Gastric endocrine cells: types, function and growth

Regulatory Peptides 93 (2000) 31–35 www.elsevier.com / locate / regpep

Gastric endocrine cells: types, function and growth a, b c d e Enrico Solcia *, Guido Rindi , Roberto Buffa , Roberto Fiocca , Carlo Capella a

Department of Pathology and Genetics, University of Pavia and IRCCS Policlinico San Matteo Hospital, via Forlanini 16, I-27100 Pavia, Italy b Department of Pathology, University of Brescia, Brescia, Italy c Department of Pathology, University of Milan, Milan, Italy d Department of Pathology, University of Genova, Genova, Italy e Department of Pathology, Insubria University at Varese, Varese, Italy Received 24 July 2000; accepted 26 July 2000

Abstract The history of gastric endocrine cells identification and functional characterization is briefly outlined. An up to date classification of such cells is given. Present status of histopathological, histochemical, ultrastructural and molecular investigations on gastric endocrine hyperplasia and neoplasia is summarized and briefly discussed.  2000 Elsevier Science B.V. All rights reserved. Keywords: Gastrin; Somatostatin; ECL cells; Endocrine tumors

1. Historical outline The history of gastric endocrine cells started with Heidenhain as early as 1870, when he observed chromaffin cells in the dog gastric mucosa. Subsequently, yellow cells were described by Nicolas in 1891, basigranular acidophil cells by Kultschitzky in 1897 and basigranular yellow cells by Schmidt in 1905 in the intestinal mucosa. The latter author correctly attributed the yellow staining of the granules to their interaction with the chromium salt of the Muller-formol fixative he used. The name enterochromaffin (EC) cells was introduced by Ciaccio in 1907 [1]. The endocrine nature of the EC cells, their silver-reducing power or argentaffinity, and their morphological and functional independence of adrenal chromaffin cells were first recognized by Masson in 1914. An indoleamine called enteramine was purified by Vialli and Erspamer in 1942 from rabbit gastric mucosa and later characterized as 5-hydroxytryptamine (5-HT) by Erspamer and Asero

*Corresponding author. Tel.: 1 39-038-250-3057; fax: 1 39-038-2525866.

(1952), who recognized its identity with serotonin, which had been isolated by Rapport, Green and Page from serum in 1949 (see Solcia et al. [1] for a more detailed outline of the early findings). The presence in the gastric mucosa of basigranular, acidophilic and / or argyrophilic cells morphologically resembling EC cells but lacking argentaffinity and reactivity for other 5-hydroxytryptamine tests was noted by several authors in the 1930–1960 period. During the late sixties, parallel histochemical and ultrastructural studies provided evidence that they represented a system of amines and peptides producing endocrine cells involved in the synthesis and secretion of known hormones, such as gastrin, or of hormones still awaiting discovery [2–7]. The discovery in the murine stomach of argyrophilic, histaminestoring ‘enterochromaffin-like’ cells [8] led to their identification with ECL cells, a type of ultrastructurally characterized cell restricted to oxyntic glands in all species investigated, including man [4,9–12]. Gastrin was the first peptide hormone to be detected in epithelial cells of the gastric mucosa [13] which, after some conflicting findings, turned out to correspond to the ‘G’ cells, a type of ultrastructurally characterized cell shown to be characteris-

