Folate, colorectal carcinogenesis, and DNA methylation: Lessons from animal studies

Abstract

Folate, a water-soluble B vitamin and cofactor in one-carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer (CRC). Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with CRC risk. Collectively, these studies suggest an approximately 40% reduction in the risk of CRC in individuals with the highest dietary folate intake compared with those with the lowest intake. Animal studies using chemical and genetically predisposed rodent models have provided considerable support for a causal relationship between folate depletion and colorectal carcinogenesis as well as a dose-dependent protective effect of folate supplementation. However, animal studies also have shown that the dose and timing of folate intervention are critical in providing safe and effective chemoprevention; exceptionally high supplemental folate levels and folate intervention after microscopic neoplastic foci are established in the colorectal mucosa promote, rather than suppress, colorectal carcinogenesis. These animal studies, in conjunction with clinical observations, suggest that folate possesses dual modulatory effects on carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect, whereas folate supplementation has a promoting effect on the progression of established neoplasms. In contrast, folate deficiency in normal epithelial tissues appears to predispose them to neoplastic transformation, and modest levels of folate supplementation suppress the development of tumors in normal tissues. Notwithstanding the limitations associated with animal models, these studies suggest that the optimal timing and dose of folate intervention must be established for safe and effective chemoprevention in humans. Folate is an important factor in DNA synthesis, stability, and integrity, the repair aberrations of which have been implicated in colorectal carcinogenesis. Folate may also modulate DNA methylation, which is an important epigenetic determinant in gene expression (an inverse relationship), in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. A mechanistic understanding of how folate status modulates colorectal carcinogenesis further strengthens the case for a causal relationship and provides insight into a possible chemopreventive role of folate.

The MTHFR C677T Polymorphism and Prostate Cancer Risk: New Findings from a Meta-analysis of 7306 Cases and 8062 Controls

“…She hypothesized an U-shape relation between folate status and breast cancer risk, in which individuals with relatively low folate status would benefit from extra folate intake, but after the folate status was increased to a certain level, more folate intake would exert no further influence on cancer prevention, instead, excessive folate may play as a risk factor to breast cancer, which means folate could act as a double-edged sword with a tolerable upper level. It is supported by animal studies from Kim, in which excessive supplementation of folate was likely to increase tumor growth (Kim, 2004). This could probably be the case not only in breast cancer but also in many other cancer types.…”

“…Kim's experiments also supported such concept. He found administration of folic acid after lesions increased colorectal neoplasia (Kim, 2004). These probably could explain the disparity of effects of folate on different cancer types, especially when different sensitivities of cancer types to folate and distinctive etiology of a certain cancer were considered.…”

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…Folate is a cofactor in a plethora of biochemical reactions due to its ability to donate or accept one-carbon units (Duthie, 1999). It is especially important during periods of rapid cell division and growth, and both children and adults need folate for the production of healthy red blood cells (Kim 2004;Bailey & Ayling, 2009). …”

“…It is not by itself biologically active but it is converted into the liver to dihydrofolate (DHF) via saturation of one of its carbon-carbon double bonds, and then to tetrahydrofolate (THF) with an addition of an extra hydrogen molecule across the second carbon-carbon double bond. These active derivatives are essential to nucleotide biosynthesis and the re-methylation of homocysteine (Kim, 2004;Hazra et al, 2007).…”

“…The data combined suggest that folate plays an important role in DNA methylation and even though the link is still unclear, folate could be associated with protection against some cancers. (Kim, 2003;Kim, 2004;Anderson et al, 2012).…”