Chemopreventive Effect of Peroxisome Proliferator–Activated Receptor γ on Gastric Carcinogenesis in Mice

Lü, Jie; Imamura, Kazuhiro; Nomura, Sachiyo; Mafune, Ken–ichi; Nakajima, Atsushi; Kadowaki, Takashi; Kubota, Naoto; Terauchi, Yasuo; Ishii, Genichiro; Ochiai, Atsushi; Esumi, Hiroyasu; Kaminishi, Michio

doi:10.1158/0008-5472.can-04-2293

Cited by 67 publications

(52 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In other gastrointestinal system malignancies, thiazolidinedione administration with RXR agonists in rat hepatocyte cell lines induces chemopreventive glutathione S-transferase 2a (49). In N-methyl-N-nitrosourea-induced gastric carcinoma, PPARg +/+ transgenic mice developed fewer tumors than their heterozygous (PPARg +/-) counterparts, but troglitazone was only effective in preventing tumors in the homozygotes (50). These data, taken together, show that troglitazone, given at pharmacologic doses, can promote tumor formation in the Min mouse model and in one study using wild-type mice.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention

Ondrey

2008

Clinical Cancer Research

120

View full text Add to dashboard Cite

The peroxisome proliferator-activated receptor (PPAR) g is one member of the nuclear receptor superfamily that contains in excess of 80 described receptors. PPARg activators are a diverse group of agents that range from endogenous fatty acids or derivatives (linolenic, linoleic, and 15-deoxy-D 12,14 -prostaglandin J 2 ) to Food and Drug Administration-approved thiazolidinedione drugs [pioglitazone (Actos) and rosiglitazone (Avandia)] for the treatment of diabetes. Once activated, PPARg will preferentially bind with retinoid X receptor a and signal antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for down-regulation of carcinogenesis. Although PPAR-g activators show many anticancer effects on cell lines, their advancement into human advanced cancer clinical trials has met with limited success. This article will review translational findings in PPARg activation and targeting in carcinogenesis prevention as they relate to the potential use of PPARg activators clinically as cancer chemoprevention strategies.

show abstract

Section: Clinical-translational Advancesmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention

Ondrey

2008

Clinical Cancer Research

120

View full text Add to dashboard Cite

show abstract

“…Min/+ and wild-type littermates, from 4 to 6 weeks of age, were given drinking water containing 240 ppm MNU on alternate weeks for a total of 10 weeks of exposure according to the protocol described in previous reports (34,35). The MNU-treated Apc Min/+ and wild-type littermates were sacrificed at 15,20,25,30, and 35 weeks of age.…”

Section: Apcmentioning

confidence: 99%

“…All the cases were also counted by a second observer to confirm the results of the first observer. After tumor counting, all of the excised stomachs, including the neoplastic nodules, were fixed for 24 h in neutral-buffered 10% formalin and then cut into eight strips, which were processed by standard methods, embedded in paraffin, sectioned at 5 Am, and stained with H&E. The defining characteristics for adenoma and adenocarcinoma were adapted from both the consensus guidelines on murine models of intestinal cancer (36) and previous reports in the literature (35,37).…”

Section: Apcmentioning

confidence: 99%

“…These animal models have been used not only for investigating the pathogenesis of gastric carcinogenesis but also for identifying possible tumor promoters and chemopreventive agents (34,35,44,45). However, mice have been known to be relatively resistant to MNU, and therefore, previous studies showed that 48 to 52 weeks were required to induce gastric carcinoma in C57BL/6J mice (35,37,46,47). In the present study, we treated Apc Min/+ mice with MNU and found MNU to strongly promote tumor development in the stomach of Apc Min/+ mice in comparison with MNU-treated wild-type mice.…”

