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Acid, helicobacter and immunity: a new paradigm for oesophagogastric cancer
Journal of Physiology - Paris 95 (2001) 423–427 www.elsevier.com/locate/jphysparis
Acid, helicobacter and immunity: a new paradigm for oesophagogastric cancer Michael J.G. Farthing*, Rebecca Fitzgerald, Zun Wu Zhang Faculty of Medicine, University of Glasgow, 12, Southpark Terrace, Glasgow, GL12 8LG, UK
Abstract Epidemiological evidence has clearly shown a highly significant relationship between Helicobacter pylori infection and the development of duodenal ulcer and distal gastric adenocarcinoma. Despite H. pylori being a common aetiological factor for both disorders, the two disease phenotypes are virtually mutually exclusive. This indicates that the host response to infection has a pivotal role in determining outcome; these disease phenotypes relate to the effect of infection on gastric acid secretion, duodenal ulcer being closely related to sustained acid secretion whereas gastric cancer follows gastric atrophy and impaired gastric acid secretion. Cancer at the oesophageal junction and that associated with Barrett’s oesophagus is now the most rapidly increasing tumour in the gastrointestinal tract. The challenge for the next millennium, therefore, is to try and develop methods for identifying patients at risk of developing oesophagogastric cancer. A common feature in the pathogenesis of both gastric and oesophageal adenocarcinoma is inflammation presenting clinically as gastritis and oesophagitis. The pathway from gastritis to gastric atrophy, dysplasia and carcinoma is thought to be a multi-step process, probably triggered by free radicals within the gastric epithelium and increased exposure to luminal carcinogens. However, it has been unclear as to which aspect of the host response determines whether an individual will move along the neoplasia pathway. Recent work has shown that qualitative aspects of the immune environment in the stomach may account for a substantial part of the phenotypic divergence following H. pylori infection. Interleukin-1b polymorphisms relate closely to the propensity for an individual to develop distal gastric cancer and maybe useful for predicting risk in family members. In Barrett’s oesophagus, we have recently shown that the immune environment may also be important in determining whether an individual will develop cancer. Although we did not find that Barrett’s oesophagus was a profoundly inflammatory condition (unlike oesohagitis in the squamous epithelium), where there was evidence of inflammation it was qualitatively different from that of oesophagitis in that a Th-2 response with increased expression of IL-4 predominated in Barrett’s, whereas a Th-1 proinflammatory response characterised oesophagitis in squamous epithelium. It seems likely that the specific immune environment within Barrett’s metaplasia may be an important driver towards dysplasia and carcinoma. Thus, the immune environment in the stomach and oesophagous may be critical in determining whether an individual is at risk of developing neoplastic complications of H. pylori infection and gastrooesphageal reflux. Identification of the genetic factors which underpin these responses may ultimately result in development of methods to identify individuals at high risk. # 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction Although the aphorisms ‘no acid. . .no ulcer’ and ‘no acid. . .no reflux’ are still largely true the complexity of the aetiopathogenesis of peptic ulcer, reflux oesophagitis and oesophagogastric cancer has been transformed by the discovery of Helicobacter pylori and the expanding knowledge of the cellular and molecular basis of
* Corresponding author. Tel.: +44-141133014249; fax: +44-141330-3360. E-mail address: [email protected] (M.J.G. Farthing).
