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Vitamin D and Health in the 21st Century: an Update |
1 From the Nutritional Sciences Research Group, National Cancer Institute, Rockville, MD
2 Presented at the National Institutes of Health conference "Vitamin D and Health in the 21st Century: an Update," held in Bethesda, MD, September 5–6, 2007.
3 Address reprint requests to CD Davis, Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Boulevard, Suite 3159, Rockville, MD 20892-7328. E-mail: davisci{at}mail.nih.gov.
ABSTRACT
A diversity of scientific literature supports a role for vitamin D in decreasing colorectal cancer incidence, but the available evidence provides only limited support for an inverse association between vitamin D status and the risk of other types of cancer. We need additional studies analyzing the dose-response relation between vitamin D status and cancer risk, the optimal level of 25-hydroxyvitamin D, the length of time required to observe an effect, and the time period of life when exposure is most relevant. Studies of vitamin D receptor polymorphisms have found that not all polymorphisms have the same association with cancer, and the cancer site could further dictate which polymorphisms might be most important; this indicates a need for more research on gene-environment interactions. Several dietary components and the balance between energy intake and expenditure influence vitamin D metabolism. These studies show that scientists need to identify confounders and modifiers of the biological response to vitamin D, including dietary factors, lifestyle factors such as exercise, and race or ethnicity. Transgenic and knockout animals are powerful tools for identifying the molecular targets of bioactive food components. Scientists should therefore make increased use of these models to identify molecular targets for vitamin D. Many research gaps relate to the need to develop predictive, validated, and sensitive biomarkers, including biomarkers that researchers can use to reliably evaluate intake or exposure to vitamin D, assess one or more specific biological effects that are linked to cancer, and effectively predict individual susceptibility as a function of nutrient-nutrient interactions and genetics.
INTRODUCTION
Interest in the potential role of vitamin D in cancer prevention continues to grow among scientists, policy makers, consumers, and the media. The National Cancer Institute and the Office of Dietary Supplements of the National Institutes of Health held a conference, "Vitamin D and Cancer: Current Dilemmas/Future Needs," on May 7–8, 2007, to assess the strengths and weaknesses of the evidence for the relation between vitamin D status and risks of developing or surviving various types of cancer, to identify gaps in knowledge, and to identify the research needed to make science-based recommendations for intake or exposure for cancer prevention (1). Conference topics included the relative importance of sunlight exposure and diet as sources of vitamin D, the epidemiologic evidence of the nature and strength of the association between vitamin D and cancer risk, how nutrigenetics has advanced our understanding of the relation between vitamin D and cancer risk, new information about the role of genes and cross-talk among genes that could influence the response to vitamin D, the interrelation between vitamin D and other dietary components that could modify the response, and information from preclinical models about the relation between vitamin D and cancer (1). This article provides a synopsis of some of the evidence presented at the conference and many of the questions that research still needs to address.
HOW STRONG IS THE EVIDENCE THAT VITAMIN D STATUS IS RELATED TO CANCER RISK?
Ecologic or geographical correlation studies were the first to offer evidence for the cancer-protective effects of vitamin D when they showed an inverse association between ultraviolet (UV) radiation exposure and cancer incidence or mortality (2). Because UV radiation can lead to vitamin D formation in the skin, this led to the hypothesis that vitamin D or one of its metabolites—25-hydroxyvitamin D [25(OH)D] or 1,25-dihydroxyvitamin D [1,25(OH)2D]—could be protective against cancer.
However, scientific acceptance of the hypothesis that vitamin D metabolites inhibit the development of cancer faced several obstacles (3). Unlike serum concentrations of 25(OH)D, which decrease with distance from the equator and are lower among persons with dark pigmentation, serum concentrations of 1,25(OH)2D are tightly regulated and do not vary with geographic latitude or race (4). The demonstration that many tissues in addition to the kidney possess the enzyme 25(OH)D-1-
-hydroxylase (CYP27B1) and, like the kidney, synthesize 1,25(OH)2D from circulating concentrations of 25(OH)D eliminated this concern (Figure 1
; 3). Research has subsequently shown the autocrine synthesis of 1,25(OH)2D by many other organs, such as the prostate, colon, breast, and pancreas. This is the presumed mechanism whereby vitamin D or sunlight influences the development of cancer at these sites (5).
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Evidence indicates that dietary vitamin D is protective against cancer. A diversity of scientific literature, including in vitro, animal, ecologic, and epidemiologic studies, supports a role for vitamin D in decreasing colorectal cancer incidence (7–12). In a recent meta-analysis of studies that examined serum 25(OH)D concentrations prospectively in relation to colorectal cancer, individuals with 25(OH)D concentrations 
82 nmol/L had a 50% lower incidence of colorectal cancer than did those with 25(OH)D 
30 nmol/L (12).
