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Center for Basic Research in Digestive Diseases, Division of Gastroenterology, Mayo Clinic, Medical School, and Foundation, Rochester, Minnesota 55905
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ABSTRACT |
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Abstract
Introduction
Summary
References
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Cell death of gastrointestinal epithelial cells occurs by a process referred to as apoptosis. In this review, we succinctly define apoptosis and summarize the role of apoptosis in the physiology and pathophysiology of epithelial cells in the liver, pancreas, and small and large intestine. The physiological mediators regulating apoptosis in gastrointestinal epithelial cells, when known, are discussed. Selected pathophysiological consequences of excessive apoptosis and inhibition of apoptosis are used to illustrate the significance of apoptosis in disease processes. These examples demonstrate that excessive apoptosis may result in epithelial cell atrophy, injury, and dysfunction, whereas inhibition of apoptosis results in hyperplasia and promotes malignant transformation. The specific cellular mechanisms responsible for dysregulation of epithelial cell apoptosis during pathophysiological disturbances are emphasized. Potential future areas of physiological research regarding apoptosis in gastrointestinal epithelia are highlighted when appropriate.
cholestasis; colon cancer; transforming growth factor-
; pancreatitis
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INTRODUCTION |
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Top
Abstract
Introduction
Summary
References
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APOPTOSIS, a morphologically and biochemically distinct form of cell death, is an important physiological process in epithelial cell biology. Cell death by apoptosis is a highly conserved evolutionary process for deleting senescent, damaged, redundant, and deleterious cells from the organism. In addition, rates of apoptosis are paired with rates of mitosis so that epithelial cell numbers remain constant and tissue homeostasis is maintained (54). Given the widespread and critical role of apoptosis in physiology, it is not surprising that dysregulation of apoptosis occurs frequently during pathophysiological disturbances. Indeed, several key concepts have recently emerged with respect to the dysregulation of apoptosis in pathophysiological processes, making a review focused on gastrointestinal epithelial cells timely and topical. First, tissue hyperplasia and atrophy can result from inhibition or potentiation of apoptosis, respectively. Second, pathophysiological processes can trigger the cellular apoptotic machinery leading to rapid and extensive cell death and tissue dysfunction. Finally, failure of apoptosis to delete genetically altered cells appears to contribute to malignant transformation. The therapeutic corollaries of these concepts are that 1) inhibition of apoptosis may prevent tissue injury and/or promote tissue regeneration and restitution, 2) induction of apoptosis of dysplastic and transformed cells may be useful in preventing and treating malignant diseases, and 3) conversion of necrotic inflammatory injury to an apoptotic noninflammatory process may ameliorate disease processes (see below). Indeed, enhanced and/or deregulated apoptosis has already been implicated in several diseases (Table 1). Although several reviews on apoptosis are available (6, 177, 178), especially regarding the intracellular mechanisms regulating apoptosis (20, 36, 88, 108, 139), this review provides an update on the physiology and pathophysiology of apoptosis as it relates to gastrointestinal epithelial cells. Because mechanisms of apoptosis are best studied when they are exaggerated or disturbed during pathological events, we frequently use pathophysiological paradigms to illustrate the mechanisms regulating apoptosis of gastrointestinal epithelia. We first review, succinctly, key general concepts on the cell physiology of apoptosis, followed by a more in-depth review of apoptosis in the liver, pancreas, and small and large intestine. The lack of information on apoptosis in the esophagus and stomach precludes a review of apoptosis in these tissues. We also highlight those areas of apoptosis that deserve further investigative attention by the physiologist.
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CELL PHYSIOLOGY OF APOPTOSIS |
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Apoptosis is characterized by stereotypical morphological features
including cell shrinkage, the disappearance of microvilli, the
formation of cell surface blebs containing organelles, nuclear chromatin condensation and margination, and nuclear fragmentation (Fig.
1). Ultimately, the cell
separates into intact, discrete, membrane-bound bodies, referred to as
apoptotic bodies. These morphological changes of apoptosis are
currently the "gold standard" for identifying apoptosis.
Apoptotic bodies are phagocytosed in vivo by neighboring epithelial
cells and professional phagocytic cells (mononuclear
cells). Indeed, phagocytosis of apoptotic bodies has been
observed in both hepatocytes and intestinal epithelial cells (111A,
126). Apoptosis is difficult to detect in tissues because the changes
of apoptosis occur rapidly (over 2-4 h) and the apoptotic bodies
are rapidly phagocytosed and removed from the tissue. Indeed,
identifying apoptotic cells in tissues has been likened to counting
meteors in the night sky (23). The intact plasma membrane of the
apoptotic body and its rapid phagocytosis are thought to limit release
of intracellular constituents into the extracellular space. Because
release of intracellular constituents into the extracellular space is
limited, the inflammatory response to the dead cell is postulated to be
nonexistent. However, apoptosis may not be as "silent" as
presumed. For example, hepatocyte apoptosis is associated with the
appearance of hepatocyte intracellular enzymes in the circulation (102,
104, 146). Furthermore, the mediators of apoptosis, such as
transforming growth factor-1 (TGF-1), may have other consequences
(e.g., tissue fibrogenesis). Current dogma suggests that isolated cell
apoptosis also occurs without a disruption of the epithelial cell
permeability barrier. However, few functional data exist to support
this morphological observation, and enhanced rates of apoptosis may
potentially alter the transmembrane resistance of epithelia, leading to
alterations in absorption and secretion.
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The biochemical features of apoptosis identified to date include
changes in the plasma membrane phospholipid orientation, alterations of
intracellular ion homeostasis, activation of proteases and
endonucleases with cleavage of proteins and DNA, respectively, intracellular generation of ceramide via sphingomyelinase, and activation of transglutaminase (21, 36, 108, 140). The precise roles of
each of these events and their relationship to each other is a topic of
current investigation. Phosphatidylserine is located predominantly on
the inner or cytoplasmic face of the plasma membrane in healthy cells.
