Intestinal-specific PPARgamma deficiency enhances tumorigenesis in ApcMin/+ mice.
Multiple investigations of the effects of peroxisome proliferator-activated receptor gamma (PPARgamma) ligands on colon cancer have produced contradictory results. While some studies demonstrated increased numbers of colonic polyps in Apc(Min/+) mice treated with various thiazolidinedione (TZD) PPARgamma ligands, others reported amelioration of tumor multiplicity and progression in both Apc(Min/+) mice and in mice with chemically-induced colon cancer. Here, we addressed the role of PPARgamma in murine intestinal tumorigenesis using gene knockout methodology. We found that either heterozygous or homozygous intestinal-specific PPARgamma deficiency enhanced the number of Apc(Min/+) tumors in both the small intestine and colon, especially in the colon, where PPARgamma deficiency also modulated tumor incidence. Gender significantly affected tumor multiplicity independent of PPARgamma genotype. Female Apc(Min/+) mice developed more tumors in the small intestine and more tumors overall, whereas male Apc(Min/+) mice developed more tumors in the colon. Nevertheless, intestinal PPARgamma deficiency enhanced tumorigenesis irrespective of gender. Our results suggest that PPARgamma functions as a tumor resistance factor in the mouse intestine and warrant further investigation of the PPARgamma-dependent and independent actions of TZDs in cancer.
McAlpine
Christen A
CA
Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, USA.
Barak
Yaacov
Y
Matise
Ilze
I
Cormier
Robert T
RT
D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D017491:Genes, APC; D005838:Genotype; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D012737:Sex Factors; D013844:Thiazoles / Q000378:metabolism*; D053778:Thiazolidines
D047495:PPAR gamma; D013844:Thiazoles; D053778:Thiazolidines; C033089:thiazoline-2-thione