Despite abundant experimental evidence in support of an inverse association between vitamin D status and breast cancer risk, the available epidemiologic evidence provides, at best, limited support for such an association (13). Similarly, the association between vitamin D status and prostate cancer risk is less clear than for colorectal cancer, which suggests that not all tissues respond identically to vitamin D (14). Inconsistencies in the literature could indicate that vitamin D is more important for cancer progression than for total incidence. The risk associated with low vitamin D status might be conferred earlier in life, and thus studies of circulating concentrations of 25(OH)D or dietary intake in adulthood might not address the most relevant time period of exposure. Furthermore, the dose-response relation between 25(OH)D and cancer risk might only be observable at quite low levels of 25(OH)D (14). We need additional studies to determine the dose-response relation between vitamin D status and cancer risk, the optimal level of 25(OH)D for cancer prevention, the length of time required to observe an effect, and the time of life when exposure is most relevant (14).
Some evidence indicates that vitamin D might promote cancer risk in some individuals. For example, a recent study suggested that higher baseline vitamin D status was associated with a 3-fold higher risk of pancreatic cancer incidence in Finnish smokers (highest versus lowest quintile, >65.5 versus <32.0 nmol/L; odds ratio: 2.92; 95% CI: 1.56, 5.48; P for trend = 0.001; 15). We need a better understanding of vulnerable individuals who could be placed at risk by higher vitamin D exposure.
Most scientists believe that the gold standard for research is a controlled intervention study. Recently, a double-blind, placebo-controlled trial showed that the combination of vitamin D and calcium reduced cancer incidence by >75% (16). Although these results are impressive, they are based on a secondary analysis from a study investigating indicators of bone health, and no treatment group received vitamin D only. Furthermore, the sample size was underpowered to determine whether vitamin D and calcium had differential effects on different cancer sites. Clearly, we need additional intervention studies to verify this response and to determine whether the response varies by specific tissue, age, sex, and duration of exposure.
HOW HAS NUTRIGENETICS ADVANCED OUR UNDERSTANDING OF THE RELATION BETWEEN VITAMIN D AND CANCER RISK?
1,25(OH)2D exerts its biological effects by binding to the vitamin D receptor (VDR) and forming a heterodimer with the retinoid X receptor. This induces transcription of genes that have a vitamin D response element in their promoter region (Figure 1
). The human VDR has >470 reported single nucleotide polymorphisms, and their distribution and frequency varies among ethnic groups (17).
Although the physiologic significance of many of these polymorphisms remains unknown, at least some have functional consequences. For example, the Fok1 polymorphism gives rise to a T
C nucleotide substitution, which results in an alteration of the start codon. Absence of the Fok 1 site (denoted F) results in a shorter VDR protein with higher transcriptional activity and therefore higher biological activity of the protein (17). Research has linked the Fok 1 f allele to decreased calcium absorption (18). Whereas dietary calcium was not important in determining colon cancer risk in individuals with the FF genotype for the VDR, low dietary calcium increased colon cancer risk with increasing copies of the f allele for the VDR (19). It is interesting that those individuals with the lowest calcium absorption because of a genetic polymorphism are the most sensitive to increased colon cancer risk with low dietary calcium.
Studies have investigated VDR polymorphisms in connection with many different types of cancer, including prostate, colorectal, bladder, breast, and melanoma (20). However, not all polymorphisms have the same association with cancer, and the cancer site could further dictate which polymorphisms might be the most important (20). The most extensively studied single nucleotide polymorphisms have been in the 3'end (Bsm1, Apa1, and Taq1); these are in linkage disequilibrium (17). Unfortunately, design issues and lack of statistical power have compromised many of these studies (17).
More recent studies have investigated the relation between polymorphisms in the promoter region, such as the Cdx-2, which modulates transcription of the VDR gene expression, and GATA 3436 GT, which influences protein-DNA complex formation (17). Studies have linked these promoter region polymorphisms to increased prostate cancer risk (21). Moreover, many different types of environmental exposures can modify the relation between VDR polymorphisms and cancer risk. For example, sunlight exposure and dietary calcium, vitamin D, energy, and fat intake could modify the association between VDR genotype and cancer risk (22). Therefore, we need a better understanding of gene-environment interactions.
WHAT OTHER GENES DETERMINE THE BIOLOGICAL RESPONSE TO VITAMIN D?
