A high‐fat diet increases angiogenesis, solid tumor growth, and lung metastasis of CT26 colon cancer cells in obesity‐resistant BALB/c mice

Abstract

We evaluated whether high-fat diet (HFD), in the absence of increased calorie intake, increases colon cancer growth and metastasis. Four-week-old male BALB/c mice were fed on an HFD (60 kcal% fat) or control diet (10 kcal% fat) for 16 wk, after which CT26 colon cancer cells were subcutaneously injected into the right flank. Solid tumor growth and the number and volume of tumor nodules in the lung were increased markedly in the HFD group with only a slight increase in body weight (5.9%). HFD feeding increased tumor tissue levels of Ki67, cyclin A, cyclin D1, CDK2, Bcl-xL, and Bcl-2; reduced p53 levels and TUNEL-positive apoptotic cells; increased the levels of CD45, CD68, CD31, VEGF, P-VEGF receptor-2, iNOS, and COX-2 as well as hemoglobin content; and increased the levels of HIF-1α, P-STAT3-Y705, P-STAT3-S727, P-IκB-α, P-p65, p65, P-c-Jun, P-Akt, P-ERK1/2, P-p38, and P-SAPK/JNK. HFD feeding increased the serum levels of EGF, insulin, IGF-I, IFN-γ, leptin, RANTES, MCP-1, IL-1ra, and SDF-1α and media conditioned by epididymal fat tissue explants from HFD-fed mice caused an increase in microvessel outgrowth from the mouse aorta and tube formation of human umbilical vein endothelial cells. These results indicate that the chronic consumption of an HFD increases colon cancer cell proliferation, tumor angiogenesis, and lung metastasis in mice in the absence of discernible weight gain. HFD feeding increases the levels of growth factors which activate transcription factors, thereby inducing the expression of many genes involved in the stimulation of inflammation, angiogenesis, and cellular proliferation.

Leptin stimulates sympathetic axon outgrowth

“…Interestingly, development of arrhythmias is seen even in the absence of obesity [47], and a high fat diet without overt obesity results in cardiac sympathetic hyperinnervation [21]. A high fat diet increases serum levels of many growth factors including EGF, IGF-1, Insulin, MCP-1, IFN-γ, and leptin [50]. In addition, adipose tissue is capable of secreting the classic sympathetic growth factor, NGF [51].…”

Vascular Endothelial Growth Factor Improves Liver Regeneration and Survival after 90% Hepatectomy in a Rat Model of Diet-Induced Steatosis

“…This is especially striking since both VEGF repression [31] and overexpression [32] protect mice against obesity and insulin resistance. Conversely, obesity seemingly impairs wound healing [33] but increases angiogenesis and solid tumor growth [34]. In addition, obesity in humans leads to elevated circulating VEGF levels [35].…”

Crown-like Structures in Breast Adipose Tissue from Normal Weight Women: Important Impact

“…Is it a consequence of obesity or do the causes of obesity independently promote the carcinogenic process? In response to this intriguing question, it is interesting to note that multiple models have now been reported wherein transplanted and/or spontaneous tumors, including breast cancer, are promoted by high-fat diet in the absence of obesity (26)(27)(28)(29)(30).…”