Curr Infect Dis Rep (2014) 16:402 DOI 10.1007/s11908-014-0402-4
INTRA-ABDOMINAL INFECTIONS, HEPATITIS, AND GASTROENTERITIS (D BOBAK, SECTION EDITOR)
Role of Helicobacter pylori in Gastric Neoplasia Tetsuya Tsukamoto & Masae Tatematsu
Published online: 27 March 2014 # Springer Science+Business Media New York 2014
Abstract Helicobacter pylori infection is one of the most important factors in gastric carcinogenesis in humans. Epidemiological studies have revealed that H. pylori-infected patients develop significantly more gastric cancers than uninfected individuals. In rodent models, H. pylori inoculation causes strong promoting effects in carcinogen-treated animals, whereas the bacterial infection alone causes only hyperplasic, atrophic, and/or metaplastic lesions. In both human and rodent models, eradication of H. pylori helps inhibit gastric carcinogenesis, especially when there is only mild gastric inflammation and no evidence of severe atrophy or intestinal metaplasia. Chemoprevention studies in humans have been reported and have shown the effectiveness of several medications including a cyclooxygenase-2 inhibitor. Candidate chemicals used in rodent models could hopefully be used in humans in the future.
Keywords Helicobacter pylori . Eradication . Mongolian gerbil . Mouse . Intestinal metaplasia . Gastric adenocarcinoma . Heterotopic proliferating glands . Chemoprevention
This article is part of the Topical Collection on Intra-abdominal Infections, Hepatitis, and Gastroenteritis T. Tsukamoto (*) Department of Diagnostic Pathology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan e-mail: [email protected] M. Tatematsu Japan Bioassay Research Center, 2445 Hirasawa, Hadano, Kanagawa 257-0015, Japan
Introduction Despite a recent decreasing trend, gastric cancer remains the fourth most common type of cancer and second leading cause of cancer-related death worldwide [1]. Prevention of this disease is one of the highest priorities of many national cancer control programs, especially in Asian countries. Since Helicobacter pylori was discovered to play a major causative role in chronic gastritis and gastric carcinogenesis, several attempts have been made to treat and prevent the lesions. In parallel, many experimental studies have been performed and have confirmed the importance of H. pylori. Among animal models, mice and Mongolian gerbils are powerful tools for analysis of H. pylori-associated gastric lesions [2, 3••]. In this article, we compare human studies with rodent models of gastric carcinogenesis, and discuss the effects of eradication and chemoprevention of H. pylori on the development of gastric cancer.
Role of H. pylori Infection in Gastric Carcinogenesis: Human Studies Helicobacter pylori, formerly Campylobacter pyloridis, was discovered in patients with chronic active gastritis. It was found to be a gram-negative, flagellate and microaerophilic bacillus, and was suggested as a causative factor in certain gastric disorders [4, 5]. Eradication of H. pylori was shown to markedly reduce the recurrence rate of gastric and duodenal ulcers in infected patients [6]. Intestinal metaplasia was found more often in H. pylori-positive patients compared with H. pylori-negative patients [7]. Helicobacter pylori infection has been shown to be a significant risk factor for development of atrophic gastritis and intestinal metaplasia [8]. Case-control studies have also revealed a positive correlation between H. pylori infection and the development of gastric
402, Page 2 of 6
Curr Infect Dis Rep (2014) 16:402
carcinogenesis [9–11]. A multicenter study from 13 countries has shown sixfold increased risk of gastric cancer in patients with H. pylori infection [12]. Similarly, gastric non-Hodgkin lymphoma has also been found to be associated with H. pylori infection [13]. In a prospective study in 1,526 Japanese patients, gastric cancer developed in 2.9 % of the H. pyloriinfected group but none of the uninfected patients [14]. These epidemiological findings led the World Health Organization/ International Agency for Research on Cancer (WHO/IARC) to define H. pylori as a “definite biological carcinogen” in 1994. In order to establish a causal relationship between H. pylori infection and the development of gastric cancer, the WHO/IARC still required direct evidence of the induction of H. pylori-associated gastric cancer using experimental animal systems [15].