inflammatory and neoplastic pathways in the gastrointestinal epithelium. Epidemiological evidence has shown a highly significant relationship between H. pylori infection and the development of duodenal ulcer and distal gastric adenocarcinoma. Despite H. pylori being a common aetiological factor for both disorders the two disease phenotypes are virtually mutually exclusive. This indicates that the host response to infection has a pivotal role in determining outcome; these disease phenotypes relate to the effect of infection on gastric acid secretion, duodenal ulcer being closely related to sustained acid secretion, whereas gastric cancer follows gastric atrophy
0928-4257/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0928-4257(01)00058-4
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M.J.G. Farthing et al. / Journal of Physiology - Paris 95 (2001) 423–427
and impaired gastric acid secretion (Fig. 1). Although H. pylori related gastric adenocarcinoma is decreasing in the industrialised world, proximal gastric cancer is the most rapidly increasing solid tumour in humans. H. pylori infection does not appear to be directly related to the development of this cancer although infection may protect against gastro-oesophageal reflux disease and reduce the risk of developing Barrett’s oesophagus and oesophageal adenocarcinoma. The challenge for the next millennium therefore is to try and develop methods for identifying patients at risk of developing oesophagogastric cancer. A common feature in the pathogenesis of both gastric and oesophageal adenocarcinoma is inflammation, presenting clinically as gastritis and oesophagitis. Chronic inflammation is associated with increased cancer risk in other conditions in the gastro-intestinal tract such as ulcerative colitis, Crohn’s disease and coeliac disease. However, not all individuals with these conditions develop cancer suggesting that other factors including host genotype may have an important part to play in triggering the neoplastic pathway.
2. Inflammation and gastric adenocarcinoma Gastric cancer is the second most common solid tumour worldwide. Although the overall incidence of distal gastric cancer has been decreasing over the past few decades, the incidence of adenocarcinomas of the proximal stomach and oesophagogastric junction is increasing [2,34]. It is one of the most common cancers in China [36]. In the UK, it accounts for almost 10,000 deaths each year [24]. About 20,000–25,000 Americans each year will be diagnosed with gastric carcinoma, and around 15,000 will die of the disease [2]. In Japan, gastric carcinoma remains the most frequent cancer in both sexes and accounts for 20–30% of all incident cancers [32]. Gastric carcinogenesis is a complex, multi-step, and multi-factorial process in which many factors have been implicated, such as ageing, autoimmune factors, malnutrition and chronic inflammation; or repeated exposure to bile, aspirin, alcohol and sodium chloride. Over the past few years, H. pylori infection, the main cause of gastritis, has been strongly linked to the development of gastric carcinoma [1,11,40]. It has recently been shown,
Fig. 1. The possible mechanisms which may relate to the diverse outcomes of H. pylori infection,namely duodenal ulcer and gastric cancer. At low gastric pH ( <4) and normal antioxidant levels, the production of NOCs (N-nitroso compounds) is inhibited and the ROMs (reactive oxygen metabolites) produced during the infection are neutralised by gastric antioxidants; therefore, the gastric cancer risk is low. However, at high gastric pH (54), the production of NOCs is enhanced by gastric bacteria, including H. pylori; unfortunately, antioxidant defence is significantly weakened by the long-standing H. pylori infection, high gastric pH and the formation of gastric atrophy/intestinal metaplasia. The gastric carcinogens, such as NOCs and ROMs are both present in the gastric lumen and within gastric mucosa at high concentrations; this can lead to DNA damage and gene mutations and thus the risk of gastric cancer is increased. ( inhibited; inhibition is blocked; promoted).
M.J.G. Farthing et al. / Journal of Physiology - Paris 95 (2001) 423–427
425
in a Mongolian gerbil model of H. pylori infection, that the formation of gastric cancer is preceded with a series of mucosal premalignant changes, such as metaplasia and atrophy [33]. However, the underlying mechanisms of H. pylori associated gastric carcinogenesis remain unknown [37]. Disturbances in cell turnover in the gastrointestinal tract are believed to predispose to cancer development [12] and it is clear that this organism is capable of modifying epithelial cell turnover within gastric glands and in gastric epithelial cells in culture [8,28,39]. We have studied the effect of H. pylori infection on gastric epithelial cell proliferation and found that patients infected with H. pylori had significantly higher proliferation rates compared with uninfected controls [5,21,28,29]. Recently, multidisciplinary research has shown that low intake of fresh fruits and vegetables is associated with an increased risk of epithelial cancers [4]. Although many substances are contained in fruits and vegetables, a prominent group is the antioxidants, especially vitamins C, E, and b-carotene [4,10]. The coexistence of H. pylori and these antioxidants in human stomach has stimulated many studies on the relationship between these antioxidants and H. pylori associated gastric carcinogenesis. [3,19,23].
