Induction of Metastatic Gastric Cancer by Peroxisome Proliferator-Activated Receptorδ Activation

Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20057, USA.
PPAR Research (Impact Factor: 1.64). 12/2010; 2010(1):571783. DOI: 10.1155/2010/571783
Source: PubMed


Peroxisome proliferator-activated receptorδ (PPARδ) regulates a multiplicity of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes likely create risk factors associated with the ability of PPARδ agonists to promote tumorigenesis in some organs. In the present study, we describe a new gastric tumor mouse model that is dependent on the potent and highly selective PPARδ agonist GW501516 following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the forestomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumors correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. The rapid development of metastatic gastric tumors in this model will be useful for evaluating preventive and therapeutic interventions in this disease.

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    • "Our study revealed that Tob1 decreased the expression of β-catenin-target genes including cyclin D1, CDK4, uPAR, and PPARδ. While cyclin D1 and CDK4 are well known biomarker of cell proliferation, uPAR (26) and PPARδ have been reported to play role in the migration and invasion of gastric cancer cells (27). Thus, the anti-proliferative effect of Tob1 in gastric cancer might be due to the decreased expression of cyclin D1 and CDK4, and the increased expression of p15, while the anti-migratory and anti-invasive potential of Tob1 may be mediated through the inhibition of uPAR and PPARδ in gastric cancer cells. "
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