Controversy: PPARγ as a target for treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) represents a significant cause of morbidity and mortality worldwide. Recently, ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) have exhibited promise in the treatment of CRC. For example, activation of PPARγ reduces the proliferation of cultured CRC cells grown in vitro or in vivo using the nude mouse xenograft model of tumor growth. Furthermore, agonists of the receptor also reduce the development of preneoplastic lesions in a model of carcinogen-induced CRC in rats. However, ligands for the receptor paradoxically enhance intestinal adenoma formation in another murine model of intestinal polyposis, the APC Min mice. These disparate results may be due to the inherent limitations of the APC Min mouse as a model for humans with CRC. Finally, genetic studies identifying loss of function mutations of PPARγ in human CRC specimens strongly suggest a tumor suppressive role for the receptor during the development of CRC.