Dietary vitamin D is a novel modulator of tumor engraftment through regulation of GC protein abundance.

The vitamin D binding protein, the GC protein, is a multifunctional protein that binds circulating vitamin D and also increases macrophage killing of tumor cells. Injecting exogenous GC protein concurrent with experimental tumor implant decreases tumor engraftment rate. Until now serum abundance of this protein was thought to be controlled by estrogen, glucocorticoids and inflammatory cytokines, but, not by vitamin D itself(1, 2). Nonetheless, increasing dietary vitamin D is thought to increase serum vitamin D, which is 98% bound by the GC protein. Based on the protection that excess GC protein offers we sought to determine if decreased GC protein abundance might decrease tumor immunity. Relatedly, we theorized, by contrast to the current model, that dietary vitamin D might affect serum abundance of GC protein. If exogenous vitamin D alters available GC levels, then this effect might indicate a novel pathway by which vitamin D enhances immunity. To examine these possibilities, we examined the effect of GC protein absence on tumor persistence or engraftment on two different and common tumor types (prostate cancer and breast cancer). We further examined the relationship between dietary vitamin D and serum GC abundance. We found that absence of GC protein allowed significantly more engraftment of breast tumor cells in female mice and of prostate tumor cells in male mice. Further, we found a U-shaped response of serum GC protein to dietary vitamin D dosage as well as to serum vitamin D, indicating the potential benefit of high exogenous doses to enhance immunity and reduce tumor burden.

Decreased Serum 25-Hydroxyvitamin D in Aging Male Mice Is Associated With Reduced Hepatic Cyp2r1 Abundance.

The prevalence of vitamin D deficiency, as determined by circulating levels of 25-hydroxycalciferol [25(OH)D], is greater in older individuals compared with the young. To examine the hypothesis that altered production or inactivation of 25(OH)D contributes to lower circulating levels of 25(OH)D, we measured the serum levels of parent vitamin D3 (cholecalciferol) and 25(OH)D. We also determined the relative abundance of transcripts encoding hepatic CYP2R1 and CYP27B1, the principal 25-hydroxylases, transcripts encoding enzymes that degrade 25(OH)D in the liver (Cyp3A11) and kidney (Cyp24A1) and transcripts encoding megalin and cubilin, proteins critical to vitamin D resorption in the kidney in mice at three different ages. We observed a significant decline in the relative abundance of Cyp2R1 in the liver with aging (one-way ANOVA, P = 0.0077). Concurrent with the decrease in mRNA, a significant decline in hepatic CYP2R1 protein (one-way ANOVA for trend, P = 0.007) and 25(OH)D (one-way ANOVA for trend, P = 0.002) and in the ratio of 25(OH)D3 to cholecalciferol (one-way ANOVA, P = 0.0003). By contrast, levels of the transcripts encoding Cyp3a11, Cyp24a1, and Cyp27b1 megalin and cubilin were unchanged with aging. A significant positive correlation was found between Cyp2r1 mRNA and 25(OH)D, and a stronger correlation was found between Cyp2r1 mRNA and the ratio of 25(OH)D3 to cholecalciferol. These results indicate that decreased expression of CYP2R1 contributes to the reduced serum levels of 25(OH)D in aging.