red and processed meat, body fatness, and alcohol may increase the risk (WCRF/AICR, 2007). The committee’s review of studies on vitamin D and calcium and risk for colorectal cancers and possible protective benefits identified for calcium and vitamin D was inconclusive.
Biological plausibility A major role of the active form of vitamin D is to enhance calcium absorption by the intestine, and the molecular and cell biology has been well defined (Song and Fleet, 2007; Xue and Fleet, 2009). The VDR and the vitamin D converting enzyme, 1α-hydroxylase, are both expressed in the colon and rectum (Cross et al., 1997; Holt et al., 2002). Vitamin D has been reported to act on colonic epithelial and cancer cells to regulate growth factor and inhibitor expression and signaling pathways, including modulation of the cell cycle, sensitivity to apoptosis, and enhancement of cellular differentiation (Harris and Go, 2004; Yang et al., 2007). Many rodent models of colon carcinogenesis suggest that there is an increased risk for colon cancer associated with vitamin D deficiency; and a decreased risk associated with supplementation (Harris and Go, 2004; Yang et al., 2008; Newmark et al., 2009). However, few studies were identified that examined vitamin D over a range of dose levels. A recent review of findings from the Vdr-null mouse model indicates an increase in hyperplasia of the distal colonic epithelium and greater deoxyribonucleic acid (DNA) damage in vitamin D–deficient compared with wild-type mice (Bouillon et al., 2008). The independent role of calcium in modulating colon cancer risk is also under investigation. Although intracellular calcium plays a key role in cell biology and influences growth control processes that may be related to carcinogenesis, serum calcium is tightly regulated over a wide range of intakes. Thus, the potential mechanisms by which serum calcium levels could mediate risk for colon cancer may be through indirect effectors in metabolic pathways involved in tumorigenesis.
Systematic reviews and meta-analyses
Colorectal cancer The AHRQ-Tufts systematic review considered evidence for associations between 25OHD levels and risk for colorectal cancer mortality or incidence. One RCT found no significant difference between colorectal mortality or incidence and supplementation with vitamin D in an elderly population. One cohort study was identified that found an inverse association between high serum 25OHD levels and risk for colorectal cancer mortality, and two nested case–control studies in women found an inverse trend between serum 25OHD level and colorectal cancer incidence. Two nested case–control studies in men and three in both men and women found no significant associations between serum 25OHD level and risk of colorectal cancer.
The IARC (2008) meta-analysis found a significant protective effect for