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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

	Abstract

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

 
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

	Introduction

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

 
Stomach cancer incidence and mortality have fallen dramatically in the United States and western countries over the past several decades. Nonetheless, it remains a major public health issue as the 4th most common cancer and the 2nd leading cause of cancer death worldwide (Crew and Neugut, 2004). In Japan, stomach cancer remains an important medical problem and its prevention is one of the most important aspects of cancer control strategy, despite its decreasing trend (Tsugane, 2005). Many pathological and biological analyses of stomach carcinomas, including precancerous lesions, have been performed with human samples and experimental animals. In this article, we review the history of stomach carcinoma research from the viewpoint of basic aspects, concentrating especial attention on pathological and biological findings and results for various important modifying factors.

	History of Animal Models for Stomach Carcinogenesis

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

 
Rat Model
Attempts to experimentally induce stomach cancers in animal were performed by many researchers using several carcinogens such as benzo[a]pyrene, 3-methylcholanthrene, and 2-acethylaminofluorene starting the 1930s (Rusch, 1940; Wilson, 1941; Stewart and Snell, 1958). However, the incidences of experimentally induced stomach cancer were low, and it was only in 1967 that Sugimura and Fujimura were able to report good yields of adenocarcinomas in the glandular stomachs of rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (Sugimura and Fujimura, 1967). In the pyloric mucosa of the rat glandular stomach exposed to MNNG, erosive lesions occur, and disordering of glandular structures and proliferation of pyloric mucosa are observed. Then, atypical glands and stomach cancer cells become detectable, and finally both differentiated and undifferentiated stomach carcinomas mimicking the histological types of human stomach cancer are induced in this model. The presence of surfactants, such as alkylbenzenesulfonate enhances the effects of carcinogens in the stomach of animals (Takahashi 1969, 1970).

Dog Model
Administration of MNNG to dogs in the drinking water was also found to result in a high incidence of tumors in the glandular stomach (Sugimura et al., 1971). With these animals, it was possible to perform endoscopic observation and take stomach biopsies on a sequential basis. Stomach cancers also occur in dogs given N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) with yields, however, being lower than with MNNG (Kurihara et al., 1974; Sugimura and Kawachi, 1976).

Mouse Model
The glandular stomach of mice has generally been found to be relatively resistant to MNNG action. Administration of MNNG in the drinking water to BRSUNT/NJms mice over the life span only resulted in adenomatous hyperplasia of stomach epithelium (Sugimura, 1973). Oral administration of 4-nitroquinoline 1-oxide (4-NQO) and 4-hydroxyaminoquinoline 1-oxide (4-HAQO) did, however, induce carcinomas in the stomach as well as various other tissues (Mori, 1967; Mori and Ohta, 1967). Then, Tatematsu et al. reported induction of good yields of adenocarcinomas (Figure 1A) in the glandular stomach of BALB/c (Tatematsu et al., 1992b) and C3H (Tatematsu et al., 1993b) mice treated with N-methyl-N-nitrosourea (MNU). The establishment of mouse models opened up new approaches using transgenic and knockout animals.

View larger version (158K): [in this window] [in a new window]   Figure 1 Macroscopic views of glandular stomach tumors. (A) A protruding type developing in an MNU-treated mouse. (B) Crater-shaped tumor in an MNU treated and H. pylori infected Mongolian gerbil. (C) Scirrhous type in an MNU treated and H. pylori-infected gerbil, difficult to identify in the mucosa but showing invasion to the serosa (inset). Tumors are indicated with red arrows.

Many animals have been successfully infected with human H. pylori to study the pathogenetic background, but none of early models studied proved sufficiently similar to the situation with human H. pylori infection and pathology (Krakowka et al., 1987; Lee et al., 1990; Radin et al., 1990; Karita et al., 1991; Karita et al. 1994; Marchetti et al., 1995; Fox et al., 1996). In 1996, however, Hirayama et al. reported a Mongolian gerbil (MG) model of human H. pylori infection, with the bacteria detectable throughout a 12-month study period (Hirayama et al., 1996). The resultant chronic active gastritis, peptic ulcers, and IM resemble lesions apparent in man. Then, in 1998, Tatematsu et al. (1998) described establishment of an animal model of stomach carcinogenesis using MGs with MNU and MNNG as carcinogens. Furthermore, H. pylori infection was found to increase the incidence of both MNU- and MNNG-induced adenocarcinomas of all histological types in the MG glandular stomach (Figures 1B and 1C) (Sugiyama et al., 1998; Shimizu et al., 1999a, 1999b). This model has proved very useful for the analysis of stomach carcinogenesis.

