Dig Dis Sci DOI 10.1007/s10620-014-3468-9
REVIEW
Gastrin May Mediate the Carcinogenic Effect of Helicobacter pylori Infection of the Stomach Helge L. Waldum • Øyvind Hauso • Øystein F. Sørdal • Reidar Fossmark
Received: 18 September 2014 / Accepted: 26 November 2014 Ó Springer Science+Business Media New York 2014
Abstract Gastric cancer occurs almost exclusively in patients with gastritis. Since Helicobacter pylori (Hp) was proved to cause gastritis, Hp was also expected to play a role in gastric carcinogenesis. Despite extensive studies, the mechanisms by which Hp cause gastric cancer are still poorly understood. However, there is evidence that the anatomical site of Hp infection is of major importance. Infection confined to the antral mucosa protects against gastric cancer but predisposes to duodenal ulcer, whereas Hp infection of the oxyntic mucosa increases the risk of gastric cancer. Hp infection does not predispose to cancers in the gastric cardia. In patients with atrophic gastritis of the oxyntic mucosa, the intragastric pH is elevated and the concentration of microorganisms in the stomach is increased. This does not lead to increased risk of gastric cancer at all anatomical sites. The site specificity of Hp infection in relation to cancer risk indicates that neither Hp nor the changes in gastric microflora due to gastric hypoacidity are carcinogenic per se. However, reduced gastric
H. L. Waldum (&) Ø. Hauso Ø. F. Sørdal R. Fossmark Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7006 Trondheim, Norway e-mail: [email protected] R. Fossmark e-mail: [email protected] H. L. Waldum Ø. Hauso R. Fossmark Department of Gastroenterology and Hepatology, St Olavs Hospital, Trondheim, Norway Ø. F. Sørdal Department of Internal Medicine, St Olavs Hospital, Trondheim, Norway
acidity also leads to hypergastrinemia, which stimulates the function and proliferation of enterochromaffin-like (ECL) cells located in the oxyntic mucosa. The ECL cell may be more important in human gastric carcinogenesis than previously realized, as every condition causing long-term hypergastrinemia in animals results in the development of neoplasia in the oxyntic mucosa. Patients with hypergastrinemia will far more often develop carcinomas in the gastric corpus. In conclusion, hypergastrinemia may explain the carcinogenic effect of Hp. Keywords Helicobacter pylori Gastrin Gastric cancer Carcinogenesis Gastritis Gastric acid secretion
Introduction Although the prevalence is declining in the Western world [1], gastric carcinomas are still among the main causes of cancer death [2]. There are many different histological classifications of gastric carcinomas, but the classification according to Laure´n seems to be the most commonly used [3]. In this system, the carcinomas are classified as intestinal or diffuse according to the presence or absence of glandular growth pattern. It seems to reflect biology since the tumors seldom or never transform into the other type [3], and they show different epidemiological behavior [4]. The gastric carcinomas of diffuse type have been thought to be adenocarcinomas based upon PAS positivity believed to reflect the presence of mucin. As for other cancers, the etiology of gastric carcinoma has not been known until rather recently. However, it is now realized that a mutation in the E-cadherin gene may cause carcinomas with diffuse morphology [5]. Moreover, during the last 20 years, the importance of Helicobacter
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pylori (Hp) infection in gastric carcinogenesis has been realized [6].
