The Effects Of Environmental Carcinogens, Chemopreventive Vegetables, And A Total Western Diet On Colon Cancer Risk

Abstract

Colon cancer is the third most common cancer in the United States. However, colon cancer risk may be reduced by a high intake of chemopreventive vegetables and phytochemicals. We previously reported that cruciferous vegetables decreased biomarkers that are indicative of colon cancer risk in rats when fed during both initiation and promotion stages of colon cancer. However, neither cruciferous vegetables nor another vegetable class, apiaceous vegetables, have been investigated for a chemopreventive effect when fed only in the post-initiation stage. In the first study, we evaluated the chemopreventive effects of apiaceous and of cruciferous vegetables on colon cancer risk in the post-initiation stage by examining morphological (aberrant crypt foci; ACF) and biochemical (β-catenin accumulated crypts; BCAC) markers, cancer stem cell surface marker (doublecortin-like kinase 1; DCLK1), and the profile of colonic miRNA expression. Compared with the vegetable-free basal diet, cruciferous vegetables reduced the number of ACF and BCAC and DCLK1-positive marker expression in the colons of 1,2-dimethylhydrazine-treated rats. Apiaceous vegetables decreased the proportion of dysplastic ACF and the formation of DCLK1-positive cells in the carcinogen-treated rat colons. Moreover, functional and pathway enrichment analysis of miRNA targets suggested that cruciferous vegetable consumption is associated with reductions in the NF-κB and Wnt/β-catenin signaling pathways and cancer stem cell formation. Apiaceous vegetables are associated with a reduction in the Wnt/β-catenin signaling pathway and cancer stem cell formation. Thus, when fed only in the post-initiation stage, both apiaceous and cruciferous vegetables appear to reduce the risk of colon carcinogenesis, although likely by different mechanisms. Environmental factors, including dietary factors and tobacco smoke, are believed to be responsible for the majority of colon cancer cases. Environmental carcinogens, including N-nitrosodimethylamine (NDMA), 2-amino-9H-pyrido[2,3-b]indole (AαC), and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), formed in grilled food, processed meat, and cigarette smoke are involved in the pathogenesis of cancer. Azoxymethane (AOM), a colon-specific carcinogen is an isomer of NDMA, and it produces the same DNA adducts as does NDMA. However, the comparative tumor-initiating potential of AαC, MeIQ, and AOM is unknown. In the second study, we evaluated the formation of DNA adducts as a measure of genotoxicity, and the induction of ACF and dysplastic ACF, as an early measure of carcinogenic potency of these compounds in the colon of male A/J mice. Both AαC and AOM induced a greater number of DNA adducts than MeIQ in the liver and colon. AOM induced a greater number of ACF and dysplastic ACF than either AαC or MeIQ. Conversely, based on adduct levels, MeIQ-DNA adducts were more potent than AαC- and AOM-DNA adducts at inducing ACF. Accumulating evidence suggests that a Western diet is associated with an increased risk of colon cancer. Recently, a new diet for rodents that reflects the average American intake in all nutritional aspects was developed, called the Total Western diet (TWD). Heterocyclic aromatic amines, such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), generated in overcooked meat, are associated with colon cancer risk. The first study found that apiaceous and cruciferous vegetables reduced colon cancer risk. Given the almost unavoidable intake of red meat and processed meat in the Western diet and the chemopreventive effects of both vegetables, it was of interest to examine their effect on reducing biomarkers of colon cancer risk in the context of a Western diet that included PhIP. Therefore, in the third study, we investigated the effects of the TWD and supplementation with chemopreventive vegetables on PhIP-induced colon cancer risk, using ACF and BCAC as markers of cancer risk. Compared with the basal diet, TWD significantly increased the number of ACF and BCAC, whereas apiaceous and cruciferous vegetables decreased the number of ACF and BCAC to levels similar to the basal diet. Thus, both apiaceous and cruciferous vegetables appear to reduce TWD-promoted colon cancer risk. In summary, different environmental carcinogens varied in their ability to form DNA adducts and ACF. A Western-style diet increased markers of colon cancer risk in mice, whereas both apiaceous and cruciferous vegetables reduced the colon cancer risk markers induced by a chemical carcinogen alone or together with Western diet.