Effects of dietary folate on intestinal tumorigenesis in the APCMIN in mouse

Song, Jacquelin; Medline, Alan; Mason, Joel B.; Gallinger, Steven; Kim, Young-In J.

doi:10.1016/s0016-5085(00)83190-x

Cited by 146 publications

(215 citation statements)

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“…In APC Min mice randomly assigned to receive diets of varying folate content after weaning, the number of small intestinal adenomas found at 3 months was inversely related to both the level of dietary folate and serum levels of folate, again corroborating evidence from humans (Song et al, 2000a). At 6 months however, mice fed a folate-deficient diet had fewer distal small intestinal adenomas compared with folate-supplemented animals, and the number of distal adenomas was positively associated with serum folate levels suggesting an inhibitory effect of folate deficiency on established distal small intestinal adenomas (Song et al, 2000a).…”

Section: Evidence From Animal Modelssupporting

confidence: 66%

Folate and colorectal cancer prevention

Hubner

Houlston

2008

Br J Cancer

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Anti-folate chemotherapy agents such as methotrexate and fluorouracil reduce proliferation of neoplastic cells by inhibiting DNA synthesis. Paradoxically epidemiological data suggests an inverse relationship between dietary folate intake and incidence of colorectal cancer (CRC). On the basis of this and other putative health benefits around 35% of the North American population take folic acid supplements, in addition to natural food folates and fortified flour and cereal grains. Recently, randomised controlled trials investigating folic acid as a secondary preventative agent in colorectal neoplasia have shed further light on the relationship between folate and colorectal carcinogenesis, corroborating data from animal models indicating opposing effects dependent on the timing of exposure in relation to the development of neoplastic foci. A 'dual-modulator' role for folate in colorectal carcinogenesis has been proposed in which moderate dietary increases initiated before the establishment of neoplastic foci have a protective influence, whereas excessive intake or increased intake once early lesions are established increases tumorigenesis. Functional polymorphic variants in genes encoding key enzymes in the folate metabolic pathway add a further layer of complexity to the relationship between folate and CRC risk. Here, we review the evidence concerning the efficacy and safety of folate as a potential CRC chemopreventive agent.

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Section: Evidence From Animal Modelssupporting

confidence: 66%

Folate and colorectal cancer prevention

Hubner

Houlston

2008

Br J Cancer

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“…25 However, high levels of folate supplementation do not appear to provide additional protection, and in some cases may enhance carcinogenesis. [26][27][28] Kim 24 further noted that progression of established neoplasia is quite likely with supplemental folate. Although caution when extrapolating animal data to humans is warranted, our data on multivitamin use support the notion that additional folate or multivitamins in an environment of adequate folate confers no added protection.…”

Section: Discussionmentioning

confidence: 99%

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

Martı́nez

Giovannucci

Jiang

et al. 2006

Intl Journal of Cancer

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In 1996, the US Food and Drug Administration mandated the fortification of grain products with folic acid, a nutrient that has been associated with lower risk of colorectal neoplasia. We assessed the relation of plasma folate and homocysteine and colorectal adenoma recurrence separately in 2 studies: the first involved an intervention of a cereal supplement that contained folic acid, wheat bran fiber (WBF), and the second was conducted primarily during postfortification of the food supply using ursodeoxycholic acid (UDCA). Analyses were stratified for multivitamin use. Results show that plasma folate and homocysteine concentrations were associated with adenoma recurrence among nonusers of multivitamins only. Among nonmultivitamin users, the odds ratio [OR] (95% confidence interval [CI]) for those in the highest versus the lowest folate quartile was 0.65 (0.40-1.06) for the WBF study and 0.56 (0.31-1.02) for the UDCA; likewise, individuals in the highest versus the lowest quartile of homocysteine had higher odds of adenoma recurrence, in both the WBF (OR 5 2.25; 95% CI 5 1.38-3.66) and UDCA (OR 5 1.93; 95% CI 5 1.07-3.49) populations. Analyses comparing multivitamin users to different plasma folate concentrations among nonusers show that odds of recurrence for supplement users was lower only when compared to nonusers who had lower concentrations. Our results show that higher plasma folate or lower homocysteine levels are associated with lower odds of recurrence among nonusers of multivitamins in both studies. Our finding, suggesting that multivitamins or supplemental folate only benefit individuals with lower plasma folate concentrations, should be taken into consideration when designing and interpreting results of intervention studies. ' 2006 Wiley-Liss, Inc.Key words: colorectal adenoma; folate; homocysteine Colorectal cancer is thought to be the result of a multistep evolutionary process that involves a precursor lesion, the adenomatous polyp. Among individuals who undergo removal of their adenoma(s), recurrence of these lesions at surveillance colonoscopy is common, making adenoma recurrence an important endpoint to study in relation to lifestyle and other risk factors.Folate is a water soluble B-vitamin that functions as a coenzyme in single-carbon transfer in nucleic and amino acid metabolism. Folic acid is the fully oxidized monoglutamyl form of folate that is used in supplements and fortified foods. A recent meta analysis showed a significant 20-25% lower risk of developing colorectal cancer among individuals in the highest compared to those in the lowest category of dietary folate 1 ; inverse associations between blood folate and colorectal neoplasia (i.e., cancer and adenoma) have also been shown. [2][3][4] Mechanisms responsible for the inverse association of folate on risk of colorectal cancer are not entirely understood and may involve disturbances in DNA synthesis, methylation and repair, 5-7 albeit alternate mechanisms have been proposed. 8 Homocysteine, a biochemical marker of folate status, is an...

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“…Such studies may help us understand the mechanisms underlying the observed inverse relationship between cancer risk and folate status. Folate status has previously been observed to have a differential effect on tumorigenesis in animals, with supplementation being protective if started before the appearance of precancerous lesions while promoting tumor growth after initiation has already occurred [47,48]. For this reason, we have chosen to perform our experiments in cells derived from the normal colon, which, to the best of our knowledge, are among the most 'normal' colonic cells currently available.…”

Section: Introductionmentioning

confidence: 99%

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

Crott

Liu

Keyes

et al. 2008

The Journal of Nutritional Biochemistry

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Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell lines derived from the normal human colon, HCEC, NCM356 and NCM460, were grown for 32-34 days in media containing 25, 50, 75 or 150 nM folic acid, and the expression of genes involved in cell-cycle checkpoints, intracellular signaling, folate uptake and cell adhesion and migration was determined. Expression of Folate Receptor 1 was increased with decreasing media folate in all cell lines, as was p53, p21, p16 and β-catenin. With decreasing folate, the expression of both E-cadherin and SMAD-4 was decreased in NCM356. APC was elevated in NCM356 but unchanged in the other lines. No changes in global methylation were detected. A significant increase in p53 exon 7-8 strand breaks was observed with decreasing folate in NCM460 cells. The changes observed are consistent with DNA damage-induced activation of cell-cycle checkpoints and cellular adaptation to folate depletion. Folate-depletion-induced changes in the Wnt/APC pathway as well as in genes involved in cell adhesion, migration and invasion may underlie observed relationships between folate status and cancer risk.

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Effects of dietary folate on intestinal tumorigenesis in the APCMIN in mouse

Cited by 146 publications

References 0 publications

Folate and colorectal cancer prevention

Folate and colorectal cancer prevention

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

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