressing the gastrin-CCK-2 receptor). We found that PACAP regulates HDC promoter activity. This is temporally biphasic, involving both adenyl cyclase and phospholipase C-dependent pathways. Deletional analysis, block mutation, and EMSA demonstrated a PACAP-response element at -177 to -170, wholly necessary for the effects of PACAP and discrete from known gastrin-responsive elements. Discrete neural and endocrine pathways regulate ECL cells through different patterns of postreceptor signaling and promoter activation, which may be appropriate to their functions in vivo.     

Properties of isolated gastric enterochromaffin-like cells.

The gastric enterochromaffin-like cell (ECL) has been studied in gastric fundic glands by confocal microscopy and as a purified cell preparation by video imaging of calcium signaling and measurements of histamine release. Regulation of gastric acid secretion is largely due to alterations of histamine activation of the H2 receptor on the parietal cell and can be divided into central neural regulation, with direct actions of neuronally released mediators and into peripheral regulation by substances released from other endocrine cells. Gastric neuronal stimulation of acid secretion by alteration of ECL cell function is probably mediated by pituitary adenylate cyclase activating peptide (PACAP) receptors on the ECL cell, which activate calcium signaling and histamine release. Peripheral stimulation of acid secretion via the ECL cell is largely mediated by gastrin stimulation of calcium signaling and histamine release. Gastric neuronal inhibition of ECL cell function is probably mediated by galanin inhibition of calcium signaling, and histamine release and peripheral inhibition of ECL cell function is mainly due to somatostatin release from D cells.     

Differentiation of the gastric mucosa. II. Role of gastrin in gastric epithelial cell proliferation and maturation

Gastrin is the principal hormonal inducer of gastric acid secretion. The cellular targets for gastrin in the stomach are the acid-secreting parietal cell and histamine-producing enterochromaffin-like (ECL) cell. Gastrin is also a growth factor, with hypergastrinemia resulting in increased proliferation of gastric progenitor cells and a thickened mucosa. This review presents insights into gastrin function revealed by genetically engineered mouse models, demonstrating a new role for gastrin in the maturation of parietal and ECL cells. Thus, gastrin regulates many aspects of gastric physiology, with tight regulation of gastrin levels required to maintain balanced growth and function of gastric epithelial cells.     

Pathobiology and management of hypergastrinemia and the Zollinger-Ellison syndrome.

Gastrin is both stimulatory and trophic to the cells of the gastric fundus--parietal and peptic cells, and enterochromaffin-like (ECL) cells which are major intermediaries of the gastrin effect. Gastrin (from the antrum) and acid (from the fundus) represent the interactive positive and negative limbs of a feedback loop. The nature and extent of sub-loops, perhaps involving the vagus, acetylcholine, histamine, and other peptides and cell products are at present unclear or unknown. Loss of either gastrin or acid has predictable consequences. Absent acid, as in pernicious anemia or as a result of omeprazole, leads to hypergastrinemia. In rats, such hypergastrinemia (gastrin > 1,000 pg/ml) causes fundic ECL hyperplasia and, eventually, carcinoids; in humans with pernicious anemia, hypergastrinemia causes ECL-cell hyperplasia, which may progress to carcinoids that are reversible upon withdrawal of gastrin, illustrated by three cases described here. Loss of gastrin by antrectomy for duodenal ulcer leads to fundic involution and marked reduction in basal acid output, maximal acid output, and fundic histamine. An uncontrolled excess of gastrin, as from a gastrinoma outside the negative feedback loop, causes acid and pepsin hypersecretion with upper GI mucosal damage, the Zollinger-Ellison syndrome. This paper summarizes the abnormal regulation of gastrin and the biology, natural history, diagnosis, and management of ZE syndrome by medical and surgical means.     

PACAP stimulates gastric acid secretion in the rat by inducing histamine release

Previous studies have shown that pituitary adenylate cyclase-activating peptide (PACAP) stimulates enterochromaffin-like (ECL) cell histamine release, but its role in the regulation of gastric acid secretion is disputed. This work examines the effect of PACAP-38 on aminopyrine uptake in enriched rat parietal cells and on histamine release and acid secretion in the isolated vascularly perfused rat stomach and the role of PACAP in vagally (2-deoxyglucose) stimulated acid secretion in the awake rat. PACAP has no direct effect on the isolated parietal cell as assessed by aminopyrine uptake. PACAP induces a concentration-dependent histamine release and acid secretion in the isolated stomach, and its effect on histamine release is additive to gastrin. The histamine H2 antagonist ranitidine potently inhibits PACAP-stimulated acid secretion without affecting histamine release. Vagally stimulated acid secretion is partially inhibited by a PACAP antagonist. The results from the present study strongly suggest that PACAP plays an important role in the neurohumoral regulation of gastric acid secretion. Its effect seems to be mediated by the release of ECL cell histamine.     