Gastritis and Gastric Cancer Gastritis has for long been recognized as a prevalent condition [7], and that gastritis predisposes to gastric cancer has been known for 100 years [8]. Gastritis is present virtually in all stomachs with cancer [9]. By the description of Hp infection as the cause of gastritis and peptic ulcer by Marshall and Warren [10], it was therefore to be expected that Hp infection was shown to be connected to gastric cancer [6]. However, patients with duodenal ulcers due to Hp infection in the antral mucosa [11] are protected from gastric cancer [12, 13]. Hp infection predisposes to gastric cancer mainly when infecting and causing gastritis [14] and particularly atrophic gastritis of the oxyntic mucosa [15], which results in hypergastrinemia [16]. In the study by Uemura et al. [14], 1,526 patients with different upper gastrointestinal conditions were followed up for up to 10 years, of whom 1,246 patients were Hp positive and the remaining 280 were negative. The Hp negative and the 275 Hp positive with duodenal ulcer did not develop cancer, whereas cancer occurred in all the other subgroups of Hp positive individuals. This is solid evidence of the protective effect of duodenal ulcer, which is accepted to be caused by isolated antral Hp gastritis. It seems therefore highly unlikely that antral Hp gastritis alone should predispose to gastric cancer [12, 13]. Moreover, the importance of oxyntic gastritis in gastric carcinogenesis has been recognized for decades [17] and has also been related to the extent and severity of oxyntic gastritis [18]. Finally, it has recently become clear that the border between oxyntic and antral glands is not strict with oxyntic glands/cells being found in the antrum in humans [19]. Autoimmune gastritis is not as prevalent as Hp gastritis, but affects only the oxyntic mucosa, leading to atrophy and reduced acidity in the stomach. Autoimmune gastritis is further associated with ECL cell carcinoids as well as gastric carcinomas [20, 21]. On the other hand, the fact that Hp infection in young mice causing tolerance without gastritis does not induce premalignant changes [22] and the cancer-protective effect of Hp infection confined to the antral area in patients both suggest that Hp itself is not directly carcinogenic. There have been reports indicating that the carcinogenic effect of different strains of Hp may vary [23], but the results have been inconsistent. Moreover, even if there should be a difference between different strains, this could be secondary to the ability to induce gastritis and not necessarily due to a direct carcinogenic effect. Admittedly, the reported effect of Hp on isolated gastric cells [24, 25] cannot be explained by an indirect mechanism via gastrin. However,
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the biological relevance to gastric carcinogenesis of such cell studies may be questioned. Thus, altogether these facts suggest that Hp infection predisposes to gastric carcinomas by causing oxyntic mucosal atrophy. On the other hand, gastric lymphomas associated with Hp infection [26] most probably are caused by chronic stimulation of proliferation of immune competent cells.
Gastric Hp Infection, Gastric Acidity, and Gastrin Gastrin is central in the regulation of gastric acid secretion [27] causing release of histamine from the ECL cell which in turn stimulates the parietal cell to secrete acid. When Hp infects the antral mucosa, it causes local alkalization due to NH3 produced from urea by urease from Hp [28]. The reduced acidity is recorded by receptors on D or G cells or both, leading to increased gastrin release. Since gastrin is very potent [29], only a slight hypergastrinemia results in increased histamine release from the ECL cell and increased acid secretion. The trophic effect of gastrin on the ECL cell and also indirectly on the parietal cell further increases gastric acid secretion [30]. The increased gastric acidity prevents the development of a marked hypergastrinemia which is virtually never found in patients with duodenal ulcer [31] with the exception of patients with gastrinoma. When the gastritis involves the oxyntic mucosa leading to oxyntic mucosal atrophy, gastric acid secretion is reduced [32], causing reduced gastric acidity and hypergastrinemia which may be marked [33] (Fig. 1). The density of G cells is not influenced by superficial antral gastritis, but may be markedly reduced by atrophic antral gastritis resulting in lower blood gastrin values than what would be expected from gastric acidity [34]. However, antral atrophy seems be unusual in patients with corpus gastritis since there exists a reciprocal relationship between maximal gastric acid secretion (MAO), an indirect parameter for the degree of oxyntic gastritis and atrophy, and serum gastrin [35]. Furthermore, in mice we have
Fig. 1 Antral infection with Helicobacter pylori (Hp) causes a slight hypergastrinemia and increased gastric acidity, but protects against gastric cancer (a). Hp infection and gastritis causing atrophy of the gastric corpus result in gastric hypoacidity, hypergastrinemia and increased risk of gastric neoplasia (b)
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previously shown that Hp infection results in reduced parietal cell function even without glandular atrophy [36].
