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Manuscript of Review Article published in: MICROSCOPY RESEARCH and TECHNIQUE 2000; 48: 303-11
ROLE OF APOPTOSIS IN GASTRIC EPITHELIAL
TURNOVER
Axel von Herbay 1 , Jochen Rudi 2
1 Institute of Pathology, 2 Medizinische Klinik IV, University of Heidelberg, Germany Address for correspondance: Priv.-Doz. Dr. med. A. von Herbay, Pathologisches Institut,Universitätsklinikum, Im Neuenheimer Feld 220, D - 69120 Heidelberg, Germany. Phone &Fax: +49 6221 56-2675. Email: [email protected] Abstract
factors such as CD95 ligand or tumornecrosis factor (TNF) alpha act as death factors. They bind to specific receptors, process. It is characterized by continous cell proliferation, which is counterbalanced by cell loss. The biological principle that gamma, or by Helicobacter pylori itself. In mediates the homeostasis of epithelium is addition to CD95, H. pylori can also induce programmed cell death, or apoptosis.
upregulation of CD95 ligand expression.
different mechanisms. Various subtypes of CD95L in the close proximity to apoptotic gastric epithelial cells suggest a functional the normal stomach, apoptosis due to cell physiological epithelial turnover. Albeit apoptosis is currently under study. Apart approximately 2% of epithelial cells in the example is given in gastric graft-versus- apoptosis and epithelial proliferation are 8% apoptotic epithelial cells. In gastritis, A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 Introduction
Gastric epithelial proliferation
process. It is characterized by continous digestive tract mucosae with respect to its cell proliferation, which is counterbalanced proliferative zone. In any subsite of the stomach, the proliferating stem cells are localized in the neck of gastric glands, and epithelial migration occurs bidirectionally.
cell death, or apoptosis (Kerr et al., 1972; One part of proliferated epithelia migrates Wyllie et al., 1980; Thompson, 1995; Raff, 1998). This article will focus on the role of which line the foveolae ("pits") and the consideration of gastric histology, which epithelia migrate downwards in the gastric differs in the four anatomical subsites of glands. In the antrum, they differentiate the stomach. These four zones, i.e. cardia, within few days to mucous-secreting cells forming the pyloric glands. In the fundus for the TNM classification system) (UICC, and corpus, they differentiate within few 1997) are lined by two basically different weeks to chief cells, parietal cells, and suspected precursor cells can be identified mucosa is characterized by rather straight, Proliferation kinetics of the gastric antral cells, chief (or zymogenic) cells, parietal have concentrated on proliferation of the 1997). A second type of mucosa is present foveloar epithelium (Lipkin et al., 1963; in the distal third of the stomach, i.e.
antrum and pylorus, and also at the cardia of epithelial cells in the antrum, but 2.8% in the gastric body epithelium were found to be in the in DNA synthesis (S-) phase of mean duration of S-phase of gastric antral different glands, fundus-type and antrum- type mucosa differ also with respect to the 1993). The median lengths of the foveolae foveolae or pits. In the antrum, foveolae were 188 cells in the gastric antrum, and 137 cells in the gastric body (Patel et al., of BrdU-labelling positions were cell 61 in the antrum, and cell 26 in the gastric body as measured from the crypt orifice (Patel localization, the gastric pits are lined by et al., 1993). Epithelial proliferation is after partial gastric resection (Lynch et al.,1995).
A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 Gastric epithelial renewal is influenced by important and characteristic feature is the various physiologic stimuli. In the gastric stimulates proliferation of epithelial cells.
gastrin. Clinical evidence for this divergent followed by overall cell shrinkage and the bodies. These bodies are phagocytosed byneighbouring cells. Biochemically, thehallmark of apoptotic cell death is Apoptosis in the stomach: general
below).
Regulation of apoptosis is complex and The diversity of cell death was recognized cell (Raff, 1998). Extracellular signals can either suppress or activate apoptosis.
signalling") molecules are survival factors, e.g. growth factors. Apoptosis-activating ("positive signalling") factors are death- inducing molecules, e.g. TGF-β or related contrast, necrosis is a passive cell death inhibiting factor), CD95 ligand, or tumor necrosis factor alpha (TNF α) and related molecules. These signals act via binding to activation of the CD95 receptor and ligand (Krammer, 1999; Weiss et al., 1997).
