Modulation of vitamin D synthesis and catabolism in colorectal mucosa: a new target for cancer prevention.

Sporadic colorectal cancer is a disease of advancing age and the percentage of the population which reaches an advanced age is strongly increasing. Multiple factors are responsible for the etiology of this cancer since the colorectal mucosa is directly influenced by nutrients reaching the colonic lumen and impacting on mucosal cells. The vitamin D system appears to be central to several preventative molecular pathways. Insufficiency of the serum precursor 25-hydroxyvitamin D3 has been linked by epidemiology to enhanced colon tumor incidence, most likely because it is a major determinant of 1,25-dihydroxyvitamin D3 synthesis in colonic mucosal cells. Bound to its receptor, vitamin D regulates colonic proliferation, differentiation and apoptosis in an autocrine/paracrine manner. During early malignancy, vitamin D synthesis is enhanced to counteract hyperproliferation, whereas in high-grade tumors catabolism by far surpasses synthesis. The colonic vitamin D system is regulated by several known natural factors. One of the most important ones is nutritional calcium that, if supply is low, will result in enhanced catabolism of colonic 1,25-dihydroxyvitamin D3. Estrogenic compounds can increase expression and activity of the synthesizing 25-hydroxyvitamin D-1alpha-hydroxylase. Due to enhanced synthesis of the active metabolite, this can lead to protection against colorectal tumors in women. During tumor progression, expression of 25-hydroxyvitamin D-1alpha-hydroxylase as well as of the catabolizing 25-hydroxyvitamin D-24-hydroxylase appears to be under epigenetic control as demonstrated by studies with phytoestrogens and folate. It is commonly accepted that sporadic colorectal cancer pathogenesis is multifactorial and these are just a few examples of the regulatory capacity of natural (nutrient) substances for improving the colonic vitamin D system. However, protection by vitamin D might have central importance, with nutrients increasing the efficiency of the vitamin D system in a targeted manner. This could result in prevention of hyperproliferation or retardation of progression to clinically manifest primary colonic tumors.