Section: Of the Stomach In Apcmentioning

confidence: 99%

See 1 more Smart Citation

Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway

Tomita¹,

Yamada²,

Oyama³

et al. 2007

Cancer Research

View full text Add to dashboard Cite

Although several lines of evidence suggest the involvement of the Wnt pathway in the development of gastric cancers, the functional significance of the pathway in gastric carcinogenesis is still poorly defined. To examine the role of the Apc/Bcatenin signaling pathway in the development of gastric cancers, we investigated the gastric mucosa of the Apc Min/+ mouse, which is a murine model for familial adenomatous polyposis, carrying a germ-line mutation at codon 850 of Apc. We found that aged ApcMin/+ mice spontaneously develop multiple tumors in the stomach, which are accompanied by loss of heterozygosity of Apc. Such tumors consisted of adenomatous glands with strong nuclear accumulation of Bcatenin. Even a single adenomatous gland already showed nuclear accumulation of B-catenin, suggesting that Apc/Bcatenin pathway is an initiating event in gastric tumorigenesis in ApcMin/+ mice. Myc and cyclin D1 expressions, which are transcriptional targets of B-catenin/Tcf, increased in the adenomatous lesions. Furthermore, B-catenin/Tcf reporter transgenic mice with Apc Min allele showed higher levels of the transcriptional activity of B-catenin/Tcf in the gastric tumors. We also treated Apc Min/+ and wild-type mice with N-methyl-Nnitrosourea (MNU), an alkylating agent that induces adenomas and adenocarcinomas in the stomach. Consequently, MNU-treated Apc Min/+ mice significantly enhanced the tumor development in comparison with Apc Min/+ mice or MNUtreated wild-type mice. Several gastric tumors in MNU-treated Apc Min/+ mice showed invasion into the submucosal layer. These results indicate that the Apc/B-catenin pathway may play an important role in at least subset of gastric carcinomas. In addition, Apc Min/+ mice combined with MNU could be a useful short-term model to investigate multistage carcinogenesis in the stomach. [Cancer Res 2007;67(9):4079-87]

show abstract

“…In addition, PPARÁ ligands can increase the expression and/or activity of tumor suppressors such as PTEN and p21 (45). Treatment with troglitazone was found to reduce gastric cancer formation in mice induced by carcinogens, and the chemopreventive effect of troglitazone was absent in PPARÁ heterozygous-deficient mice (46). In the current meta-analysis, we found that patients with G carriers had 2.31-fold (95% CI = 1.59-3.36, P heterogeneity = 0.941) increased risk of gastric cancer, suggesting the presence of the Ala12 polymorphism, which is associated with reduced PPARÁ activity, might increase the susceptibility of gastric cancer.…”

Section: /782 ----------------------------------------------------mentioning

confidence: 99%

PPARγ polymorphisms and cancer risk: A meta-analysis involving 32,138 subjects

Wu¹

2010

Oncol Rep

View full text Add to dashboard Cite

Abstract. The peroxisome proliferator-activated receptor Á (PPARÁ) has been suggested to act as a tumor suppressor gene. Two common variations of PPARÁ, P12A (Pro12Ala, rs1801282) and C161T (His447His, rs3856806), are thought to have an effect on susceptibility to various carcinomas but the results are inconsistent. In this meta-analysis, we assessed published studies of the association between two common PPARÁ polymorphisms and cancer risk from 26 studies with 27,677 subjects for PPARÁ P12A, from 4 studies with 4,461 subjects for C161T. No significant associations were found in carriers of the rare Ala allele of the P12A polymorphism versus the common Pro/Pro genotype among the studies. In the subgroup analyses by cancer types, carriers of the Ala variant of P12A polymorphism were associated with protection from colorectal cancer (OR=0.84, 95% CI=0.72-0.98, P heterogeneity = 0.014), but the inverse association was found in gastric cancer (OR=2.31, 95% CI=1.59-3.36, P heterogeneity = 0.941). In the stratified analysis by ethnicity, no significant risks were found among Asians, Americans and Caucasians. For PPARÁ C161T, no significant associations were found in any of the studies (OR=1.08, 95% CI=0.95-1.23, P heterogeneity = 0.430) or subgroups. This meta-analysis suggests that the Ala allele of the PPARÁ P12A polymorphism might be a protective factor for colorectal cancer, but a risk factor for gastric cancer. The PPARÁ C161T is marginally associated with cancer susceptibility.

show abstract

Chemopreventive Effect of Peroxisome Proliferator–Activated Receptor γ on Gastric Carcinogenesis in Mice

Cited by 67 publications

References 46 publications

Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention

Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention

Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway

PPARγ polymorphisms and cancer risk: A meta-analysis involving 32,138 subjects

Contact Info

Product

Resources

About