affecting both proliferative and apoptotic pathways ultimately in some individuals leading to the development of overt adenocarcinoma [38]. Protective effects from antioxidant vitamins such as vitamin C may facilitate the process if dietary levels are insufficient. However, it has been unclear as to which aspect of the host response determines whether an individual will move along the neoplasia pathway. Recent work has shown that qualitative aspects of the immune environment in the stomach may account for a substantial part of the phenotypic divergence following H. pylori infection [9]. Interleukin-1b polymorphisms suspected of enhancing production of IL-1b are associated with an increased risk of both hypochlorhydria induced by H. pylori and gastric cancer. Two of these polymorphisms are in near-complete disequilibrium and one is a TATAbox polymorphism that markedly affects DNA-protein interactions in vitro. The association with these H. pylori related human diseases probably relates to the biological activities of IL-1b, namely its potency as a pro-inflammatory cytokine and its impressive power to inhibit gastric acid secretion. Sreening for these polymorphisms maybe useful for predicting risk in family members.
2.1. H. pylori associated gastric mucosal oxidative stress
3. Inflammation and cancer risk in Barrett’s oesophagus
Carcinogens are able to cause permanent structural changes in DNA such as base-pair mutations, deletions, insertions, rearrangements, and sequence amplification. In addition, they are able to activate cytoplasmic and nuclear signal transduction pathways, and to modulate the activity of stress proteins and stress genes that influence cell growth, differentiation, and cell death. ROMs possess all these properties and therefore, they are one of the most important groups of human carcinogens. The gastrointestinal tract has the enzymatic machinery necessary to form large amounts of ROMs such that there is a dramatic increase of ROM production during inflammation. H. pylori infection induces marked infiltration of inflammatory cells within the gastric mucosa; these inflammatory cells such as neutrophils and monocytes synthesise and release copious amounts of toxic ROMs [18]. ROMs are highly toxic and can cause damage to all cellular components, including structural and regulatory proteins, carbohydrates, and DNA [7]. Base-pair changes in oncogenes and tumour suppressor genes are commonly found cancers and pre-cancer and are typically produced by deamination of 5-methyl-cytosine which is enhanced by ROMs, especially by nitric oxide (NO) [22,25]. Thus, the pathway from gastritis to gastric atrophy, dysplasia and carcinoma is thought to be a multi-step process probably triggered by free radicals within the gastric epithelium and increased exposure to luminal carcinogens. This will lead to alterations in the cell cycle
The pathogenesis of Barrett’s oesophagus has not been clearly defined although it is usually associated with gastro-oesophageal reflux disease (GORD) and is more common in white males [6,35]. The conventional view is that the oesophageal epithelial response to reflux depends upon its severity and chronicity. This might be regarded as the continuum theory whereby mild reflux produces no macroscopic damage in the oesophagus, moderate reflux results in oesophagitis and patients with severe and persistent reflux may progress to Barrett’s oesophagus. This presumably is the basis for Barrett’s oesophagus being classified as Grade 5 oesophagitis in the Savary-Miller grading system [26], which is often referred to as ‘‘Barrett’s oesophagitis’’. There is, however, no direct evidence that oesophagitis progresses to specialised intestinal metaplasia. Furthermore, there is mounting epidemiological and cell biological evidence to suggest that oesophagitis and Barrett’s oesophagus may be fundamentally different responses to reflux. We propose that alternative pathways exist which are probably the result of a genetically determined alteration in the balance between aggressive and protective oesophageal factors, which may be congenital or acquired as a result of the luminal environment. 3.1. Cellular mechanisms for the induction of metaplasia Metaplasia usually occurs in the context of chronic injury to a mucosal surface. Barrett’s pathogenesis has