From a mechanistic standpoint, investigators are increasingly realizing that many tissues in addition to the kidney contain enzymes that metabolize 25(OH)D (Figure 1). However, extrarenal 1,25(OH)2D synthesis influences local cell proliferation and differentiation and depends on serum 25(OH)D concentrations (23). Moreover, parathyroid hormone does not regulate the expression of colonic 1--hydroxylase or CYP27B1, and regulation by calcium is in the opposite direction of that reported for renal hydroxylases (23). Therefore, sufficiency of 25(OH)D as the precursor is the major known limiting factor for extrarenal synthesis of 1,25(OH)2D.
The balance between CYP27B1 [which allows cells to convert 25(OH)D to 1,25(OH)2D] and CYP24 [which inactivates both 25(OH)D and 1,25(OH)2D] determines cellular exposure to 1,25(OH)2D. This balance varies during tumorigenesis and is tissue specific (3, 23). For example, prostate tumors, but not colon tumors, lose their 1--hydroxylase activity as they become more aggressive. Thus, 25(OH)D might be less efficacious against aggressive prostate tumors. Furthermore, androgens can alter the balance between CYP27B1 and CYP24 (24). Dihydrotestosterone inhibits 1,25(OH)2D-mediated induction of CYP24 and several downstream molecular targets of 1,25(OH)2D. Interactions also occur between the androgen receptor and VDR signaling (24). We need a better understanding of which vitamin D metabolites can be used by various tissues or cells at different stages of the cancer process as well as the nature of their interactions with other molecular targets.
Vitamin D regulates many genes involved in prostaglandin metabolism. 1,25(OH)2D inhibits COX-2 expression and activity, inhibits expression of prostaglandin receptors, and increases prostaglandin catabolism by increasing expression of 15-prostaglandin dehydrogenase (25). In combination, these 3 mechanisms reduce prostaglandin levels and signaling, thereby attenuating the growth-stimulatory effects of prostaglandins in prostate cancer (25). Furthermore, 1,25(OH)2D and naproxen (a nonsteroidal antiinflammatory drug) act synergistically in vitro and inhibit prostate cancer cell growth more effectively than either alone in patients on the basis of a slowing of the prostate-specific antigen doubling time (25). Thus, by understanding the molecular targets for vitamin D, researchers can develop more effective strategies for cancer prevention and treatment.
WHAT ARE THE IMPORTANT DIETARY COMPONENTS THAT MODIFY THE EFFECT OF VITAMIN D?
Several dietary components and the balance between energy intake and expenditure influence vitamin D metabolism. Although research has shown that low serum calcium concentrations stimulate renal 1,25(OH)2D synthesis from 25(OH)D, evidence presented at the conference indicated that dietary genistein, an important bioactive component of soy, can also influence the metabolism of 25(OH)D and its biological effects. Genistein inhibits CYP24 activity, which, in turn, increases the production and serum half-life of 1,25(OH)2D and the expression of the VDR (26). Dietary folate can also inhibit CYP24 activity by increasing the methylation status of the promoter region and by down-regulating expression of the gene (25). These results show that establishing a definitive concentration of 25(OH)D will be very difficult because multiple dietary components can influence the metabolism of 25(OH)D. Researchers must also therefore consider nutrient-nutrient interactions.
Vitamin D status is also related to body fat and physical activity. Several large observational studies, including the third National Health and Nutrition Examination Survey, showed that obesity is associated with lower circulating concentrations of 25(OH)D (27). Although researchers have not identified the mechanism for this effect, hypotheses include sequestration in fat, negative feedback from higher circulating 1,25(OH)2D concentrations in obesity, and lower sun exposure due to avoidance of outdoor activity by the obese (27). Higher physical activity levels are linked to higher circulating concentrations of 25(OH)D; however, we do not know whether this reflects a direct relation between physical activity and vitamin D metabolism or is a result of confounding by body fat or sun exposure. Furthermore, the relations between both vitamin D status and obesity and vitamin D status and physical activity were stronger in whites than in African Americans (27). These types of relations highlight the importance of identifying confounders and modifiers of the biological response to vitamin D, including dietary factors, lifestyle factors such as exercise, and race/ethnicity.
WHAT INFORMATION HAVE PRECLINICAL MODELS PROVIDED ABOUT THE RELATION BETWEEN VITAMIN D, CALCIUM, AND CANCER?
Transgenic and knockout animals are powerful tools for identifying the molecular targets of bioactive food components. For example, VDR knockout animals provide a tool for evaluating the potential biological effects of vitamin D that are not mediated through the VDR. Studies using these animals have clearly demonstrated the importance of the VDR in influencing cancer risk. VDR knockout animals have increased numbers of chemically induced tumors in many (mammary, prostate, skin, and colon) but not all (ovary, liver, lung, and uterus) organs (28). Interestingly, supplemental vitamin D had no effect on mammary tumor development in VDR knockout animals with the neu protooncogene, which suggests that the VDR must be present for vitamin D to exert its cancer-protective effects (28). These types of studies demonstrate the need for increased use of transgenic and knockout animal models to identify molecular targets for vitamin D.