	Preneoplastic Lesions for Stomach Adenocarcinomas

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

 
Intestinal Metaplasia (IM)
IM has been extensively studied as a possible premalignant condition in human stomach (Morson, 1955; Stemmermann and Hayashi, 1968; Correa, 1992; You et al., 1993; Yuasa, 2003). However, many questions remain regarding its pathogenesis as well as the actual relationship to stomach cancers. The present widely applied classification of IM includes complete and incomplete types, the former featuring Paneth cells at the bottom of the glands (Kawachi et al., 1974; Matsukura et al., 1980). This classification is generally accepted, but is only based on intestinal properties (Tatematsu et al., 2003). We have, therefore, proposed a new IM classification based upon the cell differentiation status using both gastric and intestinal cell phenotypic markers, which take into account the gastric properties that are still preserved in association (Inada et al., 1997). Division is into 2 major types; a gastric-and-intestinal-mixed (GI) type, and a solely intestinal (I) type, which can be also applied to animal stomach lesions (Table 1).

With regard to the gastric phenotype, the cSox2 gene, a member of the transcription factor family containing an Srylike high mobility group (HMG) box, demonstrates localized expression in the chicken stomach (Ishii et al., 1998). Sox2 in fact may be a key molecule for gastric differentiation in the gastrointestinal tract, also in mammals (Yasugi, 2000). In humans, Sox2 is found localized in the nuclei of gastric foveolar cells and is decreased in IM (Tsukamoto et al., 2004).

Pancreatic-duodenal homeobox 1 (PDX1), a ParaHox gene that contributes to the genesis and development of the pancreas, duodenum, and antrum, has also been found to be frequently expressed in pseudopyloric glands and IM. MUC6 is more abundant than MUC5AC in pseudopyloric glands, while higher levels of MUC5AC than MUC6 are evident in IM. In carcinomas, PDX1 expression is closely associated with MUC6, whereas no link is apparent between PDX1 and MUC5AC reactivity. Thus, PDX1 may play an important role in the development of pseudopyloric glands and subsequent IM (Sakai et al., 2004; Faller and Kirchner, 2005).

Phenotypic Shift of Gastric Mucosa Toward GI and I Type IM
Experimentally, a phenotypic shift from GI-IM to I-IM could be clearly observed on sequential observation of rat stomachs treated with X-rays (Yuasa et al., 2002). Heterotopic proliferative glands (HPGs) frequently develop with H. pylori infection in the glandular stomach of infected MGs, with slightly dysplastic change of constituent cells (Figure 2) (Nozaki et al., 2002b). While they often resemble differentiated carcinomas, especially mucinous adenocarcinomas, they are not malignant in character. HPGs also show a phenotypic shift from G type to GI type or I type with appearance of Paneth cells during the overall course of H. pylori infection (Figure 3) (Nozaki et al., 2002b).

View larger version (59K): [in this window] [in a new window]   Figure 2 Hyperplastic mucosa showing heterotopic proliferating glands (HPG) (A and C) Uninfected gerbil. (B and D) H. pylori-infected animal. A and B, HE; C and D, Alcian blue and periodic acid Schiff staining. (Original magnification, 31x)

View larger version (136K): [in this window] [in a new window]   Figure 3 Intestinal metaplasia developing in an H. pylori-infected Mongolian gerbil. (A) Presence of intestinal absorptive and goblet cells in stomach mucosa. (B) Paneth cells appeared in some area. (Original magnification, A, 50x; B, 500x) H&E staining.

Methylation of the Pg1 gene observed early in the carcinogenesis process in fact occurs progressively with tumor development (Tatematsu et al., 1993a). PAPG are also detectable immunohistochemically in MNU-treated mice, suggesting possible general use as a preneoplastic lesion for stomach carcinogenesis (Figure 4) (Yamamoto et al., 1997), independent of the strain (Yamamoto et al., 2002). Thus, PAPG can be regarded as a common change in rodents, acting as a precursor for a variety of adenocarcinoma types (Table 1).