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been explained on the basis that the elongated papillae in oeosphagitis render the stem cells susceptible to damage by refluxate, so that only the stem cells which have the ability to de-differentiate to a mucin secreting phenotype survive [17]. Although this is an attractive hypothesis, elongation of papillae does not directly correlate with the severity of reflux and these changes in papillae have been shown to occur in 57% of healthy individuals. Interestingly, attempts to produce animal models of Barrett’s have been largely unsuccessful despite the induction of very profound reflux into the oesophagus. In contrast, oesophagitis can be readily induced in these models [16,20,30,31]. Recently, there have been several reports of genetic alterations in cytokines and growth factors that play a pivotal role in the induction of metaplasia. As discussed earlier, it has been demonstrated that IL-1b polymorphisms determine whether patients with H. pylori infection develop duodenal ulcer disease or progress along the gastric cancer pathway [9]. In patients with Barrett’s oesophagus, there are preliminary data to suggest that there are fundamental differences in the cytokine profile of the oesophageal mucosa of patients with Barrett’s oesophagus compared with patients with an non-inflamed squamous oesophagus or oesophagitis [13]. Whereas, oesophagitis is characterised by an acute inflammatory response Barrett’s epithelium is characterised by elevated levels of Th-2, anti-inflammatory cytokines [14,15,27]. This may be important since the precise cytokine environment has been shown to be a key determinant of the diverse disease manifestations, which can occur in response to a common stimulus.
[5]
[6]
[7] [8] [9]
[10]
[11] [12] [13]
[14]
[15]
[16]
[17]
4. Conclusion Thus, the immune environment in the stomach and oesophagus may be critical in determining whether an individual is at risk of developing neoplastic complications of H. pylori infection and gastrooesphageal reflux. Identification of the genetic factors which underpin these responses may ultimately result in development of methods to identify individuals at high risk.
[18]
[19] [20]
[21]
References [22] [1] Anonymous. Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7–14 June 1994. IARC Monogr. Eval. Carcinog. Risks Hum. 61 (1994) 1–241. [2] American Cancer Society. Cancer facts and figures, 1995. [3] V.K. Atanasova-Goranova, P.I. Dimova, G.T. Pevicharova, Effect of food products on endogenous generation of N-nitrosamines in rats, Br. J. Nutr. 78 (1997) 335–345. [4] G. Block, B. Patterson, A. Subar, Fruit, vegetables, and cancer
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M.J.G. Farthing et al. / Journal of Physiology - Paris 95 (2001) 423–427 [26] J.-B. Ollyo, F. Lang, C. Fontolliet, et al., Savary-Miller’s new endoscopic grading of reflux-esophagitis: A simple, reproductible, logical, complete and useful classification, Gastroenterology 98 (1990) A100. [27] B. Onwuegbusi, R. Fitzgerald, M. Elliott, W. Burnham, M. Farthing, Distinct cytokine patterns in Barrett’s oesophagus and associated adenocarcinoma: evidence for a shift towards a Th2 response, Gastroenterology 184 (2000) AG413. [28] S.E. Patchett, P.H. Katelaris, Z.W. Zhang, E.M. Alstead, P. Domizio, M.J.G. Farthing, Ornithine decarboxylase activity is a marker of premalignancy in long-standing Helicobacter pylori infection, Gut 39 (1996) 807–810. [29] R.M. Peek Jr., S.F. Moss, K.T. Tham, G.I. Perez-Perez, S. Wang, G.G. Miller, J.C. Atherton, P.R. Holt, M.J. Blaser, Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis, J. Natl. Cancer Inst. 89 (1997) 863–868. [30] R. Salmon, B. Hem, Bile reflux esophagitis: A critical study of 2 rat models, Digestion 22 (1981) 73–79. [31] Y. Seto, O. Kobori, Role of reflux oesophagitis and acid in the development of columnar epithelium in the rat oesophagus, Br. J. Surg. 80 (1993) 467–470. [32] S. Tominaga, Trends in cancer mortality, incidence and survival in Japan, Gan To Kagaku Ryoho 19 (1992) 1113–1120. [33] T. Watanabe, M. Tada, H. Nagai, S. Sasaki, M. Nakao, Helicobacter pylori infection induces gastric cancer in mongolian gerbils, Gastroenterology 115 (1998) 642–648.
