Intestinal-specific PPARγ deficiency enhances tumorigenesis in Apc^Min/+ mice

Multiple investigations of the effects of peroxisome proliferator-activated receptor γ (PPARγ) 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) PPARγ 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 PPARγ in murine intestinal tumorigenesis using gene knockout methodology. We found that either heterozygous or homozygous intestinal-specific PPARγ deficiency enhanced the number of Apc^Min/+ tumors in both the small intestine and colon, especially in the colon, where PPARγ deficiency also modulated tumor incidence. Gender significantly affected tumor multiplicity independent of PPARγ 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 PPARγ deficiency enhanced tumorigenesis irrespective of gender. Our results suggest that PPARγ functions as a tumor resistance factor in the mouse intestine and warrant further investigation of the PPARγ-dependent and independent actions of TZDs in cancer.