View larger version (93K): [in this window] [in a new window]   Figure 4 Pepsinogen 1 altered pyloric glands in an MNU-treated mouse. (A) Pg1 (red) is abundant with few bromodeoxyuridine positive proliferative cells (brown) in pyloric glands in a control mouse. (B) Hyperplastic pyloric mucosa with increased proliferation after 10-week treatment with MNU. Pyloric glands lack Pg1 (red arrow). (Original magnification, 100x).

	Characteristics and Differentiation of Stomach Cancer Cells

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

Thus, we tried to classify rodent stomach cancers morphologically into the following: (i) differentiated adenocarcinoma forming glandular (Figure 5A) or papillary structures; (ii) mucinous adenocarcinoma producing mucous lakes, in which carcinoma cells appear to float (Figure 5B); (iii) poorly differentiated lesions, growing solidly or diffusely (Figure 5C, left side); and (iv) signet-ring cell carcinomas possessing foamy mucus-filled cytoplasm and proliferating diffusely, often with submucosal invasion (Figure 5C, right side and Figure 5D).

View larger version (96K): [in this window] [in a new window]   Figure 5 Adenocarcinomas developing in MNU treated and H. pylori-infected Mongolian gerbils. (A) Well-differentiated adenocarcinoma invading the muscularis propria. (B) Mucinous adenocarcinoma producing mucous lakes. (C) Poorly differentiated adenocarcinoma (left side) in combination with a signet-ring cell carcinoma (right side). (D) Signet-ring cell carcinoma with Alcian blue positive mucin. (A–D) Hematoxylin and eosin staining. (D) Alcian blue staining. (Original magnification, A, 125x; B, 40x; C and D, 200x).

In the rat glandular stomach, experimentally induced adenocarcinomas consist mainly of G type cancer cells, with I type cancer cells appearing later in larger tumors (Tatematsu et al., 1980a, 1983, 1984, 1990b; Yuasa et al., 1994). In the H. pylori infected MG model, a series of stomach cancers could be divided phenotypically into 21 G, 24 GI, 4 I and 1 N types, with 90.0% of the lesions harboring gastric elements and 56.0% demonstrating intestinal phenotypic expression. All 6 lesions arising in non-infected MG were classified as G type. There was no clear correlation with the presence of IM in surrounding mucosa. It might thus be proposed that IM is a paracancerous phenomenon rather than a premalignant condition. H. pylori infection may trigger intestinalization of both stomach cancers and non-neoplastic mucosa (Figure 6) (Mizoshita et al., 2006), the same phenotypic shift occurring in accordance with increasing depth of invasion in human signet ring cell carcinomas and with progression in differentiated cancers (Tatematsu et al., 1986a, 1992a; Yamachika et al., 1997; Yoshikawa et al., 1998; Bamba et al., 2001). The incidence of gastric cancer cells with intestinal phenotypic expression in early differentiated cases is higher than in undifferentiated cases, suggesting that the former may be more prone to intestinalization (Tatematsu et al., 1992a; Yoshikawa et al., 1998; Mizoshita et al., 2004b).

View larger version (119K): [in this window] [in a new window]   Figure 6 Histology and phenotypes of differentiated adenocarcinomas. (A) Well-differentiated adenocarcinoma developing in a gerbil treated with MNU without H. pylori infection. Note the morphological resemblance to foveolar epithelium. (B) H&E staining of a tumor with gastric phenotypic expression in an H. pylori-infected gerbil. (C) Human gastric mucin (HGM) is present in the cytoplasm of the tumor cells. (D) Paradoxical concanavalin A staining (PCS) is positive in cytoplasm of cancer cells. (E) CD10 is present at the luminal surfaces of cancer cells. (F) Small intestinal mucinous antigen (SIMA) is evident in the cytoplasm of cancer cells. (Original magnification, A, 40x; B–E, 320x; F, 400x).

	Modifying factors for Stomach Carcinogenesis (Table 3)

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

View larger version (11K): [in this window] [in a new window]   Figure 7 Modifying factors for H. pylori-associated stomach carcinogenesis in Mongolian gerbils. Drinking water containing chemical carcinogens including MNU or MNNG induce stomach cancers (A), while H. pylori infection is not carcinogenic (B). However, when combined, H. pylori becomes a strong promoter (C and D). Early eradication of H. pylori reduces risk of stomach cancers (E and F), whereas early infection increases the risk (G and H). A high salt diet exacerbates inflammation and increases the incidence of H. pylori-associated cancer (I). Various natural products and pure chemicals appear to have chemopreventive potential (J).