Consequences of Hp-Induced Oxyntic Atrophic Gastritis with Reduced Gastric Acidity The main function of the highly acidic and proteolytic gastric juice is to kill swallowed microorganisms [37]. Reduced gastric acidity results in the presence of microorganism in the stomach as well as the small intestine. The microbiological changes in the stomach secondary to oxyntic mucosal atrophy could play a role in gastric carcinogenesis [38]. However, if gastric hypoacidity itself should have an effect on gastric carcinogenesis by an effect on intragastric microorganisms, it is difficult to understand why gastric carcinomas in anacidic/hypoacidic patients almost exclusively develop in the oxyntic mucosa and not in the antrum [39] or the cardiac region [6]. Moreover, carcinomas occurring in patients with marked hypergastrinemia show ECL cell differentiation [40], a cell confined to the oxyntic mucosa. Thus, Hp gastritis causes cancer neither in the cardiac region nor in the antrum which argues strongly against a major carcinogenic role of other microorganisms in Hp gastritis.
Consequences of Hp-Induced Oxyntic Atrophic Gastritis with Reduced Gastric Acidity with Secondary Hypergastrinemia Patients with oxyntic mucosal atrophy due to Hp infection are hypergastrinemic due to reduced gastric acidity [33]. Gastrin not only stimulates acid secretion by stimulating histamine release from the ECL cell [27], but also stimulates the proliferation of the same cell [41, 42]. In fact, gastrin has a specific trophic effect on the ECL cell [43] in line with the gastrin receptor being localized to the same cell [44–46]. The general trophic effect of gastrin on the oxyntic mucosa [43, 47] may be either an indirect one or a direct one due to a hitherto undetected gastrin receptor on the stem cell in the oxyntic mucosa. In any way, long-term marked hypergastrinemia in rodents [48–52] as well as in man [53–55] results in ECL cell-derived tumors of variable malignancy. Such tumors may be difficult to classify correctly as shown by the initial misclassification of loxtidineinduced tumors in mice [49, 56] and tumors occurring spontaneously in Mastomys natalensis [57]. In this context, it should be recalled that the maximal functional and trophic effects of gastrin are reached at a rather low concentration both in rodents [58, 59] and in man [60, 61]. As stated above, every condition with long-term hypergastrinemia results in ECL cell tumors. What is the
role of this cell, the only one with a proven gastrin receptor [44], in human gastric carcinogenesis in general? Over the last 20 years, we have repeatedly described the presence of neuroendocrine and often ECL cell markers in gastric carcinomas of diffuse type [40, 62–67]. Furthermore, in contrast to neuroendocrine gene expression, we could not find any such expression for MUC genes when using in situ method with improved sensitivity and specificity [66, 68], further supporting the view that these carcinomas are not adeno- but neuroendocrine carcinomas. During the last years, other groups have also reported on neuroendocrine differentiation of subgroups of gastric cancer, particularly diffuse type with signet ring cell phenotype [69, 70]. They have not classified tumor cells further than to neuroendocrine cells. However, taking into consideration that the ECL cell is the most prevalent gastric neuroendocrine cell [71], which is the origin of virtually all gastric carcinoids, it is probable that their neuroendocrine cells [69, 70] actually are ECL cells. Moreover, gastric carcinoid tumors have also been reported to occur in patients with atrophic gastritis due to Hp [72]. E-cadherin mutation causes familiar gastric cancer of the diffuse type [73] and is also frequent in sporadic gastric cancer of diffuse type [74]. Even early gastric carcinomas of diffuse type lack E-cadherin expression [75]. We have therefore examined normal oxyntic NE cells and could not find any E-cadherin expression [76]. This may perhaps explain that NE cells are spread and that tumors arising from them may give invasion and metastasis at an early phase. Concerning gastric carcinomas of intestinal type, which also are connected to Hp infection, they could also be due to hypergastrinemia in a more indirect way, by stimulating the release of signal substances such as histamine or REG protein [77] from the ECL cell (Fig. 2). Already in 1994 we proposed that the carcinogenic effect of Hp infection could be due to its hypergastrinemic effect [78] and that hypothesis has been supported by the results recently. As early as 1973, McGuigan and Trudeau described elevated gastrin in blood
Fig. 2 Gastrin can induce gastric carcinomas of diffuse and intestinal types by different mechanisms
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of patients with gastric cancer and particularly in those having cancer localized in the body of the stomach [79]. Recently, we therefore determined serum gastrin in a large group of patients with gastric cancer and found that gastrin was markedly elevated in patients having cancers localized to the corpus/fundus but not in those having antral localization [80], thus confirming the initial study of McGuigan and Trudeau which curiously has been more or less unnoticed for decades. Moreover, we found that the total as well as cancer-specific survival time was shorter in the patients with elevated gastrin [80]. Furthermore, in 1988, Kumamoto described gastrin receptors in human gastric carcinomas of scirrhous type [81]. The importance of oxyntic atrophy in Hp-related gastric carcinogenesis was recently amply demonstrated by the study of Yoshida et al. [82].