CD95 is constitutively expressed in a wide organelle lysis (Majno and Joris, 1995).
Due to the release of cellular constituents, Apoptosis, in contrast, is morphologically ligand is expressed in various human cells lymphocytes, lung, liver or kidney (Suda et al., 1993; 1994; Galle et al., 1995).
Binding of CD95L to the extracellular A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 A major class of intracellular regulators of intracellular domain of CD95 recruits via Similarly, binding of tumor necrosis factor trimerization, allowing the intracellular biological effects are quite different. Bcl-2, interacting protein) (Ashkenazi and Dixit, 1998). This complex then activates further initiated by other pathways (Raff, 1998).
secrete various proteins onto the surface regulatory molecules determines cell fate.
of their targets cells. One of the proteins, Beside the Bcl-2 protein family, there is at least one further family of intracellular regulators, termed the IAP (inhibitors of proteins to enter into the cell. Granzyme B apoptosis) proteins (LaCasse et al., 1998).
is a protease that cleaves and activatesintracellular death is nonrandom degradation of DNA.
This occurs in two-steps, mediated by of cysteine aspartic acid-specific enzymes, (Yuan et al., 1993). Activated ICE/CED-3proteases can cleave various substrates, fragments allows visualization of apoptotic destruction of cells. Until now, the caspase cells in tissue sections. Many studies have applied the TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick endlabelling (TUNEL) method for this purpose(Gavrieli et al., 1992).
A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 Apoptosis in the normal gastric
desctruction was suggested to occur in theintestinal crypts of irradiated rodents Physiological epithelial cell loss in the stomach is mediated by apoptosis, thus it stomach (Leithäuser et al., 1993). Later their extracellular matrix. This disruption of cell-cell- or cell-matrix-interaction may epithelia (Houghton et al., 1999; Rudi et result in a loss of external suppression of al., 1998a). Albeit the number of foveolar apoptosis (Frisch and Francis, 1994).
epithelia which express CD95 is small, it Eventually, apoptotic cells are shed into the lumen. As an alternative term for this physiological turnover of gastric epithelial be mediated by apoptosis, such as it is in apoptotic (Figure 1) (Imatani et al., 1996; but evidence for this assumption is limited Ishida et al., 1996; Moss et al., 1996; Rudi (Potten, 1998). Only few TUNEL+ cells are et al., 1998a; Steininger et al., 1998).
present in the neck zone of gastric glands Apoptotic bodies are only rarely identified where proliferating cells (Ki67+) prevail by light microscopy in the normal gastric mucosa. This virtual rarity may be due to Intracellular regulatory proteins of the Bcl- patterns in the normal gastric epithelium.
(Washington et al., 1987). When apoptotic engulfed by adjacent epithelial cells, or connective tissue (Hall et al., 1994). Of found to be limited to a few cells in the mucous neck region (Cho and Kim, 1998).
upper and lower end of the gastric glands (Hall et al., 1994; Imatani et al., 1996; epithelium, but not in glandular epithelia Beside senescent apoptosis, it is assumed by means of immunoblotting, Bcl-2 protein that there is another subtype of apoptosis is more abundant than Mcl-1 protein in the normal stomach (Krajewski et al., 1995).
The different patterns of Bcl-2 and Mcl-1 A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 apoptosis, while the pathogenesis of type (Krajewski et al., 1995). High amounts of A (A=autoimmune) gastritis is less clear.
Bax protein are present in the gastricglands, as revealed by immunohisto- Chronic gastritis, type A
chemistry and Western blot analysis(Penault-Llorca et al., 1998). The lack of a diffuse lympho-plasmacellular infiltration apoptotic features suggests that Bax alone is not sufficient to trigger cell death, but with progressive loss of parietal cells and may modulate the role of other regulators chief cells (Eidt et al., 1996). At long-term of apoptosis (Penault-Llorca et al., 1998).
