Folate, a water-soluble B vitamin, has recently garnered much attention because of its purported role in the pathogenesis of cardiovascular disease, neural tube defects, and cancer of certain organs (reviewed in references 8–12). Although the appreciation of the role of folate in carcinogenesis is a recent development, several previous observations have suggested a possible relationship between folate deficiency and the development of cancer. Cytopathologists in the 1950s and 1960s noticed cytologic similarities between exfoliated macrocytic gastric and cervical epithelial cells in individuals with folate and/or vitamin B12 deficiency and dysplastic cells. Some of these macrocytic epithelial cells persisted even after the correction of folate and/or vitamin B12 deficiency. 13 Because the cytologic appearance of these cells had some features of malignancy, it was postulated that these abnormal cells might be a transitional cell type between normal and neoplastic epithelium. However, a functional similarity between megaloblastic and neoplastic epithelial cells was not fully appreciated until recently. The concept that folate deficiency would predispose epithelial cells to a neoplastic transformation appears somewhat contradictory at first glance. Folate is an important factor for a number of metabolic pathways in the cell that involve the transfer of one-carbon groups. Among such pathways are the biosyntheses of purines and thymidylates. It is in this manner that folate plays a key role in DNA replication and cell division. Consequently, a deficiency of folate in tissues with rapidly replicating cells results in ineffective DNA synthesis, resulting in reduced cell proliferation, impaired cellular physiology, and abnormal cytologic morphology. This biochemical function of folate has been utilized in the area of how folate modulates cell proliferation in the process of carcinogenesis. Intuitively, interruption of folate metabolism in neoplastic cells would be expected to lead to ineffective DNA synthesis, resulting in the inhibition of tumor growth. Indeed, this has been the basis for antitumor therapy utilizing a number of antifolate agents, including methotrexate and 5-fluorouracil. Clinically, it has been observed that folate treatment of children with acute leukemia results in an “acceleration phenomenon” of the cancer. Experimentally, it has been shown that growth of a transplanted cancer is inhibited in folate-deficient rats, that folate deprivation reduces virally induced cancers, and that the time required for developing neoplasms in transgenic mice, which are predisposed to developing nerve sheath tumors similar to human neurofibromatosis, is significantly delayed by restricting the level of folate in the diet. Although it is well established that folic acid deficiency will retard the growth of, and occasionally kill, established cancers, it does not necessarily follow that nonneoplastic folate-deficient tissues are less likely to undergo neoplastic transformation. Conversely, a growing body of epidemiologic and clinical evidence suggests that, regardless of the systemic folate status, folate deficiency in certain epithelial tissues may be a factor that predisposes to the development of neoplasms arising from these tissues. Establishing a cause-and-effect relationship between a dietary factor and cancer is a difficult task. In some cases, correlation studies, which examine the relationship between This project has been supported in part by an operating grant and scholarship from the Medical Research Council of Canada and a Future Leader Award from the International Life Sciences Institute North America. Address correspondence to Dr. Young-In Kim, Department of Medicine, University of Toronto, Room 7258, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario, M5S 1A8 Canada. Received March 12, 1998; accepted August 13, 1998.

Folate and carcinogenesis: evidence, mechanisms, and implications.

Currently available evidence from epidemiologic, animal, and intervention studies does not unequivocally support the role of folate, a water-soluble B vitamin and important cofactor in one-carbon transfer, in the development and progression of colorectal cancer (CRC) However, when the portfolio of evidence from these studies is analyzed critically, the overall conclusion supports the inverse association between folate status and CRC risk It is becoming increasingly evident that folate possesses dual modulatory effects on colorectal 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 colorectal neoplasms In contrast, folate deficiency in normal colorectal mucosa appears to predispose it to neoplastic transformation, and modest levels of folic acid supplementation suppress, whereas supraphysiologic supplemental doses enhance, the development of cancer in normal colorectal mucosa Several potential mechanisms relating to the disruption of one-carbon transfer reactions exist to support the dual modulatory role of folate in colorectal carcinogenesis Based on the lack of compelling supportive evidence and on the potential tumor-promoting effect, routine folic acid supplementation should not be recommended as a chemopreventive measure against CRC at present

Folate and colorectal cancer: an evidence-based critical review.