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[34] S.L. Whelan, D.M. Parkin, E. Masuyer, Trends in cancer incidence and mortality, IARC Scientific Publications, Lyon, France, 1993. [35] C. Winters, T. Spurling, S. Chobanian, D. Curtis, R. Esposito, J.H. 3d, D. Johnson, D. Cruess, J. Coetligon, M. Gurney and others. Barrett’s esophagus: A prevalent occult complication of gastro-oesophageal reflux disease. Gastroenterology, 92 (1987) 118–124. [36] G.Y. Yang, Y.C. Zhang, X.D. Liu, Y.Q. Wu, M.S. Li, C.Y. Gong, B.W. Guan, D.H. Mi, S. Liu, Geographic pathology on the precursors of stomach cancer, J. Environ. Pathol. Toxicol. Oncol. 11 (1992) 339–344. [37] Z.W. Zhang, M.J.G. Farthing, H. Molecular mechanisms of, pylori associated gastric carcinogenesis, World J. Gastroenterol. 5 (1999) 369–374. [38] Z.W. Zhang, M.J.G. Farthing, Helicobacter pylori in gastric malignancy: role of oxidants, antioxidants and other co-factors, in: R.H. Hunt, G.N.J. Tytgat (Eds.), Helicobacter pylori. Basic Mechanisms to Clinical Cure 2000, Kluwer Academic Publishers, Boston, 2000, pp. 513–524. [39] Z.W. Zhang, S.E. Patchett, M.J.G. Farthing, Effect of H. pylori on gastric epithelial cell cycle progression, Gut 45 (1999) 439. [40] Z.W. Zhang, Y.Y. Xing, S.Q. Li, Z.H. Huang, Seroepidemiological investigation of Helicobacter pylori infection in a Beijing population (Chinese), Beijing Medicine 23 (1992) 250– 252.
Acid, helicobacter and immunity: a new paradigm for oesophagogastric cancer Michael J.G. Farthing*, Rebecca Fitzgerald, Zun Wu Zhang Faculty of Medicine, University of Glasgow, 12, Southpark Terrace, Glasgow, GL12 8LG, UK
Abstract Epidemiological evidence has clearly shown a highly significant relationship between Helicobacter pylori infection and the development of duodenal ulcer and distal gastric adenocarcinoma. Despite H. pylori being a common aetiological factor for both disorders, the two disease phenotypes are virtually mutually exclusive. This indicates that the host response to infection has a pivotal role in determining outcome; these disease phenotypes relate to the effect of infection on gastric acid secretion, duodenal ulcer being closely related to sustained acid secretion whereas gastric cancer follows gastric atrophy and impaired gastric acid secretion. Cancer at the oesophageal junction and that associated with Barrett’s oesophagus is now the most rapidly increasing tumour in the gastrointestinal tract. The challenge for the next millennium, therefore, is to try and develop methods for identifying patients at risk of developing oesophagogastric cancer. A common feature in the pathogenesis of both gastric and oesophageal adenocarcinoma is inflammation presenting clinically as gastritis and oesophagitis. The pathway from gastritis to gastric atrophy, dysplasia and carcinoma is thought to be a multi-step process, probably triggered by free radicals within the gastric epithelium and increased exposure to luminal carcinogens. However, it has been unclear as to which aspect of the host response determines whether an individual will move along the neoplasia pathway. Recent work has shown that qualitative aspects of the immune environment in the stomach may account for a substantial part of the phenotypic divergence following H. pylori infection. Interleukin-1b polymorphisms relate closely to the propensity for an individual to develop distal gastric cancer and maybe useful for predicting risk in family members. In Barrett’s oesophagus, we have recently shown that the immune environment