However, early in apoptosis, phosphatidylserine is translocated to the
outer leaflet of the plasma membrane, presumably for phagocytic
recognition (32). The externalization of phosphatidylserine can be
readily detected using fluorescently labeled annexin V, which has a
strong affinity for phosphatidylserine. Assays employing fluorescently
labeled annexin V are frequently used to identify apoptotic cells
experimentally (Fig. 1) (73). Increases in cytosolic free calcium and
magnesium and decreases in cytosolic pH and potassium have been
implicated as mechanisms contributing to apoptosis (10, 42, 89, 106,
127). Despite the widespread recognition of cell volume changes and
disturbances of ion homeostasis in apoptosis, this facet of apoptosis
has received little attention by transport physiologists and is a
neglected but potentially fruitful area of investigation. A variety of
proteases have been implicated in apoptosis, including members of the
caspase family (previously known as the interleukin-1-converting
enzyme family of proteases), calpains, cathepsins, and the
proteasome (108). In particular, caspases (cysteine proteases
recognizing aspartate in the P1 position of the substrate) have been
strongly implicated in apoptosis. Caspase protease cascades analogous
to the coagulation protease cascade have been suggested as a mechanism
leading to the structural changes of apoptosis. Endonuclease activation
with DNA cleavage follows protease activation in apoptosis. DNA is
initially cleaved into fragments of 300,000 and/or 50,000 base
pairs. This type of DNA cleavage appears to be universal
in apoptosis and can be detected by pulse-field gel electrophoresis or
field inversion gel electrophoresis of DNA. The large-order DNA
cleavage is often, but not always, followed by internucleosomal DNA
cleavage into fragments of 180-200 base pairs (the so-called
"ladder" pattern of DNA cleavage) (Fig. 1).
Different endonucleases are thought to mediate the two types of DNA
cleavage. Detection of DNA cleavage in extracted DNA by gel
electrophoresis techniques or in situ using cytochemical and
histochemical techniques is frequently employed to confirm and identify
apoptosis (39, 102). Activation of either neutral or acidic
sphingomyelinase occurs in many models of apoptosis, leading to the
generation of ceramide from sphingomyelin; ceramide activates a
proapoptotic cell signaling cascade (56). Cross-linking of proteins by
transglutaminase, which catalyzes the formation of
e-(
-glutamyl)lysine peptide bonds between appropriate substrates,
keeps the apoptotic bodies intact during the fragmentation of the cell
(34).
The intracellular signaling pathways for apoptosis have not yet been completely delineated. However, the Fas receptor/Fas ligand pathway of apoptosis has been elucidated more fully and remains the best characterized model of apoptosis (Fig. 2). In this model of apoptosis, binding of the Fas ligand to the Fas receptor results in trimerization of the receptor (98). The trimerized receptor then recruits the binding protein FADD/MORT1 to its death domain. The binding of FADD to the death domain results in the recruitment of caspase 8 to the resulting death-inducing signaling complex (77). Via as yet unknown mechanisms, the interaction of caspase 8 with the death-inducing signaling complex leads to caspase 8 activation. After caspase 8 activation mitochondrial dysfunction occurs, leading to the release of cytochrome c and perhaps also apoptosis-inducing factor (AIF) into the cytosol (77). Either cytochrome c or AIF can potentiate caspase 3 activation, a key protease causing the structural changes of apoptosis.
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The cellular threshold for apoptosis is also highly regulated, especially by members of the Bcl-2 family of proteins. Multiple mammalian members of this family have been reported to date, including Bcl-2, Bax, Bcl-x, Bcl-w, Bak, Bad, A1, NR-13, and Mcl-1 (37). These proteins (except for Bad) are integral membrane proteins localized predominantly to the nuclear membrane, endoplasmic reticulum, and outer mitochondrial membranes. Members of this family can be antiapoptotic [Bcl-2, Bcl-xL (long), Bcl-w, A1, Mcl-1, NR-13] and proapoptotic [Bcl-xS (short), Bax, Bad]; however, the pro- or antiapoptotic function of these proteins may also depend on the cell type, the apoptotic stimuli, the cellular context (e.g., cell cycle dependence of the process), and the cellular environment (e.g., presence or absence of growth factors). The mechanism by which these proteins modulate apoptosis is unclear, but these proteins appear to regulate each other by forming homo- and heterodimers. The crystal structure of Bcl-x has been reported; this protein appears to have a channel configuration similar to diphtheria toxin, and anion-transporting activity has been observed (96). Thus these proteins may modulate apoptosis by altering the electrochemical responses of cells to pathophysiological processes.
Rates of epithelial cell apoptosis, as with other cells, can be controlled by the presence of growth factors. Because growth factors often inhibit apoptosis by paracrine mechanisms, Raff (115) has suggested that apoptosis is a socially regulated process in that cells need each other to survive. This concept has four important conceptual ramifications. First, the default response of a cell may be to die by apoptosis unless it is kept alive by cell survival signals originating from other cells. The social control of apoptosis may be important in maintaining tissue homeostasis with regard to cell number. Second, the dependence on neighboring cells for cell survival is a strong stimulus to prevent cell metastases. Third, therapeutic administration of growth factors may block apoptosis in disease processes. Finally, inhibition of apoptotic programs may be required for cell growth.
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LIVER |
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Physiology of apoptosis in the liver. There are two epithelial cell types in the liver, hepatocytes and cholangiocytes (bile duct epithelial cells). Because much of what we know about apoptosis in the liver is based on studying hepatocytes, in this review we primarily discuss hepatocyte apoptosis. Where information is available, we also discuss what is known regarding the physiology of cholangiocyte apoptosis. Characterization of apoptosis rates in epithelial tissues such as the liver with low rates of cell turnover is problematic due to the transient nature of recognizable apoptotic events. Indeed, even in a tissue undergoing 50% involution in 3 days by steady-state apoptosis, at any given time point only 9% of the cells would be identified as apoptotic (6). In the liver, it is estimated that only 2-4 cells per 10,000 will be detected as apoptotic given the low cell turnover of both hepatocytes and cholangiocytes under physiological conditions (126). Despite the low endogenous rates of apoptosis in the liver, the importance of apoptosis in regulating liver volume is underscored by two observations. First, the nongenotoxic, peroxisome-proliferating drugs lead to increases in liver cell volume by inhibiting apoptosis (7) and the Fas knockout mouse has substantial liver cell hyperplasia (3). Second, segmental liver atrophy occurring during portal vein ligation results from enhanced hepatocyte apoptosis (70). We believe a better understanding of epithelial cell apoptosis in tissues with low turnover rates will require new and different methods for identifying apoptotic cells.