Folate, a water-soluble B vitamin and important cofactor in 1-carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer. Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with colorectal cancer risk. Collectively, these studies suggest an approximately 40% reduction in the risk of colorectal cancer 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 have also 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 the 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 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 animal studies suggest that the optimal timing and dose of folate intervention need to be established for safe and effective chemoprevention in humans.

/pdf/role-of-folate-in-colon-cancer-development-and-progression-551wnc0p1j.pdf

Role of Folate in Colon Cancer Development and Progression

Epidemiological, clinical, and animal studies collectively indicate that dietary folate intake and blood folate levels are inversely associated with colorectal cancer risk. Folate plays an essential role in one-carbon transfer involving remethylation of homocysteine to methionine, which is a precursor of S-adenosylmethionine, the primary methyl group donor for most biological methylations. DNA methylation is an important epigenetic determinant in gene expression, maintenance of DNA integrity and stability, chromosomal modifications, and development of mutations. Dysregulation and aberrant patterns of DNA methylation are generally considered to be mechanistically involved in colorectal carcinogenesis. Aberrant DNA methylation has been considered as a leading mechanism by which folate deficiency enhances colorectal carcinogenesis. However, currently available data pertaining to the effects of folate deficiency on DNA methylation are inconsistent and incomplete. The portfolio of evidence from animal, human, and in vitro studies suggests that the effects of folate deficiency on DNA methylation are highly complex; appear to depend on cell type, target organ, and stage of transformation; and are gene and site specific. In addition, the pattern of site- and gene-specific DNA methylation induced by folate deficiency may not be in concert with the direction of changes in genomic DNA methylation. Collectively, currently available evidence indicates that genomic DNA hypomethylation in the colorectum is not a probable mechanism by which folate deficiency enhances colorectal carcinogenesis. However, there is still a possibility that sequence-specific alterations of DNA methylation in critical cancer-related genes might be mechanistically involved in the folate deficiency-mediated colorectal carcinogenesis.

https://cebp.aacrjournals.org/content/cebp/13/4/511.full.pdf

Folate and DNA Methylation: A Mechanistic Link between Folate Deficiency and Colorectal Cancer?

The inheritance of information based on gene expression levels is known as epigenetics, as opposed to genetics, which refers to information transmitted on the basis of gene sequence. In contrast to genetic changes observed in cancer, epigenetic changes are gradual in onset and are progressive, their effects are dose-dependent and are potentially reversible. These observations present new opportunities in cancer-risk modification and prevention using dietary and lifestyle factors and potential chemopreventive drugs. In this regard, folate, a water-soluble B vitamin, has been a focus of intense interest because of an inverse association between folate status and the risk of several malignancies (in particular, colorectal cancer) and of its potential ability to modulate DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. Aberrant patterns and dysregulation of DNA methylation are mechanistically related to colorectal carcinogenesis. Folate plays an essential role in one-carbon transfer involving re-methylation of homocysteine to methionine, thereby ensuring the provision of S-adenosylmethionine, the primary methyl group donor for most biological methylation reactions. The portfolio of evidence from animal, human, and in vitro studies suggests that the effects of folate deficiency and supplementation on DNA methylation are gene and site specific, and appear to depend on cell type, target organ, stage of transformation, and the degree and duration of folate depletion.

/pdf/nutritional-epigenetics-impact-of-folate-deficiency-on-dna-2jomhfi2cv.pdf

Nutritional Epigenetics: Impact of Folate Deficiency on DNA Methylation and Colon Cancer Susceptibility

Folate status, DNA methylation and colon cancer risk in inflammatory bowel disease

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Folate status, DNA methylation and colon cancer risk in inflammatory bowel disease