ECL Cell: History
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The ECL cell was recognized as the cell producing histamine, taking part in the regulation of gastric acid secretion. The ECL cell carries the gastrin receptor, and gastrin regulates its function (histamine release) as well as proliferation. Long-term hypergastrinemia results in gastric neoplasia of variable malignancies, implying that gastric hypoacidity resulting in increased gastrin release will induce gastric neoplasia, including gastric cancer. Conclusions: The trophic effect of gastrin on the ECL cell has implications to the treatment with inhibitors of acid secretion.

  • ECL cell

1. Embryology of the ECL Cell

Pearse and Polak formulated the neural crest theory for the origin of NE cells [1]. However, LeDouarin and Teillet could not find evidence for neural crest origin of NE cells in the gastrointestinal tract when studying chimeric birds (chicken and quail) [2] and, therefore, NE cells in the gastrointestinal tract are presumed to be of endodermal origin. Nevertheless, NE cells have important differences compared with other mucosal cells since they can proliferate [3], and some may be pluripotent [4]

2. Functional and Trophic Regulation of the ECL Cell

The main regulator of the ECL cell function, that is histamine release, is gastrin. Gastrin released by food intake, has a high potency reflecting high affinity to the gastrin receptor. This is demonstrated by detectable stimulation of histamine release at a concentration of 2 pmol/L [5]. Moreover, maximal effect is reached at about 500 pmol/L, similar to the trophic effect in rats [6], and to the functional [7] and trophic [8] effects in humans. There is no threshold for the trophic effect of gastrin and, consequently, only moderate hypergastrinemia as usually seen during treatment with inhibitors of gastric acid secretion, induces ECL cell hyperplasia [9]. The increase in ECL cell mass results in increased histamine release [10], which is responsible for the rebound acid hypersecretion seen after stopping treatment with PPIs [11]. The cholinergic agent McN-A-323 (muscarinic-1 analogue) did not stimulate histamine release, whereas vagal stimulation increased histamine release in the isolated rat stomach, although not sufficiently completely explained the stimulation of acid secretion [12]. The vagal stimulation of histamine release is probably mediated by PACAP (pituitary adenylate cyclase-activating polypeptide) released from neurons [13]. Like gastrin, PACAP has a trophic effect on the ECL cell that could be responsible for the trophic effect of the vagal nerves, elegantly shown by unilateral vagotomy in rats by Håkanson and co-workers [14]. The role of PACAP in the trophic regulation of the ECL cell is, however, difficult to assess since, presently, there is no method to quantitate vagal activity. Somatostatin inhibits histamine release and, at the same time, parietal cell H+ secretion, making it a very efficient inhibitor of acid secretion [15]. Generally, there is a close relationship between functional and trophic regulation of a cell type, which is logical from a biological point of view. This is also the case for the ECL cell. Thus, gastrin not only stimulates histamine release, but also proliferation of the ECL cell, effects mediated by the same gastrin receptor and accordingly showing similar concentration dependence. Long-term hypergastrinemia leads to ECL cell hyperplasia, manifested by rebound acid hypersecretion [11] and in the long-term by ECL cell-derived tumours of variable malignancies [13]. Gastrin undoubtedly predisposes to ECL cell neuroendocrine tumours (NETs). There are also arguments for a role of gastrin in the pathogenesis of gastric carcinomas, as patients with autoimmune gastritis have increased risk of malignancy [16][17]. Moreover, patients with hypergastrinemia upon long-term follow-up have an increased prevalence of gastric cancer [18]. PACAP is probably responsible for the functional and trophic effects of the vagal nerves on the ECL cell [19]. Long-term treatment with the long-acting somatostatin analogue octreotide reduced ECL cell density in hypergastrinemic patients secondary to autoimmune gastritis [20]. Octreotide also reduced ECL cell density in hypergastrinemic rats due to dosing with a peroxisome proliferator type α, without affecting the gastrin concentration [21].

3. Role of the ECL Cell in Disease

3.1. Acid-Related Disorders

3.1.1. Rebound Acid Hypersecretion

Profound acid inhibition for some time induces rebound hypersecretion of acid after stopping treatment [11]. Due to the prolonged effect of PPIs, this rebound effect became detectable at first after two weeks without PPI. Therefore, PPIs were initially claimed not to induce rebound acid hypersecretion secretion since acid secretion was determined too early after stopping treatment. Healthy individuals develop dyspepsia in the period of rebound acid hypersecretion [22], and it is probable that patients with gastro-oesophageal reflux disease (GERD) will also have increased symptoms in this phase. The problem in stopping with PPIs when started [23] is most probably due to the acid rebound effect. The ECL cell hyperplasia also reduces the sensitivity for histamine-2 (H-2) receptor blockers [24], which is an important argument for starting with H-2 blockers in most of the patients with GERD.

3.1.2. Peptic Ulcer Disease

Helicobacter pylori (Hp) is the main cause of peptic ulcer disease [25]. The pathogenesis differs between duodenal and gastric ulcer. In duodenal ulcer disease, the acid secretion is increased due to Hp infection in the antrum leading to NH3 production and stimulation of gastrin release [26]. The slight hypergastrinemia stimulates acid secretion. Moreover, there is an inappropriate hypergastrinemia in relation to gastric acidity [27], probably caused by an increased ECL cell mass and histamine release due to the slight hypergastrinemia [28]. The fall in maximal (penta)gastrin stimulated acid secretion seen after Hp eradication in patients with duodenal ulcer probably reflects a fall in ECL cell density since maximal gastrin stimulated acid secretion is dependent on the ECL cell mass. On the other hand, the ECL cell is not directly involved in the pathogenesis of gastric ulcer besides taking part in the normal regulation of acid secretion. Hp predisposes to gastric ulcerations by reducing the defense mechanisms in the mucosa [mucus and bicarbonate secretions] [28].

