Advances in Food and Nutrition Research recognizes the integral relationship between the food and nutritional sciences, bringing together outstanding and comprehensive reviews that highlight this relationship.
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Vitamin D, Cancer Risk, and Mortality
Elena Tagliabue; Sara Raimondi; Sara Gandini1 Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
1 Corresponding author: email address: firstname.lastname@example.org
Antiproliferative effects of 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, are well established in various cell types by influencing cell differentiation and decreasing cell proliferation, growth, invasion, angiogenesis, and metastasis. Several meta-analyses showed that low serum levels of 25(OH)D was associated with colorectal cancer and overall mortality, while the association with cancer mortality was less consistent. VDR is a crucial mediator for the cellular effects of vitamin D and conflicting data have been reported for most malignancies. Beyond VDR, the biological effects of vitamin D are mediated by the vitamin D-binding protein. The GC (group-specific component) gene, encoding DBP, is highly polymorphic and several polymorphisms were investigated in association with cancer development with controversial results. Vitamin D supplementation was found to be associated with a reduced risk of overall mortality, reviewing all published trials on healthy subjects, whereas the evidence of an effect on cancer risk and mortality is less clear. Furthermore, long-term health effects of high doses of vitamin D, extended duration of supplementation, and the association with different baseline vitamin D levels remain to be investigated.
In summary, epidemiological and preclinical studies support the development of vitamin D as preventative and therapeutic anticancer agents, with significant associations especially found for low vitamin D status with overall mortality and cancer outcome, more than cancer incidence. However, a definitive conclusion cannot be drawn and only large randomized clinical trials, both in healthy subjects and in cancer patients, will allow to draw definitive conclusions on the effect of vitamin D supplementation on cancer risk, prognosis, and mortality.
Vitamin D receptor
Vitamin D-binding protein
Vitamin D is a group of fat-soluble prohormones and predominantly exists in two main isoforms: vitamin D3 or cholecalciferol and vitamin D2 or ergocalciferol (Dusso, Brown, & Slatopolsky, 2005).
Vitamin D is first known for its physiological traditional role in the regulation of Ca2 + and Pi transport and bone mineralization (Holick, 1996). In addition to its pivotal role for the maintenance of musculoskeletal health, vitamin D is emerging as a critical regulator of the pathogenetic process of several nonskeletal diseases such as pigmental disorders, cardiovascular, renal, infectious, autoimmune diseases, and also several types of cancers (Bouillon et al., 2008; Doorenbos, van den Born, Navis, & de Borst, 2009; Elamin et al., 2011; Hewison, 2012; Holick, 2007; Muscogiuri et al., 2012; Pilz, Tomaschitz, Drechsler, Dekker, & Marz, 2010; Pilz, Tomaschitz, Drechsler, et al., 2011; Pilz, Tomaschitz, Marz, et al., 2011; Pilz, Tomaschitz, Obermayer-Pietsch, Dobnig, & Pieber, 2009; Pinczewski & Slominski, 2010; Schwalfenberg, 2011; Slominski, Tobin, Shibahara, & Wortsman, 2004; Souberbielle et al., 2010).
