ACTIVATION OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA PROMOTES THE DEVELOPMENT OF COLON TUMORS IN C57BL 6J-APC(MIN)/+ MICE/

The development of colorectal cancer, one of the most frequent cancers , is influenced by prostaglandins and fatty acids' Decreased prostagla ndin production, seen in mice with mutations in the cyclooxygenase 2 g ene or in animals and humans treated with cyclooxygenase inhibitors, p revents or attenuates colon cancer development(2-4). There is also a s trong correlation between the intake of fatty acids from animal origin and colon cancer(5,6). Therefore, the peroxisome proliferator-activat ed receptor gamma (PPAR gamma; ref. 7), a downstream transcriptional m ediator for prostaglandins and fatty acids which is highly expressed i n the colon(8,9), may be involved in this process. Activation of PPAR gamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APC(Min)/+ mice, an animal model susc eptible 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 PPAR gamma. Treatment with PPAR ga mma agonists increased beta-catenin levels both in the colon of C57BL/ 6J-APC(Min)/+ mice and in HT-29 colon carcinoma cells. Genetic abnorma lities in the Wnt/wingless/APC pathway, which enhance the transcriptio nal activity of the beta-catenin-T-cell factor/lymphoid enhancer facto r 1 transcription complex, often underly the development of colon tumo rs. Our data indicate that PPAR gamma activation modifies the developm ent of colon tumors in C57BL/6J-APC(Min)/+ mice.