increase the incidence of MNU-induced adenocarcinoma [28]. MNNG could be substituted for the initiation of gastric carcinogenesis in H. pylori infected gerbils [29, 30]. All histological types of gastric malignancy were observed in this gerbil model, including differentiated and undifferentiated adenocarcinomas and signet-ring cell carcinoma. These lesions closely resembled those seen in human pathology. Several studies using detailed histopathological assessment only rarely showed the development of carcinoma in animals treated only with H. pylori infection [27–31]. Thus, H. pylori has been determined to be a strong promoter of gastric carcinogenesis. Subsequently, this H. pylori-infected and carcinogentreated Mongolian gerbil system has proven very useful for analyzing the processes underlying the development of gastric carcinoma [2].
Role of H. pylori Infection in Animal Models
Eradication of H. pylori is Effective in Prevention of Gastric Carcinogenesis: Human Studies
After the discovery of H. pylori, various types of experimental animal model were used to try to clarify the role of H. pylori in the pathological and molecular steps involved in carcinogenesis, but none of the early models proved sufficiently similar to the human situation to show definitive results [16, 17]. In 1990, Lee et al. [18] isolated the H. pylori-related bacterium H. felis from the stomach of cats. Using germ-free mice, they found that H. felis is able to colonize the glandular stomach and to induce acute and chronic gastric inflammation. p53 wild-type and hemizygous mice were inoculated with H. felis and the infected group showed a higher proliferative index in the gastric foveolar epithelium [19]. Helicobacter pylori isolated from human clinical samples was also used to inoculate nude and euthymic mice and was able to cause chronic active gastritis [20–22]. A strain of H. pylori, designated the Sydney strain (SS1), was established by screening of fresh clinical isolates of H. pylori in long-term mouse adaptation experiments. SS1 showed efficient colonizing ability and is currently widely used in murine systems [23]. Besides the mouse models, a Mongolian gerbil (Meriones unguiculatus) model was successfully established and was shown to mimic human H. pylori-induced infection and inflammation. The resulting chronic active gastritis, peptic ulcers and intestinal metaplasia that developed in the gerbil model closely resembled pathology seen with human lesions [24]. For the gastric carcinogenesis models, Sugimura and Fujimura [25] established a rat model using a chemical carcinogen, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), to induce gastric tumors in the glandular stomach. Tatematsu et al. [26] utilized a murine system for developing stomach cancer using N-methyl-N-nitrosourea (MNU). Similarly, in 1998, a stomach carcinogenesis model was developed in Mongolian gerbils using MNU and MNNG as the carcinogens [27]. Helicobacter pylori infection was subsequently found to
To clarify the effects of eradication of H. pylori on prevention of gastric cancer development in patients with chronic gastritis, Uemura et al. [32] conducted a nonrandomized H. pylori eradication trial in patients whose gastric cancer was removed by endoscopic resection. The results of this study suggested that H. pylori eradication might improve neutrophil infiltration and intestinal metaplasia in the gastric mucosa and inhibit the development of new carcinomas. A randomized controlled trial in 1,630 people conducted in China revealed that the overall incidence of gastric cancer in the study population was not significantly different between participants receiving H. pylori eradication treatment and those receiving placebo over the study period of 7.5 years. However, in a subgroup of 988 H. pylori carriers without precancerous lesions (including gastric atrophy, intestinal metaplasia, or gastric dysplasia), eradication of H. pylori significantly decreased the subsequent development of gastric cancer [33]. Fukase et al. [34] investigated the possible prophylactic effect of H. pylori eradication on the development of metachronous gastric carcinomas following endoscopic resection of initial gastric lesions. After a 3-year follow-up, secondary carcinomas had developed in 3.3 % of patients (9/272) in the eradication group and 8.8 % (24/272) in the control group, a significant reduction (odds ratio 0.353, P=0.009). Yanaoka et al. [35] followed 3,656 middle-aged Japanese men with persistent H. pylori infection and 473 subjects with successful H. pylori eradication for the risk of developing gastric cancer. Over a period of 9.3±0.7 years (mean ± SD) they monitored evidence of chronic active gastritis using serum pepsinogen (PG) levels and the PG I/II ratio. They observed a significant reduction in cancer incidence after H. pylori eradication only in subjects with a negative PG test with mild gastritis (P
INTRA-ABDOMINAL INFECTIONS, HEPATITIS, AND GASTROENTERITIS (D BOBAK, SECTION EDITOR)
Role of Helicobacter pylori in Gastric Neoplasia Tetsuya Tsukamoto & Masae Tatematsu
Published online: 27 March 2014 # Springer Science+Business Media New York 2014
Abstract Helicobacter pylori infection is one of the most important factors in gastric carcinogenesis in humans. Epidemiological studies have revealed that H. pylori-infected patients develop significantly more gastric cancers than uninfected individuals. In rodent models, H. pylori inoculation causes strong promoting effects in carcinogen-treated animals, whereas the bacterial infection alone causes only hyperplasic, atrophic, and/or metaplastic lesions. In both human and rodent models, eradication of H. pylori helps inhibit gastric carcinogenesis, especially when there is only mild gastric inflammation and no evidence of severe atrophy or intestinal metaplasia. Chemoprevention studies in humans have been reported and have shown the effectiveness of several medications including a cyclooxygenase-2 inhibitor. Candidate chemicals used in rodent models could hopefully be used in humans in the future.