Physiological mediators of apoptosis: growth factors, cytokines, and
Fas receptor/Fas ligand.
Although primary cultures of hepatocytes do not appear to require
growth factors for survival, this observation is confounded by the
extremely rapid dedifferentiation of hepatocytes in culture, which
precludes an assessment of their dependence on growth factors for
survival. Hepatocyte growth factor (HGF) is a potent mitogen for
hepatocytes in primary culture and appears to provide a key physiological growth stimulus after partial hepatectomy (91). After
chronic treatment of hepatocytes in vitro with HGF, acute withdrawal of
the growth factor induces hepatocyte apoptosis. These observations
suggest that in vivo, where growth factors are continually present,
hepatocytes may be dependent on growth factors for their survival (24).
HGF is able to prevent apoptosis induced by treatment of murine
hepatocytes with interferon- (95). The HGF receptor associates with
the antiapoptotic protein BAG-1, providing a mechanism for inhibition
of apoptosis by HGF (6b). Indeed, the HGF receptor when expressed as a
constitutively active form blocks apoptosis and permits hepatocyte
immortalization (5). Likewise, epidermal growth factor, also a hepatic
mitogen, inhibits hepatocyte apoptosis induced by TGF- (31). Growth
factors may potentially inhibit apoptosis by enhancing expression of
the antiapoptotic members of the Bcl-2 family of proteins. For example,
liver regeneration after partial hepatectomy is associated with
increases in the mRNA transcript for
Bcl-xL, suggesting that inhibition
of the apoptotic machinery by this protein promotes liver regeneration (76). Interleukin-6 (IL-6), also a potent growth factor in the regenerating liver, upregulates
Bcl-xL expression in myeloma
cells, preventing apoptosis (129). Liver failure from extensive cell death, presumably by apoptosis, occurs after a partial hepatectomy in
IL-6-deficient mice (25).
1 and the toxic cytokine tumor necrosis factor-
(TNF-) has
been more extensively studied. Physiological regression of the liver to
baseline volumes after cessation of treatment with hepatomitogens
occurs by induction of hepatocyte apoptosis (18, 43, 125). Hepatocyte
apoptosis is accompanied by expression of TGF-1 in apoptotic cells
(103). Another line of evidence supporting a role for TGF-1 in
hepatocyte apoptosis includes the induction of apoptosis in rat liver
by activin, a member of the TGF-1 family (128). Although TGF-1
expression in the liver is abnormal in a variety of disease states
(45), the role of TGF-1 in hepatocyte apoptosis in disease processes
requires further documentation. Escape from TGF-1-induced apoptosis
may contribute to hepatocarcinogenesis. Indeed, the development of
resistance to TGF-1, with a consequent loss of growth inhibition and
apoptosis, was shown to contribute to the spontaneous transformation of
rat liver epithelial cells to a malignant phenotype (62) and
hepatocellular cancer in vivo (31a).
TGF-1 may also provide an important link between apoptosis and
fibrogenesis in the liver (Fig. 3). In
addition to being synthesized by hepatocytes and causing hepatocyte
apoptosis, TGF-1 is also produced by and activates stellate cells,
which mediate hepatic fibrogenesis. Thus hepatocyte apoptosis and
fibrogenesis could potentially be coupled by one of several possible
mechanisms through TGF-1 (Fig. 3). In one potential scenario,
hepatocyte apoptosis may be the primary event. Secretion of TGF-1 by
apoptotic hepatocytes may lead to stellate cell activation. The
TGF-1-activated stellate cells would then synthesize and secrete
collagen. In an alternative model, stellate cell activation would be
the primary event. Secretion of TGF-1 by activated stellate cells
would then cause apoptosis of neighboring hepatocytes. Indeed,
coculture of hepatocytes with activated stellate cells, which produce
TGF-1, results in enhanced hepatocyte apoptosis (46). Hepatocyte
apoptosis induced by activated stellate cells is reduced when a
recombinant soluble receptor to TGF-1 is included in the cell
culture medium, suggesting TGF-1 is responsible for hepatocyte
apoptosis (46). Given the importance of both apoptosis and fibrogenesis
in liver diseases, the relationship between the two is an important
physiological puzzle requiring further delineation.
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, a cytokine primarily produced by macrophages, cholangiocytes,
and Kupffer cells, is capable of producing a wide range of effects in
vivo, including hepatotoxicity (35). It is now appreciated that TNF-
causes liver injury by inducing hepatocyte apoptosis (82, 104, 109).
TNF- may mediate hepatocyte apoptosis occurring during Kupffer cell
activation by lipopolysaccharide (LPS) and ischemia-reperfusion
injury, the cytokine syndromes associated with septic shock, and
ethanol-mediated liver injury (141). Indeed, TNF-
peripheral serum concentrations are increased in alcoholic hepatitis
and may contribute to the hepatocyte injury observed in this syndrome
(13). Induction of apoptosis of mouse hepatocytes by TNF- requires
transcriptional arrest but functional translation, implicating protein
synthesis as a necessary component of the pathway (81, 82). Translation
of proapoptotic proteins from preformed RNA or the activation of an
immediate-early gene response (with preformed transcriptional
machinery) may thus be inferred to be apoptotic mechanisms mediating
the signaling cascade distal to TNF- receptor ligation. In both
TNF- and LPS models of hepatocyte apoptosis the production of nitric
oxide (NO) by increased expression of inducible nitric oxide synthase
(iNOS) has been suggested as a cytoprotective mechanism; prevention of iNOS upregulation was thus suggested to be a candidate mechanism by
which transcriptional inhibition sensitizes hepatocytes to undergo
apoptosis (82). However, subsequent investigations have demonstrated
that NO generated by increased iNOS expression may itself be a toxic
mediator enhancing hepatocyte death (78). Further work is required to
clarify the potential cytoprotective and injurious actions of iNOS and
NO in hepatocyte apoptosis.
