Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Vitamin D(3) is the precursor of 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)(2)D(3) modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)(2)D(3) promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)(2)D(3) controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)(2)D(3) in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)(2)D(3) of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)(2)D(3) based on reprogramming of the phenotype of several cell types.