Stimulatory effect of dibutyryl cyclic GMP on acid secretion in mouse isolated stomach and on histamine release in gastric mucosal cells.

We previously reported that endogenous nitric oxide (NO) is involved in the peripheral control of gastric acid secretion induced by some secretagogues, and that endogenous NO is involved in the acid secretion process via histamine release from histamine-containing cells. However, the stimulus-secretion coupling in the cells remains to be clarified. In the present study, we investigated the effect of dibutyryl cyclic GMP on gastric acid secretion in mouse isolated stomach and on histamine release in gastric mucosal cells, in comparison with those of dibutyryl cyclic AMP. Dibutyryl cyclic GMP (300 microM) produced a slight but significant increase of gastric acid secretion, which was completely inhibited by the histamine-H2 receptor antagonist famotidine. In contrast, dibutyryl cyclic GMP (1 mM) markedly inhibited histamine-induced acid secretion. Dibutyryl cyclic AMP (100 microM) produced a sustained increase of gastric acid secretion. The pretreatment with famotidine partially inhibited dibutyryl cyclic AMP-induced gastric acid secretion. Dibutyryl cyclic GMP and dibutyryl cyclic AMP significantly increased the histamine release from gastric mucosal cells. These results suggest that both intracellular cyclic GMP and cyclic AMP act as second messengers for histamine release in the histamine-containing cells, probably ECL cells. On the other hand, in gastric parietal cells, cyclic AMP has a stimulatory effect on gastric acid secretion, whereas cyclic GMP has an inhibitory effect.     

A comparison of the effects of gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation

Gastrin regulates ECL cell histamine release and is a critical determinant of acid secretion. ECL cell secretion and proliferation is inhibited by gastrin antagonists and somatostatin but little is known about the role of dopamine agonists in this process. Since the ECL cell exhibits all three classes of receptor we evaluated and compared the effects of the gastrin receptor antagonist, (YF476), lanreotide (SST agonist) and novel dopaminergic agents (BIM53061 and BIM27A760) on ECL cell histamine secretion and proliferation. Highly enriched (>98%) ECL cell preparations prepared from rat gastric mucosa using a FACS approach were studied. Real-time PCR confirmed presence of the CCK2, SS2 and SS5 and D1 receptors on ECL cells. YF476 inhibited histamine secretion and proliferation with IC(50)s of 1.25 nM and 1.3 x 10(-11) M respectively, values 10-1000x more potent than L365,260. Lanreotide inhibited secretion and proliferation (2.2 nM, 1.9 x 10(-10) M) and increased YF476-inhibited proliferation a further 5-fold. The dopamine agonist, BIM53061, inhibited gastrin-mediated ECL cell secretion and proliferation (17 nM, 6 x 10(-10) M) as did the novel dopamine/somatostatin chimera BIM23A760 (22 nM, 4.9 x 10(-10) M). Our studies demonstrate that the gastrin receptor antagonist, YF476, is the most potent inhibitor of ECL cell histamine secretion and proliferation. Lanreotide, a dopamine agonist and a dopamine/somatostatin chimera inhibited ECL cell function but were 10-1000x less potent than YF476. Agents that selectively target the CCK2 receptor may provide alternative therapeutic strategies for gastrin-mediated gastrointestinal cell secretion and proliferation such as evident in the hypergastrinemic gastric carcinoids associated with low acid states.     

Relationship of ECL cells and gastric neoplasia.

The enterochromaffin-like (ECL) cell in the oxyntic mucosa has a key role in the regulation of gastric secretion since it synthesizes and releases the histamine regulating the acid secretion from the parietal cell. Gastrin is the main regulator of the ECL cell function and growth. Long-term hypergastrinemia induces ECL cell hyperplasia, and if continued, neoplasia. ECL cell carcinoids occur in man after long-term hypergastrinemia in conditions like pernicious anemia and gastrinoma. There is also accumulating evidence that a proportion of gastric carcinomas of the diffuse type is derived from the ECL cell. Furthermore, the ECL cell may, by producing substances with angiogenic effects (histamine and basic fibroblast growth factor), be particularly prone to develop malignant tumors. Although the general opinion is that gastrin itself has a direct effect on the oxyntic mucosal stem cell, it cannot be excluded that the general trophic effect of gastrin on the oxyntic mucosa is mediated by histamine or other substances from the ECL cell, and that the ECL cell, therefore, could play a role also in the tumorigenesis/carcinogenesis of gastric carcinomas of intestinal type.