Fas receptor/Fas ligand interactions are also important inducers of
apoptosis in hepatocytes (38). The Fas receptor is a member of the
nerve growth factor receptor family. Binding of the receptor by Fas
ligand results in apoptosis of the cell expressing the Fas receptor.
Unlike many ligands, Fas ligand is predominantly cell bound and it is
expressed in high numbers of cytotoxic T lymphocytes (68). Hepatocytes
constitutively express Fas receptor and may upregulate expression of
this receptor in a variety of liver diseases, including viral hepatitis
and alcohol-induced liver disease (38, 60, 92). For example,
immunohistochemical studies demonstrate Fas receptor expressed on
hepatocytes attached to infiltrating lymphocytes near the regions of
"piecemeal necrosis" in hepatitis C-positive patients, suggesting
that hepatocyte apoptosis occurs via a T cell-mediated Fas pathway in
this viral liver disease (60). In a model of fulminant hepatic failure,
intraperitoneal injection of agonistic anti-Fas antibody leads to
massive hepatocyte apoptosis and liver failure (104). In
pathophysiological processes, hepatocytes may also express Fas ligand,
raising the possibility that a Fas ligand-positive hepatocyte may
induce apoptosis in a Fas receptor-positive neighbor, an example of
fratricide (38). Because Fas ligand is constitutively expressed on
cytotoxic lymphocytes (CTL), cell-mediated immunity, a common process
contributing to hepatocyte apoptosis in autoimmune and viral hepatitis,
likely occurs via Fas-dependent pathways (68). CTL-induced apoptosis of
target cholangiocytes occurring in allograft rejection, graft vs. host
disease, and primary biliary cirrhosis may also occur via Fas-mediated
pathways (11, 75). Table 2 provides a
summary of the physiological mediators and inhibitors of
apoptosis.
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Cholestasis as a pathophysiological model of liver cell apoptosis. Cholestasis is a common but complex pathophysiological process in human liver disease leading to impaired bile formation, which affects both hepatocytes and cholangiocytes. As a pathophysiological process, it provides a useful model to study apoptosis in both cell types. The prominence of hepatocyte-derived acidophilic (apoptotic) bodies and cell dropout rather than extensive necrosis in cholestatic liver biopsy specimens is testimony to the role of hepatocyte apoptosis in cholestasis (107). Retention and accumulation of toxic bile salts during cholestasis is thought to trigger hepatocyte apoptosis. Indeed, exposure of hepatocytes in primary culture to toxic, hydrophobic bile salts has been demonstrated to directly cause apoptosis of hepatocytes (106). The mechanism of apoptosis by toxic bile salts has been partially clarified in recent years (Fig. 4). The induction of apoptosis by toxic bile salts appears to proceed through activation of protein kinase C (PKC) (67). Activation of PKC appears to cause magnesium influx into the cell, activating magnesium-dependent endonucleases that cleave DNA (66, 106). Through a process that is not yet clear, PKC activity is also associated with activation of cathepsin B, which appears to function as a key effector protease in this model of apoptosis (67, 118).
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Dysregulation of apoptosis and hepatobiliary malignancy. Development of a malignant clone may be conceptualized as proceeding in a stepwise manner. Among the requirements for successful establishment as a malignancy may be the sequential accumulation of mutations necessary to block apoptosis. For example, dysregulation of apoptosis may be necessary to promote growth, prevent elimination by CTL, and allow survival despite detachment from the substratum during metastases (8). These tenets do not mean that neoplastic cells do not undergo apoptosis, because apoptosis is common in neoplastic tissues (19). However, the mechanisms of apoptosis appear to be altered during cell dedifferentiation and malignant transformation.
p53 mutations are common in hepatocellular carcinoma. The p53 gene product acts as a genetic sentinel, acting to initiate the apoptotic process if excessive DNA damage occurs (79). A defective copy of p53 behaves as a dominant negative, resulting in a cell that is resistant to undergoing many forms of apoptosis (84). In regions of the world where both chronic hepatitis B virus infection and dietary aflatoxin B1 exposure are widely prevalent, hepatocellular carcinoma is frequently accompanied by mutation of p53 (57). Moreover, the protein product of the hepatitis X gene binds to p53 and abrogates p53-mediated apoptosis (144). A novel mechanism to escape immune recognition by neoplastic cells is loss of Fas receptor expression and the development of Fas ligand expression by the cancer (53, 93). Expression of the Fas ligand results in apoptosis of Fas-receptor-expressing CTL as they attempt to attack the neoplastic cell; loss of Fas receptor by the neoplastic cell ensures its survival despite recognition by the CTL. Indeed, hepatocellular cancers do not express Fas receptor and frequently express Fas ligand, apparently to escape immune surveillance (134). Similar observations have been made in colon cancers (93).| |
PANCREAS |
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Physiology of apoptosis in the pancreas. The pancreas contains two epithelial cell types, acinar cells and pancreatic ductal cells. Analogous to the epithelial cells in the liver, the turnover of both acinar and ductal cells in the pancreas is limited. Under basal conditions, tritiated thymidine uptake by cells in the pancreas is only 0.1-0.2% (40). Assuming basal cell proliferation is matched to apoptosis, rates of apoptosis in the normal pancreas should be equally as low. Unfortunately there is a lack of information regarding the physiological mediators of pancreatic cell apoptosis in either health or disease. Most of what we know about apoptosis in the pancreas is derived from studies of pathophysiological models of pancreatitis.