Typically, rodents do not develop colon cancer. However, when mice eat a diet similar to that of humans, a so-called Western diet that is high in fat and phosphorous and low in vitamin D, calcium, fiber, choline, methionine, and folate, 
25% spontaneously develop colon cancer in the absence of carcinogen treatment (29). If researchers supplement the Western diet with calcium and vitamin D, both colon tumor incidence and frequency decrease significantly. This suggests that vitamin D is protective against cancer and that this is a new mouse model of sporadic colon cancer (29).
Investigators are using transcriptomic or microarray approaches to understand the molecular targets for 1,25(OH)2D in both cell culture and animal models (29, 30). Researchers have generated gene expression profiles for 1,25(OH)2 D treatment in both classic (ie, bone, kidney, intestine, Caco-2, and ROS/17/2.8) and nonclassic (ie, HL-60, squamous cell carcinoma, B, and prostate epithelial) cells (30). These studies have identified a large number of genes that are differentially expressed. However, for meaningful interpretation of this plethora of information, researchers will need to compare studies to identify particular genes targeted by vitamin D by using functional annotation to define the processes involved. They also need to assign these processes to known metabolic and signaling pathways when possible (30).
Researchers successfully applied a comparative microarray approach in 3 different mouse models of colon cancer (APC1638+/–, Muc2–/–, and wild-type C57Bl6 mice) fed a Western diet (29). In all 3 models, increasing dietary calcium and vitamin D was effective in inhibiting tumor formation. Moreover, gene expression profiling of the colonic mucosa in each model identified genes and pathways that track dietary calcium and vitamin D and, hence, also track the probability of tumor formation (29). Results of studies with these models reveal genes and pathways that commonly respond to calcium and vitamin D in all 3 models and other genes and pathways specific to 1 of the 3 models.
FUTURE RESEARCH DIRECTIONS
Many of the research gaps that participants identified at the May 2007 conference related to the need to develop predictive, validated, and sensitive biomarkers. These include biomarkers that researchers can use to reliably evaluate intake or exposure to vitamin D, assess one or more specific biological effects that are linked to cancer, and effectively predict individual susceptibility as a function of nutrient-nutrient interactions and genetics (Figure 2). This information is fundamental to evaluating who will benefit most from, and who might be placed at risk by, increased vitamin D intake or exposure.
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Second, we need a better understanding of susceptibility biomarkers. Although research has linked many different polymorphisms in the VDR to cancer risk, we need additional information about gene-environment interactions and organ specificity. We need more research on the relation between polymorphisms in other genes in the vitamin D metabolic pathway (ie, CYP24 and CYP27B1), vitamin D status, and cancer risk. In addition, because obese individuals and African Americans have lower 25(OH)D concentrations than do other populations, studies need to determine whether this contributes to their increased cancer susceptibility. Additional studies should address whether persons with cancer respond to vitamin D in the same way as persons without cancer and, if so, whether their response depends on their cancer type.
Finally, we still need a better understanding of the molecular targets for vitamin D. Researchers should use various "omics" technologies, such as transcriptomics, proteomics, and metabolomics, to elucidate the mechanism of action of vitamin D in both animal models and normal versus malignant tissues of human subjects. We need additional information to determine whether the biological response differs among different tissues and between normal and neoplastic tissue.
Although a wealth of information is available from preclinical and epidemiologic studies, we need more controlled intervention studies. We also need to evaluate potential adverse effects of long-term, high-dose vitamin D exposure, including the dose of vitamin D associated with toxicity. For example, research should show whether this varies by age, race, sex, body size, and health status. Finally, we need to understand better potential adverse outcomes and how to best monitor them; animal models could be useful for this purpose. Thus, although the current body of evidence is intriguing, many unanswered questions remain.
ACKNOWLEDGMENTS
The author had no conflicts of interest.
REFERENCES
-hydroxylase and their proliferation is inhibited by the prohormone, 25-hydroxyvitamin D3. Carcinogenesis 2004;25:1015–20.This article has been cited by other articles:
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  P. M Brannon, E. A Yetley, R. L Bailey, and M. F. Picciano Overview of the conference "Vitamin D and Health in the 21st Century: an Update" Am. J. Clinical Nutrition, August 1, 2008; 88(2): 483S - 490S. [Abstract] [Full Text] [PDF]
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