Animal Studies The importance of gastrin in gastric carcinogenesis is supported by animal studies in genetically manipulated mice (INS-GAS mice) [83], Mongolian gerbils that develop both gastric carcinoids and carcinomas [84] and Japanese cotton rats [85]. In the latter species, tumor development is prevented by a gastrin antagonist [86]. In most of these animal studies, Helicobacter pylori infection causes increase in gastrin as well as gastric neoplasia [87]. The mechanism for the carcinogenic effect of gastrin could just be stimulation of proliferation since mitosis per se implies a certain risk of mutation. Even in the inflammation provoked by Helicobacter pylori infection, gastrin seems to play an important role since the gastrin antagonist netazepide prevented inflammation in the oxyntic mucosa of Mongolian gerbils [88]. Takaishi and co-workers similarly showed that netazepide in the hypergastrinemic model of INS-GAS mice infected with Helicobacter pylori reduced inflammation and gastric atrophy [89]. An even more pronounced protective effect was observed with the histamine-2 blocker loxtidine [89], indicating that histamine from the ECL cell could be a pathogenic factor.
Conclusion Helicobacter pylori was accepted by WHO and IARC as a group I carcinogen. Such a classification implies that there is sufficient evidence of carcinogenicity in humans, whether the mechanism is direct or indirect. We propose that the mechanism for its carcinogenic effect is best explained by hypergastrinemia secondary to oxyntic mucosal atrophy. There exists also a previous review from another group [90] as well as from us [91] on the role of gastrin in
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gastric carcinogenesis. Finally, very recently, there was a report describing molecular characterization of gastric carcinomas [92]. The biological significance and relationship to phenotypes of this classification are presently not established. Conflict of interest
None.
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REVIEW
Gastrin May Mediate the Carcinogenic Effect of Helicobacter pylori Infection of the Stomach Helge L. Waldum • Øyvind Hauso • Øystein F. Sørdal • Reidar Fossmark
Received: 18 September 2014 / Accepted: 26 November 2014 Ó Springer Science+Business Media New York 2014
Abstract Gastric cancer occurs almost exclusively in patients with gastritis. Since Helicobacter pylori (Hp) was proved to cause gastritis, Hp was also expected to play a role in gastric carcinogenesis. Despite extensive studies, the mechanisms by which Hp cause gastric cancer are still poorly understood. However, there is evidence that the anatomical site of Hp infection is of major importance. Infection confined to the antral mucosa protects against gastric cancer but predisposes to duodenal ulcer, whereas Hp infection of the oxyntic mucosa increases the risk of gastric cancer. Hp infection does not predispose to cancers in the gastric cardia. In patients with atrophic gastritis of the oxyntic mucosa, the intragastric pH is elevated and the concentration of microorganisms in the stomach is increased. This does not lead to increased risk of gastric cancer at all anatomical sites. The site specificity of Hp infection in relation to cancer risk indicates that neither Hp nor the changes in gastric microflora due to gastric hypoacidity are carcinogenic per se. However, reduced gastric
H. L. Waldum (&) Ø. Hauso Ø. F. Sørdal R. Fossmark Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7006 Trondheim, Norway e-mail: [email protected] R. Fossmark e-mail: [email protected] H. L. Waldum Ø. Hauso R. Fossmark Department of Gastroenterology and Hepatology, St Olavs Hospital, Trondheim, Norway Ø. F. Sørdal Department of Internal Medicine, St Olavs Hospital, Trondheim, Norway
acidity also leads to hypergastrinemia, which stimulates the function and proliferation of enterochromaffin-like (ECL) cells located in the oxyntic mucosa. The ECL cell may be more important in human gastric carcinogenesis than previously realized, as every condition causing long-term hypergastrinemia in animals results in the development of neoplasia in the oxyntic mucosa. Patients with hypergastrinemia will far more often develop carcinomas in the gastric corpus. In conclusion, hypergastrinemia may explain the carcinogenic effect of Hp. Keywords Helicobacter pylori Gastrin Gastric cancer Carcinogenesis Gastritis Gastric acid secretion
Introduction Although the prevalence is declining in the Western world [1], gastric carcinomas are still among the main causes of cancer death [2]. There are many different histological classifications of gastric carcinomas, but the classification according to Laure´n seems to be the most commonly used [3]. In this system, the carcinomas are classified as intestinal or diffuse according to the presence or absence of glandular growth pattern. It seems to reflect biology since the tumors seldom or never transform into the other type [3], and they show different epidemiological behavior [4]. The gastric carcinomas of diffuse type have been thought to be adenocarcinomas based upon PAS positivity believed to reflect the presence of mucin. As for other cancers, the etiology of gastric carcinoma has not been known until rather recently. However, it is now realized that a mutation in the E-cadherin gene may cause carcinomas with diffuse morphology [5]. Moreover, during the last 20 years, the importance of Helicobacter
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pylori (Hp) infection in gastric carcinogenesis has been realized [6].
