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
Manuscript of review article published in: Microscopy Research and Technique 2000; 48: 303-311
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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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