Vitamin D and the prevention of human disease
Vitamin D is a lipophilic steroid derivative, a precursor to a hormone, and a fat-soluble vitamin responsible for increasing the absorption of calcium, magnesium and phosphate in the intestine, among many other biological effects. For humans, the most important compounds in vitamin D are vitamin D2 (ergocalciferol) and vitamin D3 (also known as cholecalciferol). Vitamin D is important in the homeostasis and metabolism of calcium in the body and can be used to prevent rickets and "adult osteomalacia" and, in combination with calcium, to prevent the development of osteoporosis, which is common in the elderly. In addition, vitamin D has effects on neuromuscular function and inflammation, as well as influencing the expression and translation of many genes and regulating cell proliferation, differentiation and apoptosis.
The main natural source of vitamin D is through chemical reactions in the lower layers of the epidermis of the skin following exposure to sunlight to produce cholecalciferol (especially UVB radiation), while vitamin D3 is produced by a photochemical reaction of 7-dehydrocholesterol, which is contained in animal skin cells, following exposure to ultraviolet light, so getting more sunlight is an easy way to obtain vitamin D. Humans only need to be exposed to sunlight for 10 minutes a day to synthesise enough vitamin D3 on their own.
Both forms of vitamin D undergo two hydroxylations to form the active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D), which when specifically synthesised from vitamin D3 is called calcitriol (1,25(OH)2D3). The first hydroxylation occurs in the liver, where the D-25-hydroxylase enzyme encoded by CYP2R1 converts vitamin D3 into 25-hydroxyvitamin D3 (calcitriol or 25(OH)D3). With the help of DBP, 25-hydroxyvitamin D3 circulates into the renal tubules where it is hydroxylated a second time by CYP27B-encoded 25-hydroxyvitamin D-1 alpha-hydroxylase to produce 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). This reaction is inhibited by free calcium, inorganic phosphate and the final product (1,25(OH)2D) and stimulated by parathyroid hormone (PTH), the regulator of 25-hydroxyvitamin D-1 alpha-hydroxylase. Figures 1 and 2 show the synthetic pathways of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3. 1,25(OH)2D is responsible for intestinal transport of calcium, renal calcium absorption, bone formation and maintenance, insulin secretion and blood pressure regulation. To initiate these biological processes, 1,25(OH)2D binds to its high affinity vitamin D receptor (VDR), a ligand-activated transcription factor that complexes with the retinoid X receptor (RXR) to form a heterodimer leading to vitamin D response element recognition and gene transcription associated with these biological processes.
Figure 1. Synthesis of 1,25-dihydroxyvitamin D2 and D3
In the intestine, binding of the hetereodimer complex regulates transcription of the calcium-binding protein calbindin, which assists in the transfer of calcium across the cell membrane into the bloodstream. 1,25(OH)2D-assisted regulation of calbindin expression appears to control intracellular calcium flux in insulin-secreting cells. 1,25(OH)2D is essential for bone formation in osteoblasts and osteoclast maintenance is also essential. In osteoblasts, expression of the receptor activator NF-κΒ ligand (RANKL) is induced by heterodimers. binding of RANKL to the RANK receptor releases a signalling cascade leading to differentiation and osteoclast growth. In the parathyroid glands, 1,25(OH)2D is involved in the repression of PTH gene transcription, the regulation of VDR concentrations and the parathyroid response to calcium. The correlation between vitamin D deficiency and hypertension may be due to the role of 1,25(OH)2D as a negative endocrine regulator of the renin-angiotensin system. An experimental study showed that VDR knockout mice experienced high levels of renin expression and angiotensin production, leading to hypertension.
In addition to the involvement of VDR in these biological processes, VDR requires β-catenin to assist in the induction of hair follicle formation in the adult epidermis. palmer et al. demonstrated in transgenic mice constructed with a 4-hydroxy-tamoxifen (4OHT) inducible form of stable β-catenin under the control of the keratin 14 promoter (K14ΔNβ- cateninER) that vitamin D analogs inhibit β-catenin-induced hair follicle tumour formation. Figure 2, A-C compares the tails of vitamin D analogue (EB1089) treated and untreated mice, and stained tail sections of wild-type and K14ΔNβ-cateninER transgenic mice. Palmer et al, also reported that in the absence of VDR, β-catenin induces human tumours characterised by invasive basal cell carcinoma. Figure 2, D and E show human skin sections of trichofoluloma and basal cell carcinoma labelled with β-catenin and VDR. Experimental studies have suggested that VDR is a transcriptional effector of the Wnt pathway, promoting hair follicle differentiation and regulating Wnt-induced tumour formation. This investigation is an example of recent research that provides greater insight into the involvement of vitamin D in cancer-related mechanisms.