Gastritis and Gastric Cancer Gastritis has for long been recognized as a prevalent condition [7], and that gastritis predisposes to gastric cancer has been known for 100 years [8]. Gastritis is present virtually in all stomachs with cancer [9]. By the description of Hp infection as the cause of gastritis and peptic ulcer by Marshall and Warren [10], it was therefore to be expected that Hp infection was shown to be connected to gastric cancer [6]. However, patients with duodenal ulcers due to Hp infection in the antral mucosa [11] are protected from gastric cancer [12, 13]. Hp infection predisposes to gastric cancer mainly when infecting and causing gastritis [14] and particularly atrophic gastritis of the oxyntic mucosa [15], which results in hypergastrinemia [16]. In the study by Uemura et al. [14], 1,526 patients with different upper gastrointestinal conditions were followed up for up to 10 years, of whom 1,246 patients were Hp positive and the remaining 280 were negative. The Hp negative and the 275 Hp positive with duodenal ulcer did not develop cancer, whereas cancer occurred in all the other subgroups of Hp positive individuals. This is solid evidence of the protective effect of duodenal ulcer, which is accepted to be caused by isolated antral Hp gastritis. It seems therefore highly unlikely that antral Hp gastritis alone should predispose to gastric cancer [12, 13]. Moreover, the importance of oxyntic gastritis in gastric carcinogenesis has been recognized for decades [17] and has also been related to the extent and severity of oxyntic gastritis [18]. Finally, it has recently become clear that the border between oxyntic and antral glands is not strict with oxyntic glands/cells being found in the antrum in humans [19]. Autoimmune gastritis is not as prevalent as Hp gastritis, but affects only the oxyntic mucosa, leading to atrophy and reduced acidity in the stomach. Autoimmune gastritis is further associated with ECL cell carcinoids as well as gastric carcinomas [20, 21]. On the other hand, the fact that Hp infection in young mice causing tolerance without gastritis does not induce premalignant changes [22] and the cancer-protective effect of Hp infection confined to the antral area in patients both suggest that Hp itself is not directly carcinogenic. There have been reports indicating that the carcinogenic effect of different strains of Hp may vary [23], but the results have been inconsistent. Moreover, even if there should be a difference between different strains, this could be secondary to the ability to induce gastritis and not necessarily due to a direct carcinogenic effect. Admittedly, the reported effect of Hp on isolated gastric cells [24, 25] cannot be explained by an indirect mechanism via gastrin. However,
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the biological relevance to gastric carcinogenesis of such cell studies may be questioned. Thus, altogether these facts suggest that Hp infection predisposes to gastric carcinomas by causing oxyntic mucosal atrophy. On the other hand, gastric lymphomas associated with Hp infection [26] most probably are caused by chronic stimulation of proliferation of immune competent cells.
