Carcinogenesis Advance Access originally published online on September 26, 2003
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Carcinogenesis, Vol. 25, No. 1, 149-153,
January 2004
© Oxford University Press; all rights reserved
CARCINOGENESIS |
Dietary retinoic acid supplementation stimulates intestinal tumour formation and growth in multiple intestinal neoplasia (Min)/+ mice
Department of Food Toxicology, Norwegian Institute of Public Health, Oslo, Norway
Chemopreventive activity by retinoic acid (RA) has been demonstrated previously in rat colon. The spontaneous tumourigenesis in the Min/+ mouse, which harbours a germline mutation in the tumour suppressor gene adenomatous polyposis coli (Apc), is characterized by inactivation of Apc, nuclear accumulation of ß-catenin and the enhanced expression of specific genes activated by T cell factor (TCF)/ß-catenin signalling. Recently it was reported that ß-catenin interacts with retinoic acid receptor in a retinoid-dependent manner, reducing ß-catenin/TCF regulated transcription. Our hypothesis was therefore that dietary supplementation with all-trans RA may inhibit the Apc-driven tumourigenesis in Min/+ mice. Surprisingly, in two different experiments the results showed that dietary RA significantly stimulated both the formation and growth of small intestinal tumours. In the first experiment Min/+ mice were exposed to 50 mg 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine/kg bodyweight at day 3–6 after birth and then treated with 50 mg/kg dietary RA in 1–3 weeks from the age of 2 weeks. In the second experiment the mice were not treated with carcinogen, and the diet was supplemented with 5 or 10 mg/kg RA from the age of 4 weeks until termination of the experiment at 11 weeks. Immunohistochemical studies revealed no differences in ß-catenin, cyclin D1 or proliferating cell nuclear antigen staining following RA treatment. There was no intestinal toxicity in mice fed 10 mg/kg RA, indicating that the increased tumourigenesis in Min/+ mice is a specific effect of all-trans RA.
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