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Animal Models of Stomach Carcinogenesis

Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan

Correspondence: Address correspondence to: Tetsuya Tsukamoto, Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusaku, Nagoya 464-8681, Japan; email:ttsukamt{at}aichi-cc.jp

Although incidences of stomach cancer have decreased over the past several decades, the disease remains an important public health problem. To identify pathological and molecular biochemical mechanisms, various experimental animal models have been established in rats and mice with chemical carcinogens including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU). Helicobacter pylori (H. pylori) is one of the most important factors for human stomach disorders, including neoplasia, and the H. pylori-infected and carcinogen-treated Mongolian gerbil (MG) has proven very useful for analyses of underlying processes. The findings with this model support the hypothesis that intestinal metaplasia is important not as a precancerous lesion but rather as a paracancerous condition and that intestinalization of stomach cancer progresses with chronic inflammation. Furthermore, dose-dependent enhancing effects of salt on stomach carcinogenesis could be demonstrated in MGs treated with MNU and H. pylori modifying surface mucous gel layer. H. pylori itself only causes chronic inflammation and acts as a promoter of stomach carcinogenesis in experimental models. Based on the precise pathological diagnosis of stomach lesions such as noncancerous heterotopic proliferative glands (HPG) and adenocarcinomas, a basis for understanding mechanisms of carcinogenesis has been established on which chemoprevention can be modeled.

Key Words: Mouse • rat • Mongolian gerbil • Animal model • Helicobacter pylori • gastric • intestinal metaplasia

Abbreviations: MNNG, N-methyl-N'-nitro-N-nitrosoguanidine • MNU, N-methyl-N-nitrosourea; • H. pylori, Helicobacter pylori • MG, Mongolian gerbil • ENNG, N-ethyl-N'-nitro-N-nitrosoguanidine • 4-NQO, 4-nitroquinoline 1-oxide • 4-HAQO, 4-hydroxyaminoquinoline 1-oxide • IM, intestinal metaplasia • G, gastric • GI, gastric-and-intestinal-mixed • I, intestinal • GOS, galactose oxidase-Schiff • HGM, human gastric mucin • SIMA, small intestinal mucinous antigen • I-ALP, intestinal type alkaline phosphatase activity • Cdx, Caudal-type homeobox gene • Sox2, Srylike high mobility group box gene 2 • PDX1, Pancreatic-duodenal homeobox 1 • HPG(s), Heterotopic proliferative gland(s) • Pg, pepsinogen • PAPG, pepsinogen 1 altered pyloric glands • COX-2, Cyclooxygenase-2 • PPAR, Peroxisome proliferator-activated receptor

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