Pathophysiology of pancreatitis and apoptosis. Pancreatitis results from acinar cell injury and can be characterized as either acute or chronic. Acute pancreatitis is associated with extracellular release of digestive enzymes, which further propagate the inflammatory injury. In various animal models of acute pancreatitis, including pancreatic duct ligation, infusing supramaximal stimulating concentrations of caerulein, and feeding a choline-deficient, ethionine-supplemented diet, the severity of pancreatitis is directly related to the magnitude of acinar cell necrosis and inversely related to the magnitude of acinar cell apoptosis (69). The extent of the inflammation and necrosis appears to be dependent on the recruitment of neutrophils to the pancreas (48). Neutrophils may convert the process of acinar cell death from apoptosis to necrosis (122). Thus the pathophysiological form of cell death during pancreatic injury may be apoptosis, with neutrophils acting as an exogenous necrotic trigger. These data have led to the concept that potentiation of acinar cell death by apoptosis instead of necrosis may ameliorate disease severity during pancreatitis (Fig. 5) (48, 69). Indeed, feeding mice a raw soy diet to stimulate pancreatic growth followed by a switch to a normal chow diet to induce involutional acinar cell apoptosis protects against caerulein-induced apoptosis (121). Thus purposefully inducing acinar cell apoptosis may reduce the severity of pancreatitis in humans. The concept of pharmacological induction of pancreatic apoptosis during the early stages of acute pancreatitis provides a new therapeutic strategy for the treatment of this disease. To our knowledge, this is one of the few examples in which intentional induction of apoptosis in a benign disease would be of potential therapeutic benefit. Potential pharmacological approaches would include prevention of neutrophilic infiltration of the pancreas (122).
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is
capable of inducing fibrogenesis in pancreatic tissue, and conceivably
replacement of acinar tissue by fibrous scarring is in part mediated by
the apoptotic clearance of pancreatic acinar cells (124). The role of
TGF- in inducing acinar cell apoptosis as well as fibrous scarring
in vivo remains unknown. However, overexpression of the
TGF--regulated zinc finger encoding gene, TIEG, induces apoptosis in
pancreatic epithelial cells (135a). Thus it is highly likely that
TGF- can induce pancreatic cell apoptosis.
Dysregulation of apoptosis and pancreatic malignancy.
Pancreatic adenocarcinoma is an extremely aggressive cancer with an
accordingly poor prognosis. Current concepts suggest pancreatic cancers
arise primarily from the ductal epithelial cells in the pancreas. To
date, studies investigating dysregulation of apoptosis as a mechanism
of pancreatic ductal cell carcinogenesis have focused on p53, the
adenomatous polyposis coli (APC) gene, and members of the Bcl-2 family
of proteins. p53 null mice heterozygous for the APC gene lose their
remaining copy of wild-type APC through a somatic mutation. A high
proportion of pancreatic cells in this model exhibit a range of
pancreatic abnormalities, including dysplasia and preneoplastic foci
(61%) and adenocarcinoma (22%) (22). In humans, the p53 gene is
mutated in the majority of pancreatic adenocarcinomas and may
contribute to the clinical aggressiveness of these tumors (27). The
antiapoptotic oncoprotein Bcl-xL
is also strongly expressed in human pancreatic adenocarcinomas (64). The enhanced expression of Bcl-xL
suggests that an altered threshold for the induction of apoptosis (in
addition to the mutation of p53 observed in most pancreatic cancers)
has permitted clonal expansion of the cancer (85, 132). Finally, it is
interesting to note that the tumor supressor gene first identified in
pancreatic cancer, DPC4, is a downstream signaling factor for TGF-
and is now referred to as smad4 (88a). This observation suggests that inhibition of TGF--induced pancreatic apoptosis may be important in
pancreatic carcinogenesis. Although these observations suggest that
dysregulation of apoptosis may occur in pancreatic carcinogenesis, this
concept has not been adequately tested and remains a hypothesis.
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SMALL AND LARGE INTESTINE |
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Physiology of apoptosis in the small and large intestine. Both the small and large intestine have rapid cell turnover rates (3-6 days), suggesting that rates of apoptosis are equally high to provide a counterbalance to the increased cell division (110, 130). Apoptosis of cells at villus tips in the small intestine and luminal surface of the colon is an attractive hypothesis to help explain the high rates of epithelial cell turnover in these organs. However, documentation of enhanced rates of apoptosis in the villus tips and luminal surface of the small and large intestine has proved surprisingly controversial (39, 54, 90). Cells at the villus tip have been noted to be positive for DNA strand breaks with the use of the terminal dideoxynucleotide transferase (TdT) labeling technique, suggesting the cells are apoptotic (39, 54). In contrast, other investigators using the same technique did not identify labeling of cells on the villus tips (90). The controversy resulting from these disparate studies centers on the technique of TdT labeling of 3'-OH ends of DNA as a marker for apoptosis. This technique relies on digestion of tissue with proteinase K before the enzymatic labeling step. It is now apparent that the duration of proteinase K digestion and the use of diethyl pyrocarbonate-treated water influence which and how many cells are labeled using this technique (133). TdT labeling should be combined with complementary morphological techniques before it can be considered a marker for apoptosis. Furthermore, the TdT-based technique is not specific for apoptosis and can also be observed in cell death by necrosis (44). In the small intestine, TdT will label approximately four times as many cells as would be detected by morphology in the villus tip with the use of electron microscopy (130). Nonetheless, apoptosis occurs rapidly in vivo and may therefore appear underrepresented in histological sections, and kinetic analysis suggests that apoptosis rather than shedding from the luminal surface accounts for a large proportion of the cells lost (54). Although further studies will be necessary to prove or disprove the hypothesis that apoptosis is responsible for shedding of cells from the villus tips in the small intestine or luminal surface of the colon, the observation that Bcl-2 is expressed in the proliferation compartment of colonic crypts, whereas Bax is expressed near the lumen, supports this hypothesis in the colon (61, 74, 111a).