Gastric Hp Infection, Gastric Acidity, and Gastrin Gastrin is central in the regulation of gastric acid secretion [27] causing release of histamine from the ECL cell which in turn stimulates the parietal cell to secrete acid. When Hp infects the antral mucosa, it causes local alkalization due to NH3 produced from urea by urease from Hp [28]. The reduced acidity is recorded by receptors on D or G cells or both, leading to increased gastrin release. Since gastrin is very potent [29], only a slight hypergastrinemia results in increased histamine release from the ECL cell and increased acid secretion. The trophic effect of gastrin on the ECL cell and also indirectly on the parietal cell further increases gastric acid secretion [30]. The increased gastric acidity prevents the development of a marked hypergastrinemia which is virtually never found in patients with duodenal ulcer [31] with the exception of patients with gastrinoma. When the gastritis involves the oxyntic mucosa leading to oxyntic mucosal atrophy, gastric acid secretion is reduced [32], causing reduced gastric acidity and hypergastrinemia which may be marked [33] (Fig. 1). The density of G cells is not influenced by superficial antral gastritis, but may be markedly reduced by atrophic antral gastritis resulting in lower blood gastrin values than what would be expected from gastric acidity [34]. However, antral atrophy seems be unusual in patients with corpus gastritis since there exists a reciprocal relationship between maximal gastric acid secretion (MAO), an indirect parameter for the degree of oxyntic gastritis and atrophy, and serum gastrin [35]. Furthermore, in mice we have
Fig. 1 Antral infection with Helicobacter pylori (Hp) causes a slight hypergastrinemia and increased gastric acidity, but protects against gastric cancer (a). Hp infection and gastritis causing atrophy of the gastric corpus result in gastric hypoacidity, hypergastrinemia and increased risk of gastric neoplasia (b)
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previously shown that Hp infection results in reduced parietal cell function even without glandular atrophy [36].
Consequences of Hp-Induced Oxyntic Atrophic Gastritis with Reduced Gastric Acidity The main function of the highly acidic and proteolytic gastric juice is to kill swallowed microorganisms [37]. Reduced gastric acidity results in the presence of microorganism in the stomach as well as the small intestine. The microbiological changes in the stomach secondary to oxyntic mucosal atrophy could play a role in gastric carcinogenesis [38]. However, if gastric hypoacidity itself should have an effect on gastric carcinogenesis by an effect on intragastric microorganisms, it is difficult to understand why gastric carcinomas in anacidic/hypoacidic patients almost exclusively develop in the oxyntic mucosa and not in the antrum [39] or the cardiac region [6]. Moreover, carcinomas occurring in patients with marked hypergastrinemia show ECL cell differentiation [40], a cell confined to the oxyntic mucosa. Thus, Hp gastritis causes cancer neither in the cardiac region nor in the antrum which argues strongly against a major carcinogenic role of other microorganisms in Hp gastritis.
Consequences of Hp-Induced Oxyntic Atrophic Gastritis with Reduced Gastric Acidity with Secondary Hypergastrinemia Patients with oxyntic mucosal atrophy due to Hp infection are hypergastrinemic due to reduced gastric acidity [33]. Gastrin not only stimulates acid secretion by stimulating histamine release from the ECL cell [27], but also stimulates the proliferation of the same cell [41, 42]. In fact, gastrin has a specific trophic effect on the ECL cell [43] in line with the gastrin receptor being localized to the same cell [44–46]. The general trophic effect of gastrin on the oxyntic mucosa [43, 47] may be either an indirect one or a direct one due to a hitherto undetected gastrin receptor on the stem cell in the oxyntic mucosa. In any way, long-term marked hypergastrinemia in rodents [48–52] as well as in man [53–55] results in ECL cell-derived tumors of variable malignancy. Such tumors may be difficult to classify correctly as shown by the initial misclassification of loxtidineinduced tumors in mice [49, 56] and tumors occurring spontaneously in Mastomys natalensis [57]. In this context, it should be recalled that the maximal functional and trophic effects of gastrin are reached at a rather low concentration both in rodents [58, 59] and in man [60, 61]. As stated above, every condition with long-term hypergastrinemia results in ECL cell tumors. What is the
