Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice

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Abstract
The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids 1 . Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development 2, 3, 4 . There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer 5, 6 . Therefore, the peroxisome proliferator-activated receptor γ (PPARγ; ref. 7 ), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon 8, 9 , may be involved in this process. Activation of PPARγ by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APC Min /+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARγ. Treatment with PPARγ agonists increased β-catenin levels both in the colon of C57BL/6J-APC Min /+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the β-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARγ activation modifies the development of colon tumors in C57BL/6J-APC Min /+ mice.