may also be important in determining whether an individual will develop cancer. Although we did not find that Barrett’s oesophagus was a profoundly inflammatory condition (unlike oesohagitis in the squamous epithelium), where there was evidence of inflammation it was qualitatively different from that of oesophagitis in that a Th-2 response with increased expression of IL-4 predominated in Barrett’s, whereas a Th-1 proinflammatory response characterised oesophagitis in squamous epithelium. It seems likely that the specific immune environment within Barrett’s metaplasia may be an important driver towards dysplasia and carcinoma. Thus, the immune environment in the stomach and oesophagous may be critical in determining whether an individual is at risk of developing neoplastic complications of H. pylori infection and gastrooesphageal reflux. Identification of the genetic factors which underpin these responses may ultimately result in development of methods to identify individuals at high risk. # 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction Although the aphorisms ‘no acid. . .no ulcer’ and ‘no acid. . .no reflux’ are still largely true the complexity of the aetiopathogenesis of peptic ulcer, reflux oesophagitis and oesophagogastric cancer has been transformed by the discovery of Helicobacter pylori and the expanding knowledge of the cellular and molecular basis of
* Corresponding author. Tel.: +44-141133014249; fax: +44-141330-3360. E-mail address: [email protected] (M.J.G. Farthing).
inflammatory and neoplastic pathways in the gastrointestinal epithelium. Epidemiological evidence has shown a highly significant relationship between H. pylori infection and the development of duodenal ulcer and distal gastric adenocarcinoma. Despite H. pylori being a common aetiological factor for both disorders the two disease phenotypes are virtually mutually exclusive. This indicates that the host response to infection has a pivotal role in determining outcome; these disease phenotypes relate to the effect of infection on gastric acid secretion, duodenal ulcer being closely related to sustained acid secretion, whereas gastric cancer follows gastric atrophy
0928-4257/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0928-4257(01)00058-4
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M.J.G. Farthing et al. / Journal of Physiology - Paris 95 (2001) 423–427
and impaired gastric acid secretion (Fig. 1). Although H. pylori related gastric adenocarcinoma is decreasing in the industrialised world, proximal gastric cancer is the most rapidly increasing solid tumour in humans. H. pylori infection does not appear to be directly related to the development of this cancer although infection may protect against gastro-oesophageal reflux disease and reduce the risk of developing Barrett’s oesophagus and oesophageal adenocarcinoma. The challenge for the next millennium therefore is to try and develop methods for identifying patients at risk of developing oesophagogastric cancer. A common feature in the pathogenesis of both gastric and oesophageal adenocarcinoma is inflammation, presenting clinically as gastritis and oesophagitis. Chronic inflammation is associated with increased cancer risk in other conditions in the gastro-intestinal tract such as ulcerative colitis, Crohn’s disease and coeliac disease. However, not all individuals with these conditions develop cancer suggesting that other factors including host genotype may have an important part to play in triggering the neoplastic pathway.