Shimizu et al. have provided direct evidence that H. pylori eradication may be useful as a prevention approach against stomach cancer (Shimizu et al., 2000). In H. pylori-infected MGs treated with MNU, the incidences of stomach cancers after curative treatment for H. pylori were thus significantly lower than without H. pylori eradication. For further evaluation, an experimental model with eradication in the early, middle, late period was studied using H. pylori-infected and MNU-treated MGs (Nozaki et al., 2003). H. pylori infection was found to strongly enhance stomach carcinogenesis initiated with the chemical carcinogen, and following eradication at an early period this effect was effectively reduced (Figure 7). However, after complete clearance of the bacteria, reflux esophagitis often occurs (Labenz et al., 1997), and this side effect is thought to be an important risk factor for esophageal adenocarcinoma development (Naef et al., 1975). Therefore, establishment of criteria for H. pylori eradication is now a top priority.

High-Salt Diet
Salt and salted foods are probable risk factors for stomach cancer, based on evidence from a large number of case-control and ecological studies (Tajima and Tominaga, 1985; Tsugane et al., 1992; Joossens et al., 1996; Kono and Hirohata, 1996). In experimental animals, Tatematsu et al. (1975) found sodium chloride to enhance the carcinogenic effects of MNNG and 4-NQO in the rat glandular stomach. Sodium chloride possibly decreases the viscosity of the gastric mucin and may reduce the protective mucous barrier. When given alone, it has no apparent carcinogenicity in rats, but when administered with MNNG or 4-NQO, it promotes stomach carcinogenesis (Tatematsu et al., 1975) in a dose-dependent fashion (Takahashi et al., 1994). A high concentration of sodium chloride causes initial tissue damage and consequent regenerative cell proliferation (Furihata et al., 1996).

Furthermore, a high-salt diet enhances the effects of H. pylori infection on stomach carcinogenesis, and these 2 factors act synergistically to promote the development of stomach cancers in the MG model (Nozaki et al., 2002a) in a dose-dependent fashion (Figure 7) (Kato et al., 2006). High salt diet upregulates the amount of surface mucous cell mucin, suitable for H. pylori colonization, despite the lack of any increment in MUC5AC mRNA, while H. pylori infection itself has an opposite effect, stimulating transcription of MUC6 and increasing the amount of gland mucous cell mucin (GMCM). A high salt diet, in turn, decreases the amount of GMCM, which acts against H. pylori infection (Kato et al., 2006). The available data from experimental animal models clearly supports the concept that salt-preserved foods and salt itself increase the risk of stomach cancer in man.

Cyclooxygenase-2 (COX-2) Inhibitors
The effects of the selective COX-2 inhibitor, etodolac, on MNU initiated and H. pylori-infected stomach carcinogenesis have been investigated in MGs, dose-dependent inhibition being observed with effective suppression at a dose of 30mg/kg/day. Etodolac did not affect the extent of inflammatory cell infiltration or oxidative DNA damage, but significantly inhibited mucosal cell proliferation and development of IM. COX-2 may thus be a key molecule in H. pylori associated stomach carcinogenesis (Figure 7) (Magari et al., 2005). A mouse model has been also used to assess effect of nimesulide, another COX-2 inhibitor, which substantially reduced H. pylori-associated stomach tumorigenesis with induction of apoptosis (Nam et al., 2004). In contrast, COX-2 and microsomal prostaglandin E synthase (mPGES)-1 double transgenic mice developed metaplasia, hyperplasia, and tumorous growths in the glandular stomach with heavy macrophage infiltration upon Helicobacter infection (Oshima et al., 2004), through a tumor necrosis factor- (TNF-) dependent pathway (Oshima et al., 2005). Thus, COX-2 activity may be a prime target for chemoprevention of stomach cancer.

Peroxisome Proliferator-Activated Receptor (PPAR) Ligand
When PPARwild-type (+/+) and heterozygous-deficient (+/–) mice were administered MNU followed by treatment with a PPARligand, troglitazone, significant reduction of the incidence of stomach cancer was observed in PPAR(+/+) mice but not in (+/–) mice suggesting a potential chemopreventive effect (Lu et al., 2005).