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tic of pyloric glands in all species investigated [2–5,14]. Cells differing from serotonin-producing EC cells while resembling pancreatic D cells were also found to exist in the pyloric mucosa, though they proved difficult to separate from G cells in early light and electron microscopy studies. More systematic ultrastructural and immunocytochemical investigations [1,3–5] led to the clear-cut separation of gastroenteropancreatic D cells from pyloric G cells as well as from other types of gut endocrine cells. D cells were later shown to store somatostatin [15,16]. In addition to EC, ECL and D cells, other types of endocrine cells were observed during systematic ultrastructural investigation of the oxyntic mucosa, with special reference to cells resembling pancreatic glucagon-producing A cells and so-called ‘X’ cells [4,17,18]. It was soon realized that true glucagon-producing A cells are present in the dog and cat stomach but not in other mammals [18,19], with the exception of human fetuses. Thus, gastric ‘true’ A cells were separated from ‘A-like’ or ‘X’ cells, showing only a general ultrastructural resemblance (i.e. solid, round, membrane-enclosed secretory granules) to pancreatic A cells, as well as from ‘enteroglucagon’-producing intestinal ‘L’ cells, where the same proglucagon peptides as in pancreatic A cells are processed differently [20]. Despite occasional immunohistochemical findings suggesting the storage of various peptides, gastric X or A-like cells remained functionally uncharacterized until recently, when Kojima and coworkers showed their production and storage of ghrelin, a novel GH-releasing peptide [21]. Curiously enough, ghrelin has also been immunolocalized in pancreatic A cells.

are reported in Table 1 [1,22,23]. It should be added that other cellular products are likely to be of functional relevance, such as for instance opioid peptides, reported in EC cells, or uroguanylin in EC and ECL cells [24,25], although their presence and functional relevance in man remain to be confirmed. In addition, other cell types have occasionally been reported by ultrastructural studies, especially of human oxyntic mucosa, as small granule enterocatecholamine, P or D1 cells [1,3,24]. At least in part, these cells, which often showed involution signs, were more frequently found in chronic atrophic gastritis and were rarely observed in other mammals, are likely to represent a regressive form or a functional variant of other cell types. Of major functional relevance is likely to be the direct access of many pyloric endocrine cells to the gastric lumen as well as the lack of luminal access shown by oxyntic mucosa endocrine cells [1–6]. The ‘open’ or ‘closed’ type, respectively, of their relationship with the lumen found in early ultrastructural investigations suggested functional modulation by luminal contents and the pH of pyloric, but not of corpus-fundus endocrine cells, which should be regulated by blood hormones (e.g., gastrin), local factors (histamine, serotonin, trophic factors), nerve endings or mechanical distension. Subsequent functional studies largely confirmed these suggestions. Ultrastructural and immunohistochemical studies also gave support to Feyrter’s old concept of the local paracrine activity of mucosal endocrine cells [1,26], which later became popular and was supported by experimental evidence.

2. Cell types and their function

3. Hyperplastic and neoplastic growth

The cell types whose morphologic and functional identification has been delineated in the above historical outline

Well characterized hyperplastic growth has been reported both in the pyloric and corpus-fundus mucosa.

Table 1 Gastric endocrine cells: types, function and proliferative changes a Cell type

Distribution

Hyperplastic condition

Neoplasia

Gastrin G

Antrum, duodenal bulb

Secondary to type A CAG; primary, with hyperchlorhydria

Gastrinoma: pancreas, duodenum, antrum (rare) G cell tumor: duodenum, pancreas, antrum (rare)

Somatostatin D

Whole stomach, GI tract and pancreas

Secondary to hyperchlorhydria

D cell tumor: pancreas, duodenum, antrum (rare) somatostatinoma: pancreas

Serotonin EC

Whole stomach b , GI tract and pancreas

In CAG

EC cell (argentaffin) carcinoid: intestine, pancreas, stomach (rare)

Histamine ECL

Corpus, fundus

In type A CAG or MEN / ZES, secondary to hypergastrinemia

ECL cell tumor: stomach

Ghrelin X /A-like

Corpus, fundus

Not known

Not known

Not known

Not known

Glucagon A a

Corpus, fundus

c

CAG, chronic atrophic gastritis; MEN / ZES, multiple endocrine neoplasia / Zollinger–Ellison syndrome. b Restricted to pyloric mucosa in rats. c Of dog and cat, only of fetal stomach in man.

