Abstract 2479: Leptin signaling regulates colorectal tumor growth through Stat3 signaling: Tumor growth induced by dietary intake
Authors: Hiroki Endo, Kunihiro Hosono, Takashi Uchiyama, Hirokazu Takahashi, Masahiko Inamori, Atsushi Nakajima
Journal: Cancer Research (2010)

Abstract Background: Leptin, a product of the ob gene involved in energy balance and the regulation of food intake, is secreted predominantly in adipose tissue and serum leptin levels are elevated in obese individuals. Epidemiological studies have revealed that obesity, especially visceral fat, raises the risk of colorectal cancer (CRC). However, data concerning the effect of leptin on CRC development are contradictory and difficult to interpret. The aim of this study was to investigate the impact of leptin deficiency on CRC development and to determine whether leptin acts as a tumor promoter. Methods: We investigated chemical-induced colon tumors and aberrant crypt foci (ACF) formation using wild-type (WT) mice, leptin-deficient (ob/ob) mice and leptin receptor deficient (db/db) mice. Western blot analysis, PCR and immunohistochemistry were performed to examine the role of leptin signaling in the colonic epithelium. Results: Ob/ob and db/db mice exhibited dramatically decreased tumor sizes, despite exhibiting their severe obesity and hyperinsulinemia. Tumor cell proliferation was significantly lower in the ob/ob and db/db mice than in the WT mice. These results strongly indicated that leptin is indispensable for the regulation of colonic tumor growth irrespective of obesity. Conversely, normal mucosal cell proliferation was significantly higher in ob/ob and db/db mice than in WT mice. The number of ACF in ob/ob and db/db mice was also significantly higher than that in WT mice, suggesting that leptin is not a promoter of colon tumor initiation. Here, we noted a difference in the expression of leptin-receptor (Ob-R) between tumors and normal mucosa. Interestingly, the Ob-R expression level was markedly increased in the tumors, compared with normal mucosa. Furthermore, immunohistochemical analysis revealed the tumor cell nuclear localization of phosphorylated-Stat3, which is a downstream signaling pathway of Ob-R, in WT mice, and this signal was almost completely absent in the tumors of ob/ob mice. Conclusions: We clearly demonstrated a relationship between leptin and the growth of colon tumors in leptin- or leptin receptor-deficient mice. The dramatic suppression of colonic tumor growth induced by the inhibition of leptin signaling indicates that leptin is an indispensable growth factor for colon tumors. Based on the present results, colon tumors might have a tendency to develop in overeating obese individuals whose serum leptin levels are elevated. Our data provide novel insights into leptin signaling in CRC and suggest novel therapeutic and preventive approaches for colon polyps and cancers based on the inhibition of leptin-dependent Stat3 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2479.