2. Inflammation and gastric adenocarcinoma Gastric cancer is the second most common solid tumour worldwide. Although the overall incidence of distal gastric cancer has been decreasing over the past few decades, the incidence of adenocarcinomas of the proximal stomach and oesophagogastric junction is increasing [2,34]. It is one of the most common cancers in China [36]. In the UK, it accounts for almost 10,000 deaths each year [24]. About 20,000–25,000 Americans each year will be diagnosed with gastric carcinoma, and around 15,000 will die of the disease [2]. In Japan, gastric carcinoma remains the most frequent cancer in both sexes and accounts for 20–30% of all incident cancers [32]. Gastric carcinogenesis is a complex, multi-step, and multi-factorial process in which many factors have been implicated, such as ageing, autoimmune factors, malnutrition and chronic inflammation; or repeated exposure to bile, aspirin, alcohol and sodium chloride. Over the past few years, H. pylori infection, the main cause of gastritis, has been strongly linked to the development of gastric carcinoma [1,11,40]. It has recently been shown,
Fig. 1. The possible mechanisms which may relate to the diverse outcomes of H. pylori infection,namely duodenal ulcer and gastric cancer. At low gastric pH ( <4) and normal antioxidant levels, the production of NOCs (N-nitroso compounds) is inhibited and the ROMs (reactive oxygen metabolites) produced during the infection are neutralised by gastric antioxidants; therefore, the gastric cancer risk is low. However, at high gastric pH (54), the production of NOCs is enhanced by gastric bacteria, including H. pylori; unfortunately, antioxidant defence is significantly weakened by the long-standing H. pylori infection, high gastric pH and the formation of gastric atrophy/intestinal metaplasia. The gastric carcinogens, such as NOCs and ROMs are both present in the gastric lumen and within gastric mucosa at high concentrations; this can lead to DNA damage and gene mutations and thus the risk of gastric cancer is increased. ( inhibited; inhibition is blocked; promoted).
M.J.G. Farthing et al. / Journal of Physiology - Paris 95 (2001) 423–427
425
in a Mongolian gerbil model of H. pylori infection, that the formation of gastric cancer is preceded with a series of mucosal premalignant changes, such as metaplasia and atrophy [33]. However, the underlying mechanisms of H. pylori associated gastric carcinogenesis remain unknown [37]. Disturbances in cell turnover in the gastrointestinal tract are believed to predispose to cancer development [12] and it is clear that this organism is capable of modifying epithelial cell turnover within gastric glands and in gastric epithelial cells in culture [8,28,39]. We have studied the effect of H. pylori infection on gastric epithelial cell proliferation and found that patients infected with H. pylori had significantly higher proliferation rates compared with uninfected controls [5,21,28,29]. Recently, multidisciplinary research has shown that low intake of fresh fruits and vegetables is associated with an increased risk of epithelial cancers [4]. Although many substances are contained in fruits and vegetables, a prominent group is the antioxidants, especially vitamins C, E, and b-carotene [4,10]. The coexistence of H. pylori and these antioxidants in human stomach has stimulated many studies on the relationship between these antioxidants and H. pylori associated gastric carcinogenesis. [3,19,23].
affecting both proliferative and apoptotic pathways ultimately in some individuals leading to the development of overt adenocarcinoma [38]. Protective effects from antioxidant vitamins such as vitamin C may facilitate the process if dietary levels are insufficient. However, it has been unclear as to which aspect of the host response determines whether an individual will move along the neoplasia pathway. Recent work has shown that qualitative aspects of the immune environment in the stomach may account for a substantial part of the phenotypic divergence following H. pylori infection [9]. Interleukin-1b polymorphisms suspected of enhancing production of IL-1b are associated with an increased risk of both hypochlorhydria induced by H. pylori and gastric cancer. Two of these polymorphisms are in near-complete disequilibrium and one is a TATAbox polymorphism that markedly affects DNA-protein interactions in vitro. The association with these H. pylori related human diseases probably relates to the biological activities of IL-1b, namely its potency as a pro-inflammatory cytokine and its impressive power to inhibit gastric acid secretion. Sreening for these polymorphisms maybe useful for predicting risk in family members.
