Colorectal cancer is one of the main causes of cancer mortality in Western societies.
Experimental, epidemiological and clinical evidence show that diets consumed by Western populations have an important role in the modulation of this disease.
Calcium, vitamin D and folate have emerged as promising chemopreventive agents in colon cancer.
One of the main pathways used by extracellular calcium to exert its chemopreventive actions is through activation of a calcium-sensing receptor. This results in increased levels of intracellular calcium, inducing a wide range of biological effects, some of which restrain the growth and promote the differentiation of transformed colon cells.
Most of the pleiotropic actions of vitamin D are mediated by binding to a nuclear receptor, which interacts with specific consensus sites in promoters of specific genes, resulting in downregulation or upregulation of their expression. The actions of vitamin D involve cross-talk with growth factors/cytokines, inhibitory effects on the cell cycle and stimulation of apoptosis.
Folate lies at the intersection of metabolic pathways involved in DNA methylation and biosynthesis. Three main mechanisms by which decreased levels of folate (and of other dietary one-carbon donors) might increase the risk of cancer are: alteration of the normal DNA-methylation process; imbalance of the steady-state level of DNA precursors, leading to aberrant DNA synthesis and repair; and chromosome and chromatin changes.
It is proposed that, together with the application of genome methodology to elucidate nutrient–gene interactions, a deliberate effort should be made to identify nutrient-induced key events in signal-transduction pathways and in the cell cycle that are involved either in the chemoprevention or promotion of colorectal cancer.
Recent findings have indicated that dietary calcium, vitamin D and folate can modulate and inhibit colon carcinogenesis. Supporting evidence has been obtained from a wide variety of preclinical experimental studies, epidemiological findings and a few human clinical trials. Important molecular events and cellular actions of these micronutrients that contribute to their tumour-modulating effects are discussed. They include a complex series of signalling events that affect the structural and functional organization of colon cells.
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This work was supported by the Division of Cancer Prevention and Mouse Models of Human Cancers Consortium of the National Institutes of Health/National Cancer Institute, Bethesda, Maryland, USA.
- ONE-CARBON DONORS
Dietary components such as folate, methionine and choline. Folate is an important conveyor of one-carbon units at different states of oxidation, including the methyl (-CH3) group. Methionine donates the methyl group only.
- WESTERN-STYLE DIET
(WD). A standard AIN-76A diet modified to have increased fat content, and decreased levels of calcium, vitamin D, folate and other one-carbon donors. These are reduced to nutrient-density levels approximating those found in Western diets.
- ADENOMATOUS POLYPOSIS COLI
(APC) is a typical, 'gatekeeper' tumour-suppressor gene, mutations of which are crucial initiating events in the development of human colorectal cancer. Mice carrying a mutant Apc allele for example, a mutation in the region corresponding to codon 850 (Apc-mutant min mice) or to codon 1638 (Apc 1638N mice) are — predisposed to the development of intestinal polyps.
A compound that binds ions for transport across membranes.
- VITAMIN-D RESPONSE ELEMENT
(VDRE). A short DNA sequence in a gene promoter to which the activated vitamin-D receptor binds and exerts its effects on transcription.
- S-ADENOSYL METHIONINE
(SAM). SAM is a universal donor of the methyl group to DNA, histones and other bioactive molecules. After loss of the methyl group, SAM is converted to S-adenosyl homocysteine (SAH).
- MICROSATELLITE INSTABILITY
Genetic instability due to a high mutation rate, mainly in short nucleotide repeats. Cancers with this phenotype are associated with defects in DNA mismatch-repair genes.
- MISMATCH REPAIR
A genomic system that detects and repairs incorrectly paired nucleotides that are introduced during DNA replication.
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Lamprecht, S., Lipkin, M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3, 601–614 (2003). https://doi.org/10.1038/nrc1144
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