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Gastrin cell hyperplasia has been characterized qualitatively as palizade forming lines of cells at the base of pyloric gland epithelium, and quantitatively as more than 150 cells per linear millimeter of perpendicularly cut mucosa (normal values for uninflammed pyloric mucosa being less than 100 cells per linear millimeter) [27]. It is regularly observed, as a secondary change, in chronic atrophic gastritis (CAG) with severe, long-standing achlorhydria, as typically found in pernicious anemia patients [28], and, as an apparently primary change, in rare subjects with hyperchlorhydria and peptic ulcer disease with or without associated H. pylory gastritis [29]. D cell hyperplasia has also been reported [30]. In non-antral gastric mucosa, several patterns of hyperplastic (diffuse, linear, micronodular or adenomatoid) and dysplastic changes (enlarged and fused micronodules, microinvasive lesion, adenomatous lesion or nodule with newly formed stroma) have been characterized, mostly composed of ECL cells [31]. ECL cell hyperplasia was mainly found in association with hypergastrinemia and either diffuse corpus-fundus (type A) CAG with achlorhydria or hypertrophic gastropathy with Zollinger–Ellison syndrome. Dysplastic ECL cell changes were usually observed in association with multiple ECL cell tumors arising in type A CAG [31–33] or combined multiple endocrine neoplasia (MEN / ZES) Zollinger-Ellison syndrome [34]. Gastrin cell tumors, found with some frequency in the duodenal bulb, are only exceptionally observed in the stomach. Argentaffin EC cell carcinoids are also rare. Most gastric endocrine tumors have been characterized as well differentiated ECL cell tumors by electron microscopy and histochemistry, including histamine, histidine decarboxylase and vesicular monoamine transporter 2 (VMAT2) [35–37] immunodetection. In addition to relatively benign ECL cell tumors arising in a background of type A CAG or MEN / ZES syndrome, about 20% of cases have been found to arise in apparently unchanged gastric mucosa in the absence of clinically relevant hypergastrinemia and to display a more malignant behavior [35,38]. A last type of endocrine tumor reported in the stomach is the poorly differentiated neuroendocrine carcinoma [39]. This very malignant neoplasia only rarely seems to arise from the progression of a previous differentiated endocrine tumor, in most cases apparently arising ‘de novo’ from proliferation of anaplastic or poorly differentiated cells with only partial, often abortive commitment to endocrine differentiation [35] and independently from hypergastrinemia. In Table 1, tumors causing endocrine hyperfunction (gastrinoma, somatostatinoma) are considered separately from ‘non-functioning’ tumors (G, D or ECL cell tumors). Recently, some genetic factors have been implicated in gastric endocrine tumorigenesis and progression, in addition to severe long-standing hypergastrinemia, which by

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itself seems unlikely to cause endocrine tumors in man. Mutation of the CCKB / gastrin receptor [40] or in the RegIa gene, a gastrin-dependent gene regulating ECL cell growth [41], may be involved in the genesis of ECL cell tumors. Loss of heterozygosity at the 11q13 MEN1 locus has been detected in most familial ECL cell tumors associated with MEN / ZES [42] and in a minority of non-familial cases [43]. Involvement of the p53 gene or LOH at DCC gene site 18q21–22 has been consistently found only in poorly differentiated neuroendocrine carcinomas and some sporadic ECL cell tumors [44].

4. Concluding remarks Appropriate morphologic identification and functional characterization of gastrin endocrine cells has been delayed, compared to endocrine cells of established endocrine organs such as pancreatic islets, pituitary or adrenals, by their dispersed, single cell distribution pattern along the gastric mucosa. This required the development of more refined, endocrine cell selective, in situ cytological methods, efficient techniques of endocrine cell isolation and culture, and new in vivo and in vitro models of functional investigation [45,46]. Genetic mechanisms underlying functional response and pathologic growth are now under extensive investigation. The interplay between the hormonal products of gastric endocrine cells and local trophic factors, nerve regulation or feed-back (e.g., luminal acid) functional modulation still deserves careful study under physiologic, pharmacologic [47,48] or pathologic conditions before their full impact on clinical practice can be clarified.

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