Dietary Induction of Colonic Tumors in a Mouse Model of Sporadic Colon Cancer

Abstract

A defined rodent ''new Western diet'' (NWD), which recapitulates intake levels of nutrients that are major dietary risk factors for human colon cancer, induced colonic tumors when fed to wild-type C57Bl/6 mice for 1.5 to 2 years from age 6 weeks (two-thirds of their life span). Colonic tumors were prevented by elevating dietary calcium and vitamin D 3 to levels comparable with upper levels consumed by humans, but tumorigenesis was not altered by similarly increasing folate, choline, methionine, or fiber, each of which was also at the lower levels in the NWD that are associated with risk for colon cancer. The NWD significantly altered profiles of gene expression in the flat colonic mucosa that exhibited heterogeneity among the mice, but unsupervised clustering of the data and novel statistical analyses showed reprogramming of colonic epithelial cells in the flat mucosa by the NWD was similar to that initiated by inheritance of a mutant Apc allele. The NWD also caused general down-regulation of genes encoding enzymes involved in lipid metabolism and the tricarboxylic acid cycle in colonic epithelial cells before tumor formation, which was prevented by the supplementation of the NWD with calcium and vitamin D 3 that prevented colon tumor development, demonstrating profound interaction among nutrients. This mouse model of dietary induction of colon cancer recapitulates levels and length of exposure to nutrients linked to relative risk for human sporadic colon cancer, which represents the etiology of >90% of colon cancer in the United States and other Western countries.

Gut microbiome development along the colorectal adenoma–carcinoma sequence

“…Dietary components such as red meat are known risk factors for colorectal carcinoma 3,14,15 , but it is not known how diet makes a footprint on gut microbes associated with or even causing colorectal carcinoma. We assessed influence of a number of clinical or lifestyle factors on gut microbial genes or MLGs, and found that the control, adenoma or carcinoma state was indeed among the strongest factors ( Supplementary Fig.…”

“…It is not clear, however, whether more bacteria or archaea serve as markers for, or contribute to the aetiology of, colorectal carcinomas. Moreover, as perhaps the most important environmental factor for human health, or our 'other genome' 12,13 , it remains to be explored whether and how the gut microbiome integrate other risk factors, for example, diet, smoking, obesity [1][2][3]14,15 and generate a coherent signal for colorectal carcinogenesis.…”

Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer

“…sporadic | colon cancer | Western diet | microarray B oth large and small intestinal tumors develop in WT C57BL/6 mice after long-term (1.5-2 y) feeding of a fully defined Western-style diet that combines a number of risk factors for human colon cancer (NWD1: higher fat, lower calcium, vitamin D 3 , donors to the single carbon pool, and fiber, and carbohydrate supplied by sucrose, a refined sugar commonly consumed in developed but not undeveloped countries) (1,2). These dietaryinduced tumors arise with an incidence, frequency, and lag (i.e., two-thirds of the host lifespan) similar to those of human colon tumors, making them a useful model of sporadic intestinal cancer, the form of the disease responsible for >90% of intestinal cancer in the human (1,2).…”

“…These dietaryinduced tumors arise with an incidence, frequency, and lag (i.e., two-thirds of the host lifespan) similar to those of human colon tumors, making them a useful model of sporadic intestinal cancer, the form of the disease responsible for >90% of intestinal cancer in the human (1,2).…”

“…Western-style diets increase and accelerate the tumor phenotype of Apc +/− mice (7,8), establishing that dietary and genetic stimulation of tumorigenesis involve at least partially distinct and interactive effects. Indeed, although there are overlaps in the expression signatures of intestinal epithelial cells of mice fed the Western-style diet and Apc 1638N/+ mice, there are also many differences (2). Furthermore, inactivation of the cdk inhibitors p21 Waf1/cip1 or p27 Kip1 in Apc 1638N/+ mice also produced a more aggressive tumor phenotype than in Apc 1638N/+ mice, but even in these compound mutant mice, a Western-style diet amplified and accelerated tumor development, establishing that multiple distinct pathways interact in altering probability of intestinal tumorigenesis (9)(10)(11).…”