In humans, most vitamin D is derived from the action of sunlight on the skin, converting provitamin D3 to previtamin D3 under the influence of ultraviolet B (UVB) radiation, and this source accounts for about 80% of the total vitamin D (Holick, 2007). Exogenous vitamin D2 or D3 comes from dietary intake through the consumption of foods that are naturally rich in or fortified with it, or through supplementation (Tang et al., 2012), but in North America and Europe dietary vitamin D3 intake is a minor component of vitamin D3 acquisition because dairy products, eggs, fish, and fortified foods contain only small quantities of vitamin D (Hollis, 2005). The overall vitamin D intake is the sum of cutaneous vitamin D and nutritional vitamin D2 and D3. Previtamin D undergoes two hydroxylations to become biologically active (DeLuca, 2004). First, vitamin D3 from the skin and vitamin D2 and D3 from the diet are metabolized in the liver to 25-hydroxyvitamin D (25[OH]D), which is the main circulating vitamin D metabolite measured for the classification of vitamin D status. Second, it is hydroxylated in the kidney by the enzyme 1-ahydroxylase to form the biologically active form of vitamin D: 1,25-hydroxyvitamin D (1,25[OH]D). 1,25(OH)2D, the hormonal derivative of vitamin D (Holick, 2007), may play an important role in the development of cancers by regulating the expression of tumor-related genes or mediating inhibition of cell growth, adhesion, migration, metastases, and angiogenesis in vitro and in vivo (Chen et al., 2013; Colston, Colston, & Feldman, 1981; Eisman, Barkla, & Tutton, 1987; Evans et al., 1996; Fu et al., 2013; Hansen et al., 1998; Newton-Bishop et al., 2009; Osborne & Hutchinson, 2002; Yudoh, Matsuno, & Kimura, 1999). Furthermore, it exerts transcriptional activation and repression of target genes by binding to the vitamin D receptor (VDR). VDR is an intracellular receptor that, once activated, leads to the regulation of hundreds of genes by binding to so-called vitamin D response elements on the DNA (Bouillon et al., 2008). VDR is active in virtually all tissues including colon, breast, lung, ovary, bone, kidney, parathyroid gland, pancreatic b-cells, monocytes, T lymphocytes, melanocytes keratinocyte, and also in cancer cells.
2 Latitude and Solar Exposure
Sunlight is the major provider of vitamin D for humans. The UVB spectrum of sunlight (290-315 nm) induces skin synthesis of vitamin D (Holick, 2002). Environmental UVB radiation is absent from November until February at the geographic latitude of 40°N and from October until March at the geographic latitude of 50°N or 60°N, while there is environmental UVB radiation throughout the year at the geographic latitude of 30°N or closer to the equator (Holick, 2002). Moreover, available data from America and Europe indicate that the winter values of serum 25(OH)D are higher in healthy subjects who live at lower latitudes compared with subjects living at higher latitudes (Zittermann, Schleithoff, & Koerfer, 2005). A pronounced seasonal variation is evident in most of the published investigations on 25(OH)D: summer values can be 100% larger than winter values (Moan, Porojnicu, Dahlback, & Setlow, 2008).
Other studies have shown that the survival of patients with cardiovascular disease (CVD) or with some cancers (e.g., lung, colorectal, prostate, and breast cancer) was greater if the diagnosis was made during summer as compared with winter (Lim et al., 2006; Scragg, 1981). Increasing distance from the equator and winter period were equated to decreasing exposure to sunlight, especially to UVB radiation (280-315 nm) because with increasing latitude, amounts of UVB radiation reaching the earth surface decrease faster than amounts of UVA radiation (315-400 nm) (IARC, 1992). Also, seasonal variations are more pronounced for UVB radiation than for the UVA radiation (IARC, 1992). Because UVB radiation is necessary for the synthesis of vitamin D in the skin, it has been hypothesized that associations found between latitude or seasonality and mortality from several chronic conditions could be owing to variations in vitamin D status (Garland et al., 2006; Giovannucci, 2005; Grimes, 2006; Kricker & Armstrong, 2006; Poole et al., 2006). In populations with similar skin types, there are clear latitude gradients of all major forms of skin cancer and also of the incidence rates of major internal cancers, indicating a north-south gradient in real sun exposure. However, the survival prognosis also improves significantly from north to south. These data suggest that increased vitamin D may lead to improved cancer prognosis (Moan et al., 2008).
However, we have to remember that sunburns and intermittent sun exposure increase significantly melanoma risk (Gandini et al., 2005) and the entire UV spectrum was classified as carcinogenic to humans by the International Agency for Research on Cancer (El Ghissassi et al., 2009).
The serum level of 25(OH)D is a result of skin exposure to sunlight, total vitamin D intake, and other factors such as age and skin pigmentation. Serum levels vary with season, with the highest levels in summer and autumn. 25(OH)D has a half-life in the circulatory system of about 2-3 weeks (Tjellesen & Christiansen, 1983). In contrast, serum 1a,25-dihydroxyvitamin D is tightly biochemically regulated, except in situations of extreme deficiency, in keeping with its role in calcium homeostasis. It has a circulating half-time of 5-15 h and exhibits little seasonal variability (Hine & Roberts, 1994; Tjellesen & Christiansen, 1983). For these reasons, the serum 25(OH)D is considered...