Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer

Abstract

Many observational epidemiologic studies suggest an association between high-fat-diet (HFD) and colon cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in colon cancer progression and HFDs have been reported to increase inflammation; however, the inflammatory effects of HFD in colon cancer have yet to be firmly established. We examined the effects of a novel HFD that closely mimics the standard American diet (12% and 40% of total caloric intake from saturated fat and total fat, respectively) on macrophage markers and inflammatory mediators in a mouse model of intestinal tumorigenesis and relate this to polyp characteristics as well as measures of adiposity. Male ApcMin/+ mice (7–8/group) were fed a Control Diet (Con) or novel high-fat-diet (HFD) from 4 to 12 weeks of age. Body weight and body composition were measured weekly and monthly, respectively. Intestinal tissue was analyzed for polyp burden (number and size). Gene expression of macrophage markers and inflammatory mediators were examined in the adipose tissue and polyps. The HFD increased the expression of macrophage markers and inflammatory mediators in the adipose tissue (F4/80, CD11c, TLR-4 and MCP-1) and tumor microenvironment (IL-12, MCP-1, IL-6 and TNF-α). As expected, the HFD increased body weight, body fat percent, fat mass and blood glucose (P < 0.05), and was associated with an increase in the number of large polyps (P < 0.05) but not total polyps. In summary, consumption of a HFD, similar in macronutrient composition to the standard American diet, altered the expression of macrophage phenotypic markers and inflammatory mediators in adipose tissue and intestinal polyps and this was associated with increased tumorigenesis.

High-fat diets rich in saturated fat protect against azoxymethane/dextran sulfate sodium-induced colon cancer

“…The majority of studies have used either the Apc min/ϩ mouse model of intestinal tumorigenesis or chemically induced models, namely azoxymethane (AOM) or a combination of AOM and dextran sulfate sodium (AOM/DSS). For instance, we have reported that consumption of a HFD was associated with an increase in the number of large polyps in the Apc min/ϩ mouse (12). However, given that Apc min/ϩ mice develop cachexia at ϳ13 wk of age, the duration of HFD feedings was limited to 8 wk (4 -12 wk of age), greatly restricting our ability to develop an obese phenotype.…”

“…The intake of total dietary fat and fatty acid (FA) composition can alter pathways that are known to affect colon cancer development independent of obesity. For example, we recently examined the influence of three HFDs (40% of total calories from fat) differing in the percentage of total calories from saturated fat (SF) (6,12, and 24%) on body composition, macrophage behavior, inflammation, and metabolic dysfunction in mice and found marked differences across the diets (13,15). However, there is currently little evidence on the impact of dietary total fat or FA composition on colon cancer.…”

Dietary Aloe Vera Gel Powder and Extract Inhibit Azoxymethane-induced Colorectal Aberrant Crypt Foci in Mice Fed a High-fat Diet

“…The administration of lophenol and cycloartanol have been shown to improve hyperglycemia and glucose metabolism and also reduced intra-abdominal fat accumulation in Zucker diabetic fatty (ZDF) rats fed a high-fat diet (Misawa et al, 2008). These findings have been attributed to the down-regulation of fatty acid synthesis and slight up-regulation of fatty acid oxidation in the liver with the administration of lophenol and cycloartanol (Misawa et al, 2008), thereby suggesting that Aloe vera gel could reduce the higher risk of colon cancer associated with fat intake as reported by epidemiological studies (Day et al, 2013).…”

“…Previous studies performed on animals described a relation between HFD consumption and the risk of colon cancer (Day et al, 2013). ACF are commonly accepted precursor lesions for colorectal cancer (Waly et al, 2014).…”

“…We previously repored that AVGE reduced large-sized intestinal polyps in Apc-decifient Min mice fed a high-fat diet (Chihara et al, 2013), suggesting that AVGE protected against colonic inflammation and colorectal cancer. The treatment of Min mice with a high-fat diet was shown to increase the number of polyps (Day et al, 2013).…”