Colon epithelial proliferation and carcinogenesis in diet-induced obesity

• Published in: Journal of gastroenterology and hepatology 2013-12, Vol.28 (S4), p.41-47
• Main Authors: Takahashi, Hirokazu, Hosono, Kunihiro, Endo, Hiroki, Nakajima, Atsushi
• Format: Article
• Language: English
• Subjects: aberrant crypt foci; Aberrant Crypt Foci - blood; Aberrant Crypt Foci - etiology; Aberrant Crypt Foci - pathology; Aberrant Crypt Foci - prevention & control; adiponectin; Adiponectin - blood; Adiponectin - physiology; AMP-Activated Protein Kinases - physiology; AMPK; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Colon - pathology; colorectal carcinogenesis; Colorectal Neoplasms - blood; Colorectal Neoplasms - etiology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; Diet, High-Fat - adverse effects; Disease Models, Animal; Epithelial Cells - pathology; Humans; Hypoglycemic Agents - therapeutic use; metformin; Metformin - therapeutic use; Mice; Obesity, Abdominal - blood; Obesity, Abdominal - etiology; Obesity, Abdominal - pathology; Risk Factors; Signal Transduction - physiology; Sirolimus
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.12240

Colorectal cancer is the third leading cause of cancer death in Japan and the United States and is strongly associated with obesity, especially visceral obesity. Several metabolic mediators, such as adiponectin, have been suspected to play a role in obesity‐related carcinogenesis. In a previous human study, the existence of a significant correlation between the number of human dysplastic aberrant crypt foci (ACF) and the visceral fat area was demonstrated, and also that of a significant inverse correlation between the number of dysplastic ACF and the plasma adiponectin level. Other studies have investigated the effect of adiponectin under the normal and high‐fat diet conditions in a mouse model of azoxymethane‐induced colon cancer. Enhanced formation of both ACF and tumors was observed in the adiponectin‐deficient mice, as compared with that in the wild‐type, under the high‐fat diet condition but not under the normal diet condition. Furthermore, that the 5′‐AMP‐activated kinase/mammalian target of rapamycin pathway is involved in the promotion of colorectal carcinogenesis in adiponectin‐deficient mice under the high‐fat diet condition was shown. Therefore, that the 5′‐AMP‐activated kinase/mammalian target of rapamycin signaling pathway may play an important role in colorectal carcinogenesis was speculated. Metformin, a biguanide derivative widely used in the treatment of diabetes mellitus, has been shown to exert a suppressive effect on ACF formation in both mouse models and humans. Therefore, metformin might be a promising candidate as a safe drug for chemoprevention of colorectal carcinogenesis. Further studies with high evidence levels, such as randomized, controlled studies, are needed to clarify these relationships.