2.1. H. pylori associated gastric mucosal oxidative stress
3. Inflammation and cancer risk in Barrett’s oesophagus
Carcinogens are able to cause permanent structural changes in DNA such as base-pair mutations, deletions, insertions, rearrangements, and sequence amplification. In addition, they are able to activate cytoplasmic and nuclear signal transduction pathways, and to modulate the activity of stress proteins and stress genes that influence cell growth, differentiation, and cell death. ROMs possess all these properties and therefore, they are one of the most important groups of human carcinogens. The gastrointestinal tract has the enzymatic machinery necessary to form large amounts of ROMs such that there is a dramatic increase of ROM production during inflammation. H. pylori infection induces marked infiltration of inflammatory cells within the gastric mucosa; these inflammatory cells such as neutrophils and monocytes synthesise and release copious amounts of toxic ROMs [18]. ROMs are highly toxic and can cause damage to all cellular components, including structural and regulatory proteins, carbohydrates, and DNA [7]. Base-pair changes in oncogenes and tumour suppressor genes are commonly found cancers and pre-cancer and are typically produced by deamination of 5-methyl-cytosine which is enhanced by ROMs, especially by nitric oxide (NO) [22,25]. Thus, the pathway from gastritis to gastric atrophy, dysplasia and carcinoma is thought to be a multi-step process probably triggered by free radicals within the gastric epithelium and increased exposure to luminal carcinogens. This will lead to alterations in the cell cycle
The pathogenesis of Barrett’s oesophagus has not been clearly defined although it is usually associated with gastro-oesophageal reflux disease (GORD) and is more common in white males [6,35]. The conventional view is that the oesophageal epithelial response to reflux depends upon its severity and chronicity. This might be regarded as the continuum theory whereby mild reflux produces no macroscopic damage in the oesophagus, moderate reflux results in oesophagitis and patients with severe and persistent reflux may progress to Barrett’s oesophagus. This presumably is the basis for Barrett’s oesophagus being classified as Grade 5 oesophagitis in the Savary-Miller grading system [26], which is often referred to as ‘‘Barrett’s oesophagitis’’. There is, however, no direct evidence that oesophagitis progresses to specialised intestinal metaplasia. Furthermore, there is mounting epidemiological and cell biological evidence to suggest that oesophagitis and Barrett’s oesophagus may be fundamentally different responses to reflux. We propose that alternative pathways exist which are probably the result of a genetically determined alteration in the balance between aggressive and protective oesophageal factors, which may be congenital or acquired as a result of the luminal environment. 3.1. Cellular mechanisms for the induction of metaplasia Metaplasia usually occurs in the context of chronic injury to a mucosal surface. Barrett’s pathogenesis has
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been explained on the basis that the elongated papillae in oeosphagitis render the stem cells susceptible to damage by refluxate, so that only the stem cells which have the ability to de-differentiate to a mucin secreting phenotype survive [17]. Although this is an attractive hypothesis, elongation of papillae does not directly correlate with the severity of reflux and these changes in papillae have been shown to occur in 57% of healthy individuals. Interestingly, attempts to produce animal models of Barrett’s have been largely unsuccessful despite the induction of very profound reflux into the oesophagus. In contrast, oesophagitis can be readily induced in these models [16,20,30,31]. Recently, there have been several reports of genetic alterations in cytokines and growth factors that play a pivotal role in the induction of metaplasia. As discussed earlier, it has been demonstrated that IL-1b polymorphisms determine whether patients with H. pylori infection develop duodenal ulcer disease or progress along the gastric cancer pathway [9]. In patients with Barrett’s oesophagus, there are preliminary data to suggest that there are fundamental differences in the cytokine profile of the oesophageal mucosa of patients with Barrett’s oesophagus compared with patients with an non-inflamed squamous oesophagus or oesophagitis [13]. Whereas, oesophagitis is characterised by an acute inflammatory response Barrett’s epithelium is characterised by elevated levels of Th-2, anti-inflammatory cytokines [14,15,27]. This may be important since the precise cytokine environment has been shown to be a key determinant of the diverse disease manifestations, which can occur in response to a common stimulus.
[5]
[6]
[7] [8] [9]
[10]
[11] [12] [13]
[14]
[15]
[16]
[17]
4. Conclusion Thus, the immune environment in the stomach and oesophagus may be critical in determining whether an individual is at risk of developing neoplastic complications of H. pylori infection and gastrooesphageal reflux. Identification of the genetic factors which underpin these responses may ultimately result in development of methods to identify individuals at high risk.
[18]
[19] [20]
[21]
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