Studies have shown that vitamin D deficiency is associated with colon, prostate, breast, ovarian, lymphoma and other devastating types of cancer. It is claimed that raising the average circulating 25(OH)D level in the population to approximately 50ng/mL could prevent approximately 58,000 cases of breast cancer and approximately 49,000 cases of colorectal cancer per year. However, upper dose limits are essential as effective treatment levels may produce hypercalcaemia. This information is based on the results of observational studies combined with randomised trials. The vitamin D guidelines for cancer prevention focus on 25(OH)D levels rather than 1,25(OH)2D in the blood, as 1,25(OH)2D production is strictly controlled by the kidneys.
Enhanced vitamin D levels through sunlight exposure or dietary intake do not result in a measurable increase in 1,25(OH)2D production, but do result in a measurable increase in 25(OH)D concentration. The kidney is not the only site of 25(OH)D hydroxylation; a variety of tissues, including the skin, breast, colon, lung and brain have the enzymatic capacity to metabolise 25(OH)D to 1,25(OH)2D. It is thought that increasing blood levels of 25(OH)D may provide sufficient 25(OH)D substrate to enable various tissue types to use locally synthesised 1,25(OH)2D to protect against uncontrolled cell growth and maturation and the risk of malignancy.
Control of cell growth and maturation may be attributed to the anti-angiogenic properties of vitamin D. Mantell et al. showed that treatment of 'activated' endothelial cells with 1,25(OH)2D significantly inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell sprouting and elongation, a necessary stage in the angiogenic process. Another in vivo study showed that 1,25(OH)2D treatment produced tumours that were less vascularised than those formed in mice without 1,25(OH)2D treatment.
The results of previous studies on vitamin D and cancer have led to the creation of a new model of cancer etiology known as DINOMIT (Dissociation, Initiation, Natural Selection, Overgrowth, Metastasis, Involution and Transition). The model describes the loss of communication between cells as the driving force behind cancer development. This new model is very different from the oncogenicity and cancer stem cell models. Cedric Garland of the University of California, San Francisco said, "In this new model, we propose that this loss may play a key role in cancer because it disrupts communication between cells that are critical for healthy cell turnover, allowing more aggressive cancer cells to take over." When there are sufficient levels of vitamin D, cells adhere, communicate and act as mature epithelial cells, but if vitamin levels are insufficient, they may lose their adhesion, along with their identity as differentiated cells, and revert to a stem cell state. Garland further states that "vitamin D may block the first stage of the cancer process by re-establishing intercellular junctions in malignant tumours with intact vitamin D receptors".
Although the DINOMIT model and the other scientific reports presented here provide a strong explanation for the beneficial value of vitamin D, more research and long-term clinical studies are needed to fully understand the impact of vitamin D on disease prevention in humans.
References
1.GARLAND CF, GARLAND FC. 1980. Do Sunlight and Vitamin D Reduce the Likelihood of Colon Cancer?. Int J Epidemiol. 9(3):227-231. https://doi.org/10.1093/ije/9.3.227
2.Holick MF. 2005. The Vitamin D Epidemic and its Health Consequences. 135(11):2739S-2748S. https://doi.org/10.1093/jn/135.11.2739s
3.Deeb KK, Trump DL, Johnson CS. 2007. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 7(9):684-700. https://doi.org/10.1038/nrc2196
4.Dusso AS, Brown AJ, Slatopolsky E. 2005. Vitamin D. American Journal of Physiology-Renal Physiology. 289(1):F8-F28. https://doi.org/10.1152/ajprenal.00336.2004
5.Pálmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM. The Vitamin D Receptor Is a Wnt Effector that Controls Hair Follicle Differentiation and Specifies Tumor Type in Adult Epidermis. PLoS ONE. 3(1):e1483. https://doi.org/10.1371/journal.pone.0001483
6.Mantell DJ. 2000. 1alpha,25-Dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo. et al., Circ. Res.. 87, 214-220
7.Garland CF, Gorham ED, Mohr SB, Garland FC. 2009. Vitamin D for Cancer Prevention: Global Perspective. Annals of Epidemiology. 19(7):468-483. https://doi.org/10.1016/j.annepidem.2009.03.021
8.2009, May 26. University of California - San Diego. New Model Of Cancer Development: Low Vitamin D Levels May Have Role. ScienceDaily.