Keywords Helicobacter pylori . Eradication . Mongolian gerbil . Mouse . Intestinal metaplasia . Gastric adenocarcinoma . Heterotopic proliferating glands . Chemoprevention
This article is part of the Topical Collection on Intra-abdominal Infections, Hepatitis, and Gastroenteritis T. Tsukamoto (*) Department of Diagnostic Pathology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan e-mail: [email protected] M. Tatematsu Japan Bioassay Research Center, 2445 Hirasawa, Hadano, Kanagawa 257-0015, Japan
Introduction Despite a recent decreasing trend, gastric cancer remains the fourth most common type of cancer and second leading cause of cancer-related death worldwide [1]. Prevention of this disease is one of the highest priorities of many national cancer control programs, especially in Asian countries. Since Helicobacter pylori was discovered to play a major causative role in chronic gastritis and gastric carcinogenesis, several attempts have been made to treat and prevent the lesions. In parallel, many experimental studies have been performed and have confirmed the importance of H. pylori. Among animal models, mice and Mongolian gerbils are powerful tools for analysis of H. pylori-associated gastric lesions [2, 3••]. In this article, we compare human studies with rodent models of gastric carcinogenesis, and discuss the effects of eradication and chemoprevention of H. pylori on the development of gastric cancer.
Role of H. pylori Infection in Gastric Carcinogenesis: Human Studies Helicobacter pylori, formerly Campylobacter pyloridis, was discovered in patients with chronic active gastritis. It was found to be a gram-negative, flagellate and microaerophilic bacillus, and was suggested as a causative factor in certain gastric disorders [4, 5]. Eradication of H. pylori was shown to markedly reduce the recurrence rate of gastric and duodenal ulcers in infected patients [6]. Intestinal metaplasia was found more often in H. pylori-positive patients compared with H. pylori-negative patients [7]. Helicobacter pylori infection has been shown to be a significant risk factor for development of atrophic gastritis and intestinal metaplasia [8]. Case-control studies have also revealed a positive correlation between H. pylori infection and the development of gastric
402, Page 2 of 6
Curr Infect Dis Rep (2014) 16:402
carcinogenesis [9–11]. A multicenter study from 13 countries has shown sixfold increased risk of gastric cancer in patients with H. pylori infection [12]. Similarly, gastric non-Hodgkin lymphoma has also been found to be associated with H. pylori infection [13]. In a prospective study in 1,526 Japanese patients, gastric cancer developed in 2.9 % of the H. pyloriinfected group but none of the uninfected patients [14]. These epidemiological findings led the World Health Organization/ International Agency for Research on Cancer (WHO/IARC) to define H. pylori as a “definite biological carcinogen” in 1994. In order to establish a causal relationship between H. pylori infection and the development of gastric cancer, the WHO/IARC still required direct evidence of the induction of H. pylori-associated gastric cancer using experimental animal systems [15].
increase the incidence of MNU-induced adenocarcinoma [28]. MNNG could be substituted for the initiation of gastric carcinogenesis in H. pylori infected gerbils [29, 30]. All histological types of gastric malignancy were observed in this gerbil model, including differentiated and undifferentiated adenocarcinomas and signet-ring cell carcinoma. These lesions closely resembled those seen in human pathology. Several studies using detailed histopathological assessment only rarely showed the development of carcinoma in animals treated only with H. pylori infection [27–31]. Thus, H. pylori has been determined to be a strong promoter of gastric carcinogenesis. Subsequently, this H. pylori-infected and carcinogentreated Mongolian gerbil system has proven very useful for analyzing the processes underlying the development of gastric carcinoma [2].
