Abstract 1823: Chronic consumption of a high-fat diet stimulates tumor growth and metastasis via the activation of key transcription factors in a CT26 mouse colon cancer allograft model
Authors: Heesook Park, Do Young Lim, Minhee Kim, Jung Han Yoon Park
Journal: Cancer Research (2011)

Abstract We previously demonstrated that dietary fat increased solid tumor growth and metastasis of CT26 colon cancer cells when injected subcutaneously into BALB/c mice. The present study examined the mechanisms by which high-fat diet (HFD) feeding stimulates tumor development and progression. 4-week old, male BALB/c mice were fed a purified diet containing 34.9% (w/w) fat or 4.3% fat (control diet) for a period of 16 weeks. After 16 weeks, CT26 cells were injected subcutaneously into the animals’ left flank. 4.5 weeks after cell injection, mice were killed. In the tumor tissues of mice fed on the HFD, the expression of hypoxia-inducible factor (HIF)-1 and inducible nitric oxide synthase (iNOS) was increased markedly, which was accompanied by a marked increase in the expression of platelet endothelial cell adhesion molecule-1 (CD31, an angiogenesis marker) and vascular endothelial growth factor (VEGF), a down stream target gene product of HIF-1α. Conditioned media by explants of epididymal fat tissues from the HFD-fed mice caused an increase in microvessel outgrowth from the mouse aorta. The infiltration of macrophages was increased into tumor tissues of mice fed on the HFD. Additionally, the levels of chemoattractants and pro-inflammatory cytokines (IFN-γ, IL-1ra, RANTES, MCP-1, SDF-1α, and leptin) were increased in the sera of the HFD group compared to the control group. The expression of p53, another downstream target gene of HIF-1α, was reduced and that of BCL-xL was increased in the tumor tissues obtained from the mice fed on the high-fat diet. These changes in p53 and Bcl-xL may have induced a reduction in the apoptosis of tumor cells in the mice fed on the HFD. In addition to changes in the expression of proteins involved in the regulation of apoptosis, the expression of the cell proliferation marker ki67 as well as that of other proteins involved in the stimulation of cell cycle progression, including cyclin-dependent kinase (CDK)2, CDK4, cyclin D1, and cyclin A, was increased in the tumor tissues from mice fed on the HFD. The levels of phosphorylated ERK1/2, AKT, IκB-α, NFκB p65, VEGFR-2, c-Jun and signal transducer and activator of transcription (STAT3, pY705, pS727) were increased in the tumor tissues of HFD-fed mice. Together, these results suggest that, in obese mice, pro-angiogenic and pro-inflammatory cytokines/chemokines generated by adipose tissues stimulate tumor growth and macrophage infiltration into the tumor microenviroment, and thus play an important role in the activation of the key transcription factors HIF-1α, NFκB, and STAT3; this subsequently activates the transcription of many genes involved in the stimulation of inflammation, proliferation, and angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1823. doi:10.1158/1538-7445.AM2011-1823