Induction of Glandular Stomach Cancers in C3H Mice Treated with N‐Methyl‐N‐nitrosourea in the Drinking Water

Tatematsu, Masae; Yamamoto, Masami; Iwata, Hitoshi; Fukami, Hiroko; Yuasa, Hirofumi; Tezuka, Noriaki; Masui, Tsuneo; Nakanishi, Hayao

doi:10.1111/j.1349-7006.1993.tb02831.x

Cited by 64 publications

(48 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23,24) Therefore, the establishment by Tatematsu et al of a mouse experimental gastric cancer model using MNU to yield both differentiated and undifferentiated type carcinomas was important. 11,12) In the present study undifferentiated type carcinomas were similarly induced, being positively linked to high concentrations of MNU. It has been suggested that differentiated and undifferentiated types of gastric carcinomas in man may develop through different genetic pathways.…”

Section: Discussionmentioning

confidence: 67%

“…However in a recently established mouse experimental gastric cancer model using MNU the types of tumors proved more similar to human gastric cancers in terms of their histopathological features than those typically found in rats. 11,12) The present study was performed to assess the effects of carcinogen concentration on the histopathological type and incidence of gastric carcinomas induced in our mouse model. For this purpose MNU was given at different concentrations for different periods so that all groups would receive the same total quantity of carcinogen, in theory.…”

mentioning

confidence: 99%

See 1 more Smart Citation

N‐Methyl‐N‐nitrosourea Concentration‐dependent, Rather than Total Intake‐dependent, Induction of Adenocarcinomas in the Glandular Stomach of BALB/c Mice

Yamachika

Nakanishi

Inada

et al. 1998

Japanese Journal of Cancer Research

Self Cite

View full text Add to dashboard Cite

The influence of the level of carcinogen exposure on histopathological types and cellular differentiation of the induced tumors was examined in 100 male BALB/c mice given N-methyl-Nnitrosourea (MNU) in their drinking water at 240 ppm on alternate weeks (total exposure: five weeks) (group 1), at 120 ppm similarly (total exposure: ten weeks) (group 2), at 60 ppm for 20 weeks continuously (group 3), or at 30 ppm for 40 weeks continuously (group 4). Forty-three differentiated and 17 undifferentiated type adenocarcinomas were induced. Glandular stomach carcinomas and undifferentiated type lesions were more common in mice treated with a high concentration of MNU for a short period than with a low concentration of MNU for a long period, even though total measured intake of MNU was smaller (P< < < <0.01). All the induced glandular stomach carcinomas, independent of the treatment schedule, consisted entirely of gastric phenotype cells. In conclusion, the induction of glandular stomach cancers and the proportion of undifferentiated type lesions depend not on the total quantity, but rather on the concentration of the carcinogen, while the phenotypic expression of tumor cells is not affected by the differences in the administration protocol.

show abstract

Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

N‐Methyl‐N‐nitrosourea Concentration‐dependent, Rather than Total Intake‐dependent, Induction of Adenocarcinomas in the Glandular Stomach of BALB/c Mice

Yamachika

Nakanishi

Inada

et al. 1998

Japanese Journal of Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Gastric cancers were induced in C3H mice by providing N-methyl-N-nitrosourea (MNU) in drinking water (Tatematsu et al, 1993), and four cell lines derived from these mouse glandular stomach carcinomas were isolated (Ichinose et al, 1998). In this study, we found that these mouse gastric cancer cells exhibit properties remarkably similar to those of human gastric cancer cells.…”

mentioning

confidence: 60%

Inhibition of growth of mouse gastric cancer cells by Runx3, a novel tumor suppressor

et al. 2002

Self Cite

View full text Add to dashboard Cite

We reported recently that the silencing of RUNX3 is causally related to gastric cancer in humans. Here we report that in three of four cell lines derived from Nmethyl-N-nitrosourea-induced mouse glandular stomach carcinomas, Runx3 is silenced due to hypermethylation of CpG islands in the promoter region, as we also observed for human gastric cancer cells. Although two of the sites we tested in the promoter of the fourth line were not methylated, in all four cases the silencing of Runx3 could be reversed by treatment of the cells with 5'-azacytidine and trichostatin A. Interestingly, the exogenous expression of RUNX3 in cell lines that do not express the endogenous gene caused an inhibition of growth in soft agar, suggesting that anchorage-independent growth could be used as an assay of RUNX3 activity in vitro. These observations suggest that the mouse system described here may be useful as a model for the study of human gastric carcinogenesis.

show abstract

“…To examine the role of ASK1 in GC, we used a mouse model of chem-ically induced gastric tumorigenesis. As the administration of N-methyl-N-nitrosourea (MNU) results in efficient gastric tumor induction in mice (14), wild-type (WT) and ASK1 −/− mice were administered MNU as described previously ( Fig. 2A).…”

Section: Increased Expression Of Ask1 In Human Gastricmentioning

confidence: 99%

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Hayakawa

Hirata

Nakagawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. JNK | c-JunG astric cancer (GC) is a common cancer worldwide, associated with a high mortality despite its declining incidence in recent decades. Smoking, salted or smoked foods, and Helicobacter pylori appear to be major environmental inducers of GC (1-3). Although the role of H. pylori in causing mucosal effects has been investigated, which molecular signal(s) initiate the program of irreversible transformation remain unclear, and thus molecular targeting therapies for GC have not been well established.Mitogen-activated protein kinase (MAPK) pathways are important for the development of gastric tumorigenesis (4). Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed MAPK kinase kinase (MAP3K), activated by various stress stimuli, including reactive oxygen species (ROS), TNF-α, and LPS (5-7). ASK1 activates the JNK and p38 signaling pathways and is required for both oxidative stress and cytokine-induced apoptosis (5). Furthermore, ASK1 affects multiple cellular functions, including survival, differentiation, and the innate immune response (5,7,8) and has been reported to be involved in the pathogenesis of various human diseases, including neurodegenerative (9), cardiovascular (10), and inflammatory diseases (11,12). Additionally, ASK1 has been shown to participate in both colon (12) and skin (13) tumorigenesis through the regulation of inflammation and apoptosis. However, no reported study has demonstrated a role for ASK1 in gastric tumorigenesis.In this study, we examined the role of ASK1 in gastric tumorigenesis using both human GC samples and ASK1-deficient (ASK1 −/− ) mice. We demonstrated that ASK1 is important for gastric tumorigenesis through the regulation of cyclin D1 e...

show abstract

Induction of Glandular Stomach Cancers in C3H Mice Treated with N‐Methyl‐N‐nitrosourea in the Drinking Water

Cited by 64 publications

References 13 publications

N‐Methyl‐N‐nitrosourea Concentration‐dependent, Rather than Total Intake‐dependent, Induction of Adenocarcinomas in the Glandular Stomach of BALB/c Mice

N‐Methyl‐N‐nitrosourea Concentration‐dependent, Rather than Total Intake‐dependent, Induction of Adenocarcinomas in the Glandular Stomach of BALB/c Mice

Inhibition of growth of mouse gastric cancer cells by Runx3, a novel tumor suppressor

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Contact Info

Product

Resources

About