A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice

Abstract

Decreased dietary intakes of calcium, vitamin D and folic acid have been suggested as risk factors for human colon cancer. We previously fed a Western-style diet (WD) containing reduced calcium, vitamin D and increased fat content to normal C57/Bl6 mice: hyperproliferation, hyperplasia and whole crypt dysplasias developed in the colon following WD administration. Utilizing the same diet, we now also decreased the levels of several nutrients that are required for biochemical reactions involving methyl group inadequacy, i.e. folic acid, methionine, choline and vitamin B(12). Dietary levels of these nutrients were reduced to nutrient-density levels approximating those consumed by large segments of human Western populations. This further modification of the WD resulted in adenoma and carcinoma development in normal mouse colon (P < 0.04 compared with AIN-76A diet). The results indicate, for the first time, that a semi-purified rodent diet designed to mimic the human Western diet can induce colonic tumors in normal mice without carcinogen exposure.

How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men

“…In Newmark's model, normal mice were fed a "Western diet", which contains high fat and phosphate, and low calcium, vitamin D, fibres, folic acid and vitamin B12. Eighteen months later, spontaneous colon tumours were observed in five mice out of twelve (98). Could this model be the ultimate one to predict tumour prevention in humans, as advocated by Bruce (99)?…”

“…Could this model be the ultimate one to predict tumour prevention in humans, as advocated by Bruce (99)? This notion is a distinct possibility, because, like in humans, the addition of calcium (and vitamin D) to the diet reduced tumour incidence in mice (98).…”

A pilot randomised controlled trial to reduce colorectal cancer risk markers associated with B-vitamin deficiency, insulin resistance and colonic inflammation

“…Low folate status can result in increased chromosome instability, DNA damage, impaired repair, aberrant DNA methylation and point mutations (Cravo et al, 1994;Fenech et al, 1997;Kim, 1999). These initiate colon carcinogenesis Folic acid (Kim et al, 1996;Newmark et al, 2001;Konings et al, 2002) (2) Insulin resistance/plasma insulin, free fatty acids and triacylglycerol (McKeown-Eyssen, 1994;Giovannucci, 1995;Kim, 1998) Dietary factors including a hypercaloric diet with refined sugars, increased saturated fat, and reduced n-3 fatty acids, together with reduced energy expenditure, increase the accumulation of energy substrates in the body and lead to insulin resistance (Storlien et al, 1991;Tran et al, 1996Tran et al, , 2003Koohestani et al, 1998;Bruce et al, 2000;Kaaks et al, 2000). Insulin resistance is a state of decreased insulin action that is usually accompanied by increased concentrations of: insulin (due to compensatory hypersecretion of insulin), free fatty acid (FFA, due to the impaired antilipolytic action of insulin) and triacylglycerols (TG, derived from the released FFA) (DeFronzo and Ferrannini, 1991).…”

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).…”