gastric foveolar epithelial cells, as revealed (produced by parietal cells) are present inabout 90% of patients, it is considered pathogenic (Toe et al., 1997). In contrast worm cell death gene ced-3, is present in the cytosol of human gastric epithelial l lympho-epithelial lesions. Thus, thepathogenesis of parietal cell and chief cell Apoptosis in chronic gastritis
loss in type A chronic gastritis is poorlyunderstood. Apoptosis mediated by the epithelial proliferation. Several studies Chronic gastritis, type B
induced chronic gastritis, by means ofimmunohistochemical Gastritis induced by Helicobacter pylori is proliferating cells (Ki67; PCNA), by silver al., 1993; Cahill et al., 1995; Fraser et al., mononuclear cells and neutrophils, in the 1994; Harvard et al., 1996; Lynch et al., presence of bacterial colonization but not 1996; Murakami et al., 1995; Tsuji et al.,1992). proliferation is a common feature in H.
independently of H. pylori infection (Fraser et al., 1999). Of note, chronic gastritis is foveolar cells in the S-phase of the cell hyperproliferation is apparently balanced epithelial cell loss in type B (B=bacterial, mechanisms to explain this increasedproliferation, which may act in concert.
First, it may caused by H. pylori urease A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 activity producing ammonia (Tsuji et al., 1993; Matsui et al., 1997). Second, H.
epithelial proliferation (Peek et al., 1997).
epithelial cell kinetics (Anti et al., 1998).
This dissociation of proliferation andapoptosis was suggested as a possibleexplanation for the heightened risk ofgastric carcinoma that is associated withinfection by CagA+ and VacA+ strains of H. pylori (Blaser et al., 1995; Rudi et al., (Moss et al., 1996; Mannick et al., 1996; Nardone et al., 1999). Thus, the increase of apoptosis in active H. pylori-infection is In a subgroup of patients with H. pylori-gastritis extending from the antrum intothe corpus, antigastric antibodies are Fig. 1 Gastric epithelial apoptosis in the present which bind to the canaliculi within normal antrum (H.p.-negative), and in chronic antral gastritis (H.p.-positive). Biopsies were antibodies correlates with the severity of assessed after TUNEL staining, and at least 300 cells were counted in each histologicsection. The number of positive cells per 100 epithelial cells is expressed as percentage apoptotic cells (TUNEL+) was found in thecorpus foveolar and glandular epithelium(Steininger et al., 1998).
Common view suggests that apoptosis is a direct effect of H. pylori infection, and is increase in the number of apoptotic cells is not an effect of the inflammatory infiltrate supported by experimental findings in rats counted (Anti et al., 1998; Atallah et al., well characterized H. pylori strain (MTCC 1996; Rudi et al., 1998a; Steininger et al., counting of various cells (foveolar vs.
glandular epithelium, or both), and by the strains (Rudi et al., 1998b). However, no patient´s CagA status and apoptosis (Peek A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 epithelial hyperproliferation (Houghton et In gastritis, the number of epithelial cells al., 1999). Indeed, an overall increase of substantially increased, both in the antral surface epithelium (30%, vs. 0,8% in non- inflamed stomach; p < 0.003), and in the infection and gastroduodenal ulcer disease (Rudi et al, 1998a). This upregulation in staining indicated an increase of apoptosis in pyloric gland epithelia (Kohda et al., inflammatory cytokines such as interferon- γ or TNF-α by infiltrating leucocytes, but role of these cytokines (see below).
activity, and not for the number of colony Alternatively H. pylori appears itself to Evidence for this is provided by in vitro epithelial proliferation, may explain theoutcome of H. pylori-induced gastritis with infiltrating lymphocytes in the gastricmucosa, and interestingly also by the Chronic Gastritis, Type C
epithelial cells themselves (Houghton etal., 1999; Rudi, et al., 1998a). CD95L Gastritis induced by chemical agents, e.g.
bile reflux, drugs, alcohol, is frequently form on epithelial cells by contact with H.
erosions in the presence of a rather scarce apoptosis by "fratricide" interacting with leucocyte infiltration in the lamina propria.
arthritis treated with non-steroidal anti- CD95L in the close proximity to apoptotic significantly increased (Zhu et al., 1998).
