No abstract

Recent epidemiological studies have shown a positive association of a high-fat diet with the risk of colon cancer. Indeed, increments in the serum levels of triglycerides (TG) and cholesterols are positively related with colon carcinogenesis. We previously reported that an age-dependent hyperlipidemic state is characteristic of Min mice, an animal model for human familial adenomatous polyposis (FAP). However, qualitative and quantitative changes of lipid metabolism are poorly understood in this state. Here, we provide detailed analysis of serum lipids in Min mice using reverse-phased liquid chromatography/electrospray ionization mass spectrometry (RPLC/ESI-MS). We also demonstrate local analysis of lipid droplets in the villi of the small intestine using laser capture microdissection and a sensitive chip-based nanoESI-MS system. As a result, oxidized phosphatidylcholines (PC) such as aldehyde and carboxylic acid types were increased, even at an early stage of intestinal polyp formation in serum. In addition, hydroperoxidizable TG precursors containing linoleic acid (18:2n-6) were deposited at the tip of the villi with aging, and these hydroperoxidized TG were also increased in serum. Meanwhile, increments of the oxidizable TG precursors in serum and small intestinal mucosa were suppressed by treatment with pitavastatin, a novel third generation lipophilic statin. These results suggest that quantitative and qualitative lipid changes such as hydroperoxidizable TG precursors are important in the course of intestinal polyp formation and oxidative stress might lead to the development of intestinal polyp formation in Min mice. (Cancer Sci 2011; 102: 79-87) T he incidence and mortality of colon cancer, which is associated with obesity, a high-fat diet and hyperlipidemia according to several epidemiological studies, has increased in developed countries.(1-5) We previously reported an agedependent hyperlipidemic state in adenomatous polyposis coli (Apc)-deficient Min and Apc 1309 mice, animal models of familial adenomatous polyposis (FAP).(6-8) Min mice develop large numbers of intestinal polyps due to truncation mutation in both alleles of the Apc gene, leading to activation of Wnt signaling to promote cell growth, which is increased by consumption of a high-fat diet. (9) Although the direct link between Apc-deficiency and hyperlipidemia is yet to be clarified, it is notable that serum triglyceride (TG) levels in Min mice are almost 10 times higher than those observed in wild-type littermates (C57BL ⁄ 6J) at 20 weeks of age, even though both mice were fed a non-high-fat diet, AIN-76A, including corn oil (5% of total components).(6) Both groups of mice ate almost the same amount of diet, but the mean bodyweight was 16% lower in Min mice compared with that of their wild-type littermates at 20 weeks of age, which might be due to the development of intestinal polyps. Consumption of a high-fat diet is associated with hyperlipidemia and leading obesity.(10) However, Min mice featured hyperlipidemia without a high fat-diet ...

It has been suggested that hyperlipidemia is positively associated with colon carcinogenesis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, reduce serum lipid levels. In this study, we clarified the effects of a novel chemically synthesized statin, pitavastatin, on intestinal polyp formation in Min mice, and further examined serum lipid and adipocytokine levels, and proinflammatory and adipocytokine gene levels in intestinal mucosa of Min mice. Treatment with pitavastatin at doses of 20 and 40 ppm decreased the total number of polyps dose-dependently to 85.2% and 65.8% (P < 0.05) of the untreated value, respectively. Serum levels of total cholesterol and triglyceride were slightly reduced and those of IL-6, leptin, and MCP-1 were decreased by 40-ppm pitavastatin treatment. mRNA expression levels of cyclooxygenase-2, IL-6, inducible nitric oxide (iNOS), MCP-1, and Pai-1 were significantly reduced in intestinal nonpolyp parts by pitavastatin treatment. Among them, iNOS mRNA levels were also reduced in the intestinal polyps. Moreover, oxidative stress represented by 8-nitroguanosine in the small intestinal epithelial cells was reduced by pitavastatin treatment. Related to these proinflammatory genes, PPARg activity was activated in the intestinal nonpolyp parts and in the liver of Min mice with pitavastatin treatment. These results indicated that pitavastatin has potential benefit for the suppression of intestinal polyp development. Cancer Prev Res; 4(3); 445-53. Ó2011 AACR.

Obesity is associated with colon carcinogenesis. However, not much information is available regarding the mechanisms of obesity-associated colorectal cancer, and there are only few useful animal models for investigating the underlying mechanism between obesity and colorectal cancer. KK-A y mice exhibit severe obesity. Amount of visceral fat assessed by micro-computed tomography was almost 15 times higher than that of same aged C57BL/6J mice. Treatment with azoxymethane (AOM; 200 lg/mouse injected once a week for 3 times) resulted in markedly increased colon aberrant crypt foci (ACF) development (%70 ACF/mouse) in KK-A y mice compared with lean C57BL/6J mice (%9 ACF/mouse). Moreover, administration of AOM at a dose of 200 lg/mouse once a week for 6 times developed colorectal adenocarcinomas within only 7 weeks after the last AOM injection. The incidence of adenocarcinoma was 88% in KK-A y mice and was markedly higher than the 4% observed in C57BL/6J mice. The number of tumors/mouse was 7.80 in KK-A y mice and also markedly higher than the 0.12 in the C57BL/6Jcase. Interestingly, adenocarcinomas were observed in most of the AOM-treated KK-A y mice along with remarkable tumor angiogenesis, and some showed submucosal invasion. These results indicate that the KK-A y mouse, featuring intact leptin and leptin receptor Ob-Rbl, could be a useful animal model to investigate obesity-associated cancer.Epidemiological studies have suggested that metabolic syndrome, characterized by hyperglycemia, hyperinsulinemia, hyperlipidemia and hypertension, is a risk factor for colorectal cancer.

Apc-deficient Min mice feature low expression of lipoprotein lipase (LPL), high concentration of serum triglyceride (TG), fatty change of the liver and large numbers of intestinal polyps. We have reported that induction of LPL expression reduces serum lipid, especially TG, improves fatty change of the liver and inhibits intestinal polyp formation in the mice. In this study, fatty change/ lipid accumulation in intestinal mucosa and polyps in Min mice were analyzed by Oil-red O staining and electron microscopy. A number of large lipid droplets were found in the epithelia of the upper part of polyps. On the other hand, small lipid droplets were only slightly observed at the tip of the villi in non-tumoros parts of the small intestine of Min mice and in the villi of wild-type mice. Moreover, low-density lipoprotein receptor (LDLR) was overexpressed in the area where lipid droplets were observed. The expression levels of LDLR mRNA in the intestinal polyps of Min mice were 3 times higher compared to those in the non-tumoros parts. Remarkable expression of cyclooxygenase-2 was mainly distributed in stromal cells and some in epithelial cells. It is speculated that lipid accumulation in the intestinal polyps may play an important role in intestinal polyp formation in Apc-deficient mice. ' 2009 UICC