Nature Reviews Cancer 3, 601 -614 (2003); doi:10.1038/nrc1144


CHEMOPREVENTION OF COLON CANCER BY CALCIUM, VITAMIN D AND FOLATE:
MOLECULAR MECHANISMS

Sergio A. Lamprecht & Martin Lipkin about the authors

Preface
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.

Summary

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.