	Oncogenes and Tumor Suppressor Genes in Rodent Stomach Cancers

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

 
p53 Tumor Suppressor Gene
Mutations of the p53 tumor suppressor gene constitute 1 of the most frequent molecular changes in a wide variety of human cancers but Hirayama et al. reported that MNNG induced rat stomach adenocarcinomas had a mutation of the p53 gene, at the second position of codon 171 (Val –> Glu), in only one of 10 cases (Hirayama et al., 1999b). Furthermore, Furihata et al. found no mutations in exons 5, 6, 7, and 8 in a total of 30 stomach tumors in MNU treated BALB/c mice (Furihata et al., 1997). We have investigated the susceptibility of p53 nullizygote (–/–), heterozygote (+/–) and wild-type (+/+) mice to MNU stomach carcinogenesis and in a 15-week experiment, adenomas and a well-differentiated adenocarcinoma were observed in p53 (–/–) animals. However, after 40 weeks, there were no significant difference in the incidences of stomach tumors between p53 (+/+) and (+/–) mice and there were no mutations in p53 genes (Ohgaki et al., 2000; Yamamoto et al., 2000). p53 may not be a direct target of chemical carcinogens but rather play an important role as a gatekeeper in rodent stomach carcinogenesis (Tsukamoto et al., 2005).

Ras Oncogenes
Ras is one of the most frequently activated oncogenes in human cancers. However, none of 10 stomach cancers had mutations in codons 12, 13, or 61 of Ki-ras gene in one rat series (Hirayama et al., 1999b). In mouse, one mutation of GGT to AGT at K-ras codon 12 was found in an MNU induced adenocarcinoma from a total of 19 specimens (Furihata et al., 1997). Moreover, no mutations were detected in H- and N-ras oncogenes at exons 1 (codons 12 and 13) and 2 (codon 61) in a total of 26 specimens (Furihata et al., 1997).

β-Catenin Oncogene
Aberrant Wnt/β-catenin signaling caused by mutations in exon 3 of the β-catenin gene has been identified in a number of human malignancies, including stomach cancers. Among 22 MNNG-induced rat differentiated adenocarcinomas, 4 tumors (18.2%) contained dysplastic regions that displayed nuclear β-catenin localization featuring mutations in exon 3, at glycine 34, threonine 41, and serine 45, which affected phosphorylation sites. β-Catenin mutations appear to be associated with the late progression stage of adenocarcinoma development in rat stomach carcinogenesis (Tsukamoto et al., 2003). Nuclear localization of β-catenin in stomach cancers is more frequently observed in mouse cases (Takasu et al., manuscript in preparation) (Figure 8).

View larger version (136K): [in this window] [in a new window]   Figure 8 Nuclear accumulation of β-catenin in a moderately differentiated adenocarcinoma in an MNU-treated mouse glandular stomach. (A) H&E staining. (B) β-Catenin immunohistochemistry. Original magnification, A and B, 100X; inset, 640X.

Other Gene Alterations
Hirayama et al. reported no amplification of K-sam or c-erbB-2 in 7 rat adenocarcinomas (Hirayama et al., 1999b) and no microsatellite alterations in 12 loci in nine cases (Hirayama et al., 1999b).

	Conclusions

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

 
Many animal models for stomach cancers have been established using rats, dogs, and mice. However, since the discovery of H. pylori, the MG has become one of the most important model animals for analysis of stomach carcinogenesis and trials of chemoprevention. It should be noted that H. pylori itself only causes chronic inflammation and acts as promoter in stomach carcinogenesis, as revealed by the experimental models described above. With a firm base of precise pathological diagnosis of stomach lesions such as HPGs and adenocarcinomas, further analyses can now be conducted to determine mechanisms of carcinogenesis and contribute to chemopreventive methods.

	Acknowledgments

 
The authors thank colleagues in our laboratory for their expert technical assistance and valuable discussion. We also are grateful to Dr. Malcolm Moore for comments on the scientific English language. This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

	References

TOP Abstract Introduction History of Animal Models... Preneoplastic Lesions for... Characteristics and... Modifying factors for Stomach... Oncogenes and Tumor Suppressor... Conclusions References

 

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Toxicologic Pathology, Vol. 35, No. 5, 636-648 (2007)
DOI: 10.1080/01926230701420632


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