role of this cell, the only one with a proven gastrin receptor [44], in human gastric carcinogenesis in general? Over the last 20 years, we have repeatedly described the presence of neuroendocrine and often ECL cell markers in gastric carcinomas of diffuse type [40, 62–67]. Furthermore, in contrast to neuroendocrine gene expression, we could not find any such expression for MUC genes when using in situ method with improved sensitivity and specificity [66, 68], further supporting the view that these carcinomas are not adeno- but neuroendocrine carcinomas. During the last years, other groups have also reported on neuroendocrine differentiation of subgroups of gastric cancer, particularly diffuse type with signet ring cell phenotype [69, 70]. They have not classified tumor cells further than to neuroendocrine cells. However, taking into consideration that the ECL cell is the most prevalent gastric neuroendocrine cell [71], which is the origin of virtually all gastric carcinoids, it is probable that their neuroendocrine cells [69, 70] actually are ECL cells. Moreover, gastric carcinoid tumors have also been reported to occur in patients with atrophic gastritis due to Hp [72]. E-cadherin mutation causes familiar gastric cancer of the diffuse type [73] and is also frequent in sporadic gastric cancer of diffuse type [74]. Even early gastric carcinomas of diffuse type lack E-cadherin expression [75]. We have therefore examined normal oxyntic NE cells and could not find any E-cadherin expression [76]. This may perhaps explain that NE cells are spread and that tumors arising from them may give invasion and metastasis at an early phase. Concerning gastric carcinomas of intestinal type, which also are connected to Hp infection, they could also be due to hypergastrinemia in a more indirect way, by stimulating the release of signal substances such as histamine or REG protein [77] from the ECL cell (Fig. 2). Already in 1994 we proposed that the carcinogenic effect of Hp infection could be due to its hypergastrinemic effect [78] and that hypothesis has been supported by the results recently. As early as 1973, McGuigan and Trudeau described elevated gastrin in blood
Fig. 2 Gastrin can induce gastric carcinomas of diffuse and intestinal types by different mechanisms
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of patients with gastric cancer and particularly in those having cancer localized in the body of the stomach [79]. Recently, we therefore determined serum gastrin in a large group of patients with gastric cancer and found that gastrin was markedly elevated in patients having cancers localized to the corpus/fundus but not in those having antral localization [80], thus confirming the initial study of McGuigan and Trudeau which curiously has been more or less unnoticed for decades. Moreover, we found that the total as well as cancer-specific survival time was shorter in the patients with elevated gastrin [80]. Furthermore, in 1988, Kumamoto described gastrin receptors in human gastric carcinomas of scirrhous type [81]. The importance of oxyntic atrophy in Hp-related gastric carcinogenesis was recently amply demonstrated by the study of Yoshida et al. [82].
Animal Studies The importance of gastrin in gastric carcinogenesis is supported by animal studies in genetically manipulated mice (INS-GAS mice) [83], Mongolian gerbils that develop both gastric carcinoids and carcinomas [84] and Japanese cotton rats [85]. In the latter species, tumor development is prevented by a gastrin antagonist [86]. In most of these animal studies, Helicobacter pylori infection causes increase in gastrin as well as gastric neoplasia [87]. The mechanism for the carcinogenic effect of gastrin could just be stimulation of proliferation since mitosis per se implies a certain risk of mutation. Even in the inflammation provoked by Helicobacter pylori infection, gastrin seems to play an important role since the gastrin antagonist netazepide prevented inflammation in the oxyntic mucosa of Mongolian gerbils [88]. Takaishi and co-workers similarly showed that netazepide in the hypergastrinemic model of INS-GAS mice infected with Helicobacter pylori reduced inflammation and gastric atrophy [89]. An even more pronounced protective effect was observed with the histamine-2 blocker loxtidine [89], indicating that histamine from the ECL cell could be a pathogenic factor.
Conclusion Helicobacter pylori was accepted by WHO and IARC as a group I carcinogen. Such a classification implies that there is sufficient evidence of carcinogenicity in humans, whether the mechanism is direct or indirect. We propose that the mechanism for its carcinogenic effect is best explained by hypergastrinemia secondary to oxyntic mucosal atrophy. There exists also a previous review from another group [90] as well as from us [91] on the role of gastrin in
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gastric carcinogenesis. Finally, very recently, there was a report describing molecular characterization of gastric carcinomas [92]. The biological significance and relationship to phenotypes of this classification are presently not established. Conflict of interest
None.
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