Stem cells in the large and small intestine also appear to undergo apoptosis (112). The proportion of stem cells in the small intestinal crypt that undergo apoptosis under physiological conditions has been estimated to be 10% (113). The spontaneous apoptosis of stem cells not exposed to exogenous insults may represent detection and deletion of defective cells (i.e., random genetic defects), as well as control of cell number per se (111). p53 null mice exhibit normal levels of spontaneous apoptosis in the intestinal crypts (28). This suggests either that p53 is not involved in the detection of genetic flaws in recent progeny of stem cells or that the prime function of induction of apoptosis is regulation of cell number. The low incidence of small intestinal tumors despite rapid cellular division in contrast to the relatively high rate of neoplasia in the colon implies more effective eradication of malignant precursor lesions via apoptosis in the small vs. large intestine. The absence of Bcl-2 expression and the presence of the proapoptotic Bax protein in the small intestinal crypt would favor a proapoptotic threshold helping to facilitate apoptosis of genetically altered stem cells (74, 90). In contrast, stem cells in the colon do express the antiapoptotic Bcl-2 protein favoring cell survival despite genetic damage. These observations provide insight into the mechanisms contributing to the high rates of colon cancer in the large intestine compared with the low rates of cancer in the small intestine (80, 87, 119). Expression of Fas ligand has been described as a feature of "immune privileged" sites. Cells expressing Fas ligand can produce apoptosis of Fas receptor-expressing immune effector cells, thereby conferring an immune privilege (47). The Paneth cells of the small intestine express Fas ligand at a high level under normal circumstances (94). The reason for this unique status of Paneth cells is currently unclear. Normal colonic epithelial cells also constitutively express Fas receptor and undergo apoptosis on Fas ligation. Based on these observations it has been proposed that the Fas system contributes to epithelial cell injury in ulcerative colitis and graft vs. host disease (120a, 134a).Physiological mediators of apoptosis: growth factors and dietary
factors.
As we have discussed, TGF- directly induces apoptosis in most
epithelial cells, including colonic epithelial-derived cell lines (6c).
Immunohistochemical studies have shown that, in the small bowel,
TGF-1 is localized primarily in the villus tip (6a, 6c).
In colonic tissue, TGF-1 is expressed predominantly in
nonreplicating cells at the top of the colonic crypts (6a). Positive
expression of TGF- and the absence of Bcl-2 expression by
the cells at the top of the crypts would appear to prime these cells
for apoptosis (54).
Dysregulation of apoptosis and colorectal cancer. Although there are scant data on apoptosis as a mechanism of tissue injury in the small and large intestine, dysregulation of apoptosis as a mechanism contributing to colon carcinogenesis has received considerable attention (Fig. 6). Studies in the colon on dysregulation of apoptosis as a mechanism of carcinogenesis are providing fundamental, pioneering observations highly relevant to the broad field of carcinogenesis in general. Therefore, instead of the the pathophysiological consequences of excessive apoptosis in the intestine, this portion of the review focuses on dysregulation of apoptosis as a cellular mechanism of colon carcinogenesis. Bcl-2, an antiapoptotic oncogene product first implicated in the pathogenesis of follicular lymphoma, has been implicated in the genesis of the adenoma/carcinoma sequence of events in colon carcinogenesis. In normal colon, Bcl-2 protein is expressed only in the base and the lower third of the epithelial column (26). However, increased expression of Bcl-2 was found in most dysplastic, adenomatous, and early adenocarcinomatous lesions (16, 90). Although Bcl-2 may not be expressed in advanced, anaplastic cancers, it is expressed in virtually 100% of adenomas, suggesting that Bcl-2 contributes to the early stages of neoplastic transformation by blocking apoptosis during the transformation process of genetically altered cells (15, 16). These observations suggest that impaired induction of apoptosis due to aberrant Bcl-2 expression facilitates the development of colonic neoplasia.
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type II receptor (4,
86). The resulting frameshift mutations in the gene for this receptor
encode truncated proteins that lack transmembrane and cytoplasmic
domains for the receptor (86). The truncated protein is inactive in
cell signaling and prevents TGF--mediated apoptosis of colonic
epithelium (86). Failure of TGF--mediated apoptosis interrupts a key
physiological mediator of apoptosis in the colon and likely contributes
to colon carcinogenesis in this syndrome. Indeed, mutation of the
TGF- type II receptor occurs in 90% of colon cancers displaying
microsatellite instability, a phenotypic marker for defects in the
base-base mismatch repair enzymes (2, 63, 86, 105, 137). Recently,
frameshift mutations in the bax gene
have also been identified in colon cancers from patients with this
syndrome (116). Loss of Bax function by this mutation would alter the
apoptotic threshold. How failure of TGF-- or Bax-mediated apoptosis
of colonic epithelium leads to colon carcinogenesis remains unclear;
however, failure of apoptosis likely helps to prolong cell survival
during the multiple mutations involved in the multistep stages of colon
carcinogenesis.
Alterations in eicosanoid production within colonic epithelium may also
promote colon carcinogenesis by blocking apoptosis. Most colon cancers
overexpress prostaglandin endoperoxide synthase 2, commonly referred to
as cyclooxygenase-2 (COX-2) (123). Intestinal epithelial
cells overexpressing COX-2 increase expression of Bcl-2, decrease
expression of retinoblastoma kinase, cyclin D1, and TGF- receptors,
and enhance cellular adherence to matrix proteins such as
E-cadherin (29, 30, 138). These phenotypic alterations lead
to a cellular phenotype resistant to butyrate-induced apoptosis (138).
The resistance to apoptosis can be reversed by nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the enzymatic activity
of COX-2, suggesting that enhanced eicosanoid production leads to the
altered phenotype. Compared with histologically normal mucosa, tissue
from human colon cancers showed a 2.3-fold increase of prostaglandin
E2 and a 3.5-fold decrease of
prostaglandin I2 levels, with
unaltered levels of thromboxanes and leukotrienes (representing
products of the 5-lipoxygenase pathway of arachidonic acid metabolism)
(114). However, leukotriene B4 and
12-(R)-hydroxyeicosapentaenoic acid
have also been shown to increase the rate of proliferation of colon
cancer cells in vitro, suggesting that at least some metabolites from
the lipoxygenase and cytochrome P-450
pathways may also be responsible for increased proliferation in colon
cancer (14). These exciting studies provide insight into the resolution of colonic adenomas, which have been reported in patients taking NSAIDs. The use of specific COX-2 inhibitors currently under
development may prove efficacious in the chemoprevention of human
colonic neoplasia. However, it should be noted that induction of
apoptosis by NSAIDs may be independent of blocking eicosanoid pathways. For example, induction of apoptosis cannot be prevented by the addition
of exogenous prostaglandins, and these compounds induce apoptosis in
HCT-15 cells, which lack both COX-1 and COX-2 transcripts (55). The NSAID sulindac and its metabolite sulindac sulfide reduce
the level and activity of multiple cyclin-dependent kinases and induce
expression of p21WAF-1/cip1.