(TUNEL+) gastric epithelial cells suggest a concurrent H. pylori-gastritis the increase in the induction of apoptosis in H. pylori- NSAID are taken (Zhu et al., 1998). Inexperimental alcohol-induced gastropathy, No significant upregulation of Bcl-2 protein as early as 30 minutes after ingestion of was found in H. pylori-gastritis of non-H.
alcohol mucosal lesions are present in the fold increase in apoptosis, and a 2.5-fold expression of Bak protein was reported to increase in TNF-alpha. These effects could be increased in H. pylori-gastritis (Chen et lesions result from apoptotic cell losses A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 Gastric Graft-versus-host Disease
more frequent in glands with incompletethan complete intestinal metaplasia, Apoptosis is the hallmark of graft-versus- presumably indicating elimination of more DNA-damaged cells (Ishida et al., 1996).
This is consistent with the finding that Bcl- classic target organs of GvHD (i.e. skin, incomplete intestinal metaplasia, but only than previously appreciated (Snover et al., 1985; Washington et al., 1997). Usuallynumerous large apoptotic bodies are Mechanisms
apoptosis
present which tend to be located in theneck portion of the gland, while gastric epithelial cell lines
inconspicious (Washington et al., 1997).
performed in gastric epithelial cell lines, all sparse lamina propria infiltrate, if any, (e. g. 5-fluorouracil, cisplatin) or other drugs (e.g. paclitaxel, green tea catechin point of study (Chang et al., 1996; Inadaet al., 1997; Ikeguchi et al., 1997; Intestinal metaplasia
Hibasami et al., 1998; Vollmers et al.,1995). Beside these kind of studies, some mechanisms of apoptosis in the stomach.
atrophy, as defined by the presence ofmetaplastic glands with intestinal-type The capacity of transforming growth factor 1997). Intestinal metaplasia is considered reproduced in a dozen gastric cancer cell lines. Binding of TGF-β to TGF receptors I or II on the surface of gastric cancer cells resulted consistently in activation of the attempted to characterize gastric epithelial turnover in intestinal metaplasia. Overall increased (Imatani et al., 1996; Ishida et receptors were investigated in gastric cell intestine but different from normal gastric glands (Imatani et al., 1996; Ishida et al., from cultures of gastric mucosal biopsies, 1996). Apoptotic cells (TUNEL+) are found as well as from gastric epithelial cell lines, (Imatani et al., 1996; Ishida et al., 1996).
A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 increase in apoptotic cells (Chen et al., were found to be actively produced in H.
pylori infected gastric mucosa. The sTNF- TNF in vitro to induce apoptosis in gastric strains of H. pylori (Wagner et al., 1997).
difference in the rate of apoptotic cells study. In a gastric cancer cell line (Kato- cytotoxic H. pylori strain (i.e. a vacA s1 and cagA positive strain) compared with a non-cytotoxic strain (Rudi et al., 1998a).
histocompatibility complex (MHC) class II induced apoptosis, the expression of CD95 (Fan et al., 1998). This effect was partially was studied in various gastric epithelial cells lines (AGS, Kato-III, Hs 746T).
Incubation of cells with sublethal doses of a cytotoxic H. pylori supernatant resulted molecules in the induction of apoptosis in H. pylori-gastritis (Fan et al., 1998).
from a basal expression in 7% of cells up to 50% of AGS cells within 48 hours.
mutated, or wild-type p53 gene. Apoptosis TNF-α (Rudi et al., 1998a; Wagner et al., between 35 to 60% of cells with wild-type reached with non-gastric cancer cell lines p53, but only 20% of cells with mutated or 1998a). The mechanism of this effect is so Another effect of H. pylori was observed in investiganted in few studies. Cocultivation in gastric epithelial cell lines (AGS, Kato- III; Hs 746 T). In untreated cells, CD95L cultured cell counts (Wagner et al., 1997).
support for an active epithelial production This effect was shown to be due to direct experiment. After pretreatment with H.
pylori supernatant, gastric epithelial cell sensitization of cancer cells for apoptosis a CD95L-sensitive lymphoma line (Jurkat).
cocultivation of other gastric cancer cell lines (AGS, Kato-III, Hs746T) with H.
pylori supernatant resulted also in a rapid A. von Herbay, J. Rudi : Role of apoptosis in gastric epithelial turnover
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Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311 induced apoptosis and proliferation ingastric epithelial cells. Dig. Dis. Sci., 43:1957--1963 Legends to the other figures
Apoptotic bodies (*) at the surface offoveolar glands in active H. pylori-gastritis in the antrum (hemalaun-eosin, original slide magnificationx158).
glandular and foveolar epithelial cellsin chronic

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