Role of H. pylori Infection in Animal Models
Eradication of H. pylori is Effective in Prevention of Gastric Carcinogenesis: Human Studies
After the discovery of H. pylori, various types of experimental animal model were used to try to clarify the role of H. pylori in the pathological and molecular steps involved in carcinogenesis, but none of the early models proved sufficiently similar to the human situation to show definitive results [16, 17]. In 1990, Lee et al. [18] isolated the H. pylori-related bacterium H. felis from the stomach of cats. Using germ-free mice, they found that H. felis is able to colonize the glandular stomach and to induce acute and chronic gastric inflammation. p53 wild-type and hemizygous mice were inoculated with H. felis and the infected group showed a higher proliferative index in the gastric foveolar epithelium [19]. Helicobacter pylori isolated from human clinical samples was also used to inoculate nude and euthymic mice and was able to cause chronic active gastritis [20–22]. A strain of H. pylori, designated the Sydney strain (SS1), was established by screening of fresh clinical isolates of H. pylori in long-term mouse adaptation experiments. SS1 showed efficient colonizing ability and is currently widely used in murine systems [23]. Besides the mouse models, a Mongolian gerbil (Meriones unguiculatus) model was successfully established and was shown to mimic human H. pylori-induced infection and inflammation. The resulting chronic active gastritis, peptic ulcers and intestinal metaplasia that developed in the gerbil model closely resembled pathology seen with human lesions [24]. For the gastric carcinogenesis models, Sugimura and Fujimura [25] established a rat model using a chemical carcinogen, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), to induce gastric tumors in the glandular stomach. Tatematsu et al. [26] utilized a murine system for developing stomach cancer using N-methyl-N-nitrosourea (MNU). Similarly, in 1998, a stomach carcinogenesis model was developed in Mongolian gerbils using MNU and MNNG as the carcinogens [27]. Helicobacter pylori infection was subsequently found to
To clarify the effects of eradication of H. pylori on prevention of gastric cancer development in patients with chronic gastritis, Uemura et al. [32] conducted a nonrandomized H. pylori eradication trial in patients whose gastric cancer was removed by endoscopic resection. The results of this study suggested that H. pylori eradication might improve neutrophil infiltration and intestinal metaplasia in the gastric mucosa and inhibit the development of new carcinomas. A randomized controlled trial in 1,630 people conducted in China revealed that the overall incidence of gastric cancer in the study population was not significantly different between participants receiving H. pylori eradication treatment and those receiving placebo over the study period of 7.5 years. However, in a subgroup of 988 H. pylori carriers without precancerous lesions (including gastric atrophy, intestinal metaplasia, or gastric dysplasia), eradication of H. pylori significantly decreased the subsequent development of gastric cancer [33]. Fukase et al. [34] investigated the possible prophylactic effect of H. pylori eradication on the development of metachronous gastric carcinomas following endoscopic resection of initial gastric lesions. After a 3-year follow-up, secondary carcinomas had developed in 3.3 % of patients (9/272) in the eradication group and 8.8 % (24/272) in the control group, a significant reduction (odds ratio 0.353, P=0.009). Yanaoka et al. [35] followed 3,656 middle-aged Japanese men with persistent H. pylori infection and 473 subjects with successful H. pylori eradication for the risk of developing gastric cancer. Over a period of 9.3±0.7 years (mean ± SD) they monitored evidence of chronic active gastritis using serum pepsinogen (PG) levels and the PG I/II ratio. They observed a significant reduction in cancer incidence after H. pylori eradication only in subjects with a negative PG test with mild gastritis (P