Multiple cellular mechanisms may lead to apoptosis by these pharmacological agents (41, 131).
Finally, alterations in the APC gene, which lead to colon
carcinogenesis, may also regulate apoptosis. The protein product of
this gene is expressed in the nonproliferating, differentiated cell in
the upper half of the crypt. Patients with germline mutations of this
gene produce a truncated protein that presumably has loss of function
(17, 71, 101). APC has been reported to associate with - and
-catenin, proteins that associate with E-cadherin, suggesting that
APC is involved in cell adhesion (120, 135). Recent data suggest APC
may be involved in the apoptotic pathway, and loss of function could
inhibit apoptosis, promoting an expansion of the proliferative zone in
the colon crypt, or could conceivably facilitate metastasis (17).
Expansion of the proliferating zone and prolonged cell survival may
provide the cellular substrate for the enhanced mutagenesis and the
early development of colon cancers observed in affected individuals.
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SUMMARY |
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Top
Abstract
Introduction
Summary
References
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Recent knowledge regarding cell death by apoptosis has markedly altered our concepts of the physiology and pathophysiology of gastrointestinal epithelial cells. We now realize that enhanced apoptosis can lead to tissue injury during vascular, inflammatory, infectious, metabolic, and drug-induced disease processes. Dysregulation or inhibition of apoptosis appears to be important in cell proliferation, tissue hyperplasia, and malignant transformation of gastrointestinal epithelia. Nonetheless, we believe much remains to be learned regarding the role of apoptosis in gastrointestinal diseases. Two fundamental questions remain: 1) What are the initiators and regulators of apoptosis in gastrointestinal epithelia? and 2) What are the intracellular pathways culminating in apoptosis in gastrointestinal epithelial cells? Although the role of Fas receptor and Fas ligand pathways of apoptosis (a pathway fully elucidated in lymphocytes) needs to be further explored in gastrointestinal diseases, many of the initiators and regulators of apoptosis in the gastrointestinal tract will not be shared by lymphocytes (i.e., private pathways of apoptosis). In particular, characterization of the expression of the Bcl-2 family members of proteins and their role in promoting or preventing apoptosis as well as their regulation by cytokines, dietary factors, neuroendocrine peptides, and neurotransmitters needs further delineation. In contrast, the intracellular pathways of apoptosis (e.g., caspase activation, mitochondrial dysfunction) are likely to be shared between lymphocytes and gastrointestinal epithelial cells. Investigators interested in intracellular mechanisms of apoptosis in epithelial cells will need to compare and contrast differences and similarities between the intracellular mechanisms known in lymphocytes and those of epithelial cells. As new knowledge becomes available, the purposeful, therapeutic regulation of apoptosis should prove useful in disease processes.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge the superb secretarial assistance of Sara Erickson.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-41876, by the Gainey Foundation, St. Paul, MN, and by the Mayo Foundation, Rochester, MN.
Address for reprint requests: G. J. Gores, Mayo Medical School, Clinic, and Foundation, 200 First St. SW, Rochester, MN 55905.
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L. Liu, L. Li, J. N. Rao, T. Zou, H. M. Zhang, D. Boneva, M. S. Bernard, and J.-Y. Wang Polyamine-modulated expression of c-myc plays a critical role in stimulation of normal intestinal epithelial cell proliferation Am J Physiol Cell Physiol, January 1, 2005; 288(1): C89 - C99. [Abstract] [Full Text] [PDF]
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T. Zou, J. N. Rao, X. Guo, L. Liu, H. M. Zhang, E. D. Strauch, B. L. Bass, and J.-Y. Wang NF-{kappa}B-mediated IAP expression induces resistance of intestinal epithelial cells to apoptosis after polyamine depletion Am J Physiol Cell Physiol, May 1, 2004; 286(5): C1009 - C1018. [Abstract] [Full Text] [PDF]
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 M. J. Redlak, M. S. Dennis, and T. A. Miller Apoptosis is a major mechanism of deoxycholate-induced gastric mucosal cell death Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G870 - G879. [Abstract] [Full Text] [PDF]
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L. Liu, R. Santora, J. N. Rao, X. Guo, T. Zou, H. M. Zhang, D. J. Turner, and J.-Y. Wang Activation of TGF-{beta}-Smad signaling pathway following polyamine depletion in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G1056 - G1067. [Abstract] [Full Text] [PDF]
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 E. M. Dahly, Z. Guo, and D. M. Ney Alterations in Enterocyte Proliferation and Apoptosis Accompany TPN-Induced Mucosal Hypoplasia and IGF-I-Induced Hyperplasia in Rats J. Nutr., July 1, 2002; 132(7): 2010 - 2014. [Abstract] [Full Text] [PDF]
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C. A. Martin and A. Panja Cytokine regulation of human intestinal primary epithelial cell susceptibility to Fas-mediated apoptosis Am J Physiol Gastrointest Liver Physiol, January 1, 2002; 282(1): G92 - G104. [Abstract] [Full Text] [PDF]
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S. Fiorucci, E. Distrutti, M. N. Ajuebor, A. Mencarelli, R. Mannucci, B. Palazzetti, P. Del Soldato, A. Morelli, and J. L. Wallace NO-mesalamine protects colonic epithelial cells against apoptotic damage induced by proinflammatory cytokines Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G654 - G665. [Abstract] [Full Text] [PDF]