3.1.3. Gastroesophageal Reflux Disease (GERD)

Incompetence of the gastro-oesophageal valve function is the most important pathogenic factor for GERD. However, the acidity of the gastric content is also of utmost importance as evidenced by the efficiency of inhibitors of gastric acid secretion in the treatment. Moreover, increased gastric acidity per se may induce GERD as demonstrated in patients with gastrinoma [29], and indirectly by the subjects who developed dyspepsia during the rebound acid hyper-secretory phase [22]. The importance of keeping gastric pH above 4.0 [30] most likely reflects the important role of pepsin in the damage of the oesophageal epithelium since pepsin is destroyed above this pH.

3.2. Gastric Neoplasia

3.2.1. Neuroendocrine Neoplasms (Neuroendocrine Tumours and Neuroendocrine Carcinomas)

The interest for gastric neuroendocrine neoplasms [NENs] started in the 1870s when endoscopic examination of the upper gastrointestinal tract became available. Gastric neuroendocrine tumours (NETs) are usually small and with a low malignant potential. Nevertheless, they can metastasize and kill the patient. Gastrin plays a central role in their pathogenesis since hypergastrinemia secondary to autoimmune gastritis with hypoacidity [8][31] and gastrinoma [32] with hyperacidity predispose to these tumours. Thus, gastric NETs are hormone-dependent tumours [33]. With the development of efficient inhibitors of gastric acid secretion like the PPIs [34] and insurmountable H-2 blockers [35], long-term dosed rodents developed NETs in the oxyntic mucosa, and the gastrin hypothesis was developed [36]. A relationship between an ordinary NET and a highly malignant one has also recently been described for the EC cell [37]. Based upon immune-histochemical examinations, there is every reason to postulate that gastric NECs also have their origin in the ECL cell. Gastric NECs are very malignant tumours having a poor prognosis [38]. They may be due to a mutation in a central gene in the regulation of the ECL cell growth. Whether gastrin in normal concentrations has a growth stimulating effect on such mutated cells is unknown.

3.2.2. Gastric Adenocarcinomas

The role of the ECL cell in gastric carcinogenesis has been disputed since the description of ECL cell derived tumours in rodents after long-term profound acid inhibition [34][35]. In reality, this question is connected to the implications of neoplastic tumour cells with endocrine differentiation found in tumours classified as adenocarcinomas [39]. From a biological point of view the distinction between NENs and non-NENs based upon the percentage of tumour cells expressing a NE marker is curious and imprecise since this figure is dependent of the sensitivity of the method applied. By such an attitude neoplasia showing NE positivity in less than 30% of the cancer cells are classified as adenocarcinomas, whereas those displaying positivity in a higher percentage of neoplastic cells are regarded as NENs or mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN), previously known as mixed adeno-neuroendocrine carcinoma (MANEC) [40]. There are many examples of the problems to distinguish between NENs and non-NENs. Thus, Soga et al. reclassified gastric tumours in the African rodent Mastomys from adenocarcinomas to NECs [41]. Moreover, Poynter changed the classification of tumours occurring in rodents after long-term profound acid inhibition, from adenocarcinomas [42] to NENs [35]. Similarly, gastric neoplasia in humans have also been reclassified from adenocarcinomas to NENs [43][44]. Since Hp is the dominating cause of gastritis [25], it was therefore natural that Hp early was recognized as the principal factor causing gastric cancer [45]. The mechanism of the carcinogenic effect of Hp has been intensively searched for 25 years. Studies have often focused on changes in chromatin and genes in gastric cells [46][47], but the mechanism has not been found. Since Hp predisposes to gastric cancer only when having induced oxyntic atrophy [48], we have proposed that the carcinogenic effect of Hp infection is mediated by gastrin [49].
Histologically, gastric carcinomas often show resemblance to intestinal mucosa/tumours, and the classification systems are as a rule based upon such similarities. They are all classified according to their growth pattern into adenocarcinomas of intestinal type (showing a glandular growth pattern), or diffuse type (showing a non-cohesive growth of the carcinoma cells) according to Laurén [39]. PAS positivity believed to represent mucin is the argument for classifying carcinomas of diffuse types as adenocarcinomas.  In general, gastrin and its target cell, the ECL cell, seem to play a crucial role in gastric carcinogenesis. A proportion of gastric carcinomas express the gastrin receptor even in a late phase [50], which could indicate that these carcinomas may respond to treatment with a gastrin antagonist like netazepide [51]. The prevalence of gastric carcinomas is falling, probably due to a reduction in Helicobacter pylori infections. On the other hand, up to 10% of the population uses PPIs [52]. PPIs give profound inhibition of gastric acid secretion resulting in hypoacidity and secondary hypergastrinemia, which, in turn, may predispose to gastric carcinomas [53]. In fact, the first epidemiological studies reporting increased prevalence of gastric carcinomas in PPI users have appeared [54][55]Figure 1 summarizes the regulation of gastric acid secretion and its connection with gastric neoplasia.
Figure 1. Gastrin and the ECL cell are central in gastric physiology and carcinogenesis.

This entry is adapted from the peer-reviewed paper 10.3390/ijms20102444


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