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L. Li, J. N. Rao, X. Guo, L. Liu, R. Santora, B. L. Bass, and J.-Y. Wang Polyamine depletion stabilizes p53 resulting in inhibition of normal intestinal epithelial cell proliferation Am J Physiol Cell Physiol, September 1, 2001; 281(3): C941 - C953. [Abstract] [Full Text] [PDF]
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F. Wolter, B. Akoglu, A. Clausnitzer, and J. Stein Downregulation of the Cyclin D1/Cdk4 Complex Occurs during Resveratrol-Induced Cell Cycle Arrest in Colon Cancer Cell Lines J. Nutr., August 1, 2001; 131(8): 2197 - 2203. [Abstract] [Full Text] [PDF]
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 U. Heczko, C. M. Carthy, B. A. O'Brien, and B. B. Finlay Decreased Apoptosis in the Ileum and Ileal Peyer's Patches: a Feature after Infection with Rabbit Enteropathogenic Escherichia coli O103 Infect. Immun., July 1, 2001; 69(7): 4580 - 4589. [Abstract] [Full Text] [PDF]
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 G. Gomez, H.-M. Lee, Q. He, E. W. Englander, T. Uchida, and G. H. Greeley Jr. Acute Pancreatitis Signals Activation of Apoptosis-Associated and Survival Genes inMice Experimental Biology and Medicine, July 1, 2001; 226(7): 692 - 700. [Abstract] [Full Text] [PDF]
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 G. Yue, P.-S. Lai, K. Yin, F. F. Sun, R. G. Nagele, X. Liu, K. K. Linask, C. Wang, K.-T. Lin, and P. Y-K. Wong Colon Epithelial Cell Death in 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis Is Associated with Increased Inducible Nitric-Oxide Synthase Expression and Peroxynitrite Production J. Pharmacol. Exp. Ther., June 1, 2001; 297(3): 915 - 925. [Abstract] [Full Text]
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R. Gauthier, C. Harnois, J.-F. Drolet, J. C. Reed, A. Vezina, and P. H. Vachon Human intestinal epithelial cell survival: differentiation state-specific control mechanisms Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1540 - C1554. [Abstract] [Full Text] [PDF]
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L. Li, J. N. Rao, B. L. Bass, and J.-Y. Wang NF-{kappa}B activation and susceptibility to apoptosis after polyamine depletion in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, May 1, 2001; 280(5): G992 - G1004. [Abstract] [Full Text] [PDF]
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 E. M. Brown and R. J. MacLeod Extracellular Calcium Sensing and Extracellular Calcium Signaling Physiol Rev, January 1, 2001; 81(1): 239 - 297. [Abstract] [Full Text] [PDF]
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 A. H. GITTER, K. BENDFELDT, J.-D. SCHULZKE, and M. FROMM Leaks in the epithelial barrier caused by spontaneous and TNF-{alpha}-induced single-cell apoptosis FASEB J, September 1, 2000; 14(12): 1749 - 1753. [Abstract] [Full Text]
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 C Schaeffer, M Diab-Assef, M Plateroti, F Laurent-Huck, J M Reimund, M Kedinger, and C Foltzer-Jourdainne Cytokine gene expression during postnatal small intestinal development: regulation by glucocorticoids Gut, August 1, 2000; 47(2): 192 - 198. [Abstract] [Full Text] [PDF]
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N. L. Jones, A. Islur, R. Haq, M. Mascarenhas, M. A. Karmali, M. H. Perdue, B. W. Zanke, and P. M. Sherman Escherichia coli Shiga toxins induce apoptosis in epithelial cells that is regulated by the Bcl-2 family Am J Physiol Gastrointest Liver Physiol, May 1, 2000; 278(5): G811 - G819. [Abstract] [Full Text] [PDF]
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 M. M. Remacle-Bonnet, F. L. Garrouste, S. Heller, F. André, J. L. Marvaldi, and G. J. Pommier Insulin-like Growth Factor-I Protects Colon Cancer Cells from Death Factor-induced Apoptosis by Potentiating Tumor Necrosis Factor {{alpha}}-induced Mitogen-activated Protein Kinase and Nuclear Factor {{kappa}}B Signaling Pathways Cancer Res., April 1, 2000; 60(7): 2007 - 2017. [Abstract] [Full Text]
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Q. Ding, Q. Wang, Z. Dong, and B. M. Evers Characterization and regulation of E2F activity during Caco-2 cell differentiation Am J Physiol Cell Physiol, January 1, 2000; 278(1): C110 - C117. [Abstract] [Full Text] [PDF]
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K M Ekelund and E Ekblad Structural, neuronal, and functional adaptive changes in atrophic rat ileum Gut, August 1, 1999; 45(2): 236 - 245. [Abstract] [Full Text] [PDF]
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M. Varedi, G. H. Greeley Jr., D. N. Herndon, and E. W. Englander A thermal injury-induced circulating factor(s) compromises intestinal cell morphology, proliferation, and migration Am J Physiol Gastrointest Liver Physiol, July 1, 1999; 277(1): G175 - G182. [Abstract] [Full Text] [PDF]
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 S.L. Abrahamse, B.L. Pool-Zobel, and G. Rechkemmer Potential of short chain fatty acids to modulate the induction of DNA damage and changes in the intracellular calcium concentration by oxidative stress in isolated rat distal colon cells Carcinogenesis, April 1, 1999; 20(4): 629 - 634. [Abstract] [Full Text] [PDF]
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 R. M. Rai, F. Y. J. Lee, A. Rosen, S. Q. Yang, H. Z. Lin, A. Koteish, F. Y. Liew, C. Zaragoza, C. Lowenstein, and A. M. Diehl Impaired liver regeneration in inducible nitric oxide synthasedeficient mice PNAS, November 10, 1998; 95(23): 13829 - 13834. [Abstract] [Full Text] [PDF]
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Q.-M. Ding, T. C. Ko, and B. M. Evers Caco-2 intestinal cell differentiation is associated with G1 arrest and suppression of CDK2 and CDK4 Am J Physiol Cell Physiol, November 1, 1998; 275(5): C1193 - C1200. [Abstract] [Full Text] [PDF]
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A. Celli, F. G. Que, G. J. Gores, and N. F. LaRusso Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes Am J Physiol Gastrointest Liver Physiol, October 1, 1998; 275(4): G749 - G757. [Abstract] [Full Text] [PDF]
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