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Vitamin D and Its Role in Cancer and Immunity: A Prescription for Sunlight
Gerard E. Mullin, MD, MHS, FACP, CNSP, FACN, AGAF*
Adrian Dobs, MD, MHS
* Integrative GI Nutrition Services, Capsule
Endoscopy, Division of Gastroenterology and Liver Disease, Johns Hopkins
Hospital, Baltimore, Maryland
Correspondence: Correspondence: Gerard E. Mullin, MD, MHS, FACP, CNSP, FACN, AGAF, Director of
Integrative GI Nutrition Services, Johns Hopkins Hospital, 600 N. Wolfe
Street, Baltimore, MD 21205. Electronic mail may be sent to
gmullin1{at}jhmi.edu.
Vitamin D has been recognized for more than a century as essential for the
normal development and mineralization of a healthy skeleton. More extensive
roles for vitamin D were suggested by the discovery of the vitamin D receptor
(VDR) in tissues that are not involved in calcium and phosphate metabolism.
VDR has been discovered in most tissues and cells in the body and is able to
elicit a wide variety of biologic responses. These observations have been the
impetus for a reevaluation of the physiologic and pharmacologic actions of
vitamin D. Here, we review the role of vitamin D in regulation of the immune
system and its possible role in the prevention and treatment of cancer and
immune-mediated diseases.
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Vitamin D Overview
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Most humans depend on sun exposure to satisfy their requirements for
vitamin D. Brief exposure to direct sunlight on a bright summer day is all the
body needs to produce sufficient cholecalciferol (or vitamin
D3).1
Skin exposure to ultraviolet B light (wavelength 290–315 nm) initiates
the photochemical conversion of 7-dehydrocholesterol to previtamin
D3 in the epidermis and dermis. Body heat then catalyzes the rapid
isomerization of previtamin D3 to vitamin D3
(cholecalciferol), which binds to the vitamin-D-binding protein (VDBP) in the
extracellular
space.2 Vitamin
D3 is transported to the liver, which uses 25-hydroxylase to
produce 25-hydroxyvitamin D3, or 25(OH)D3.
Although endogenous production of vitamin D typically provides most of the
vitamin D requirement, vitamin D can be ingested orally as either vitamin
D3 (cholecalciferol) or D2 (ergocalciferol, derived from
the irradiation of plant sterols). Very few foods naturally contain vitamin D:
oily fish and fish products such as cod-liver oil, salmon, mackerel, and
herring contain approximately 300–500 international units (IU) of
vitamin D per
serving.3 Foods in
the United States that are fortified with vitamin D include milk, orange
juice, and some cereals, breads, yogurts, and cheeses. Most European countries
permit margarine and some cereals to be fortified with vitamin D, and a few
countries, including Sweden, also permit milk to be fortified with this
vitamin.
25-Hydroxyvitamin D [25(OH)D] derived from endogenous production or
exogenous sources is the major vitamin D metabolite in the human body's
circulation system and is the best known indicator of vitamin D status. There
is debate regarding cutoffs for vitamin D deficiency and insufficiency using
25(OH)D concentrations. The current thinking is that the traditional cutoff
for deficiency, 10 ng/mL of 25(OH)D (above which protection from rickets or
osteomalacia is conferred), is too low to indicate vitamin D adequacy. A low
serum 25(OH)D concentration, often referred to as hypovitaminosis D, is not
simply a biochemical abnormality. It is associated with physiologic,
pathologic, and clinical evidence of vitamin D deficiency, including increased
parathyroid hormone secretion, increased bone turnover, osteoporosis and mild
osteomalacia, and an increased risk of hip and other fractures. To prevent
more subtle or long-term effects of vitamin D insufficiency, circulating
concentrations of at least 30 ng/mL 25(OH)D may be
warranted.3
In the kidney, 25(OH)D is further hydroxylated to
1 ,25-dihydroxyvitamin D [1,25(OH)2D3,
calcitriol], the most biologically active form of the vitamin, by renal
1-hydroxylase under the control of parathyroid hormone.
1,25(OH)2D3 principally targets the intestine,
kidney, and bone to regulate calcium and phosphate homeostasis. Calcitriol is
a lipid-soluble hormone that interacts with its vitamin D receptor (VDR) in
the small intestine to increase the expression of an epithelial calcium
channel, calcium-binding protein, and a variety of other proteins to help in
transport of calcium from the intestinal lumen into circulation. Calcitriol
also interacts with its VDR in the osteoblasts, which results in an increase
in the mobilization of osteoclast precursors to become mature osteoclasts. The
end result is mobilization of calcium stores from the skeleton to maintain
calcium
homeostasis.1–6
These well-defined, calcemic functions of vitamin D are illustrated in
Figure 1. It should be noted
that 1,25(OH)2D3 circulates at concentrations
1000-fold less than that of 25(OH)D, and that its half-life is hours rather
than weeks, as is the case for 25(OH)D.
More recently, VDRs were found in cells of tissues not involved in calcium
homeostasis, and extrarenal tissues were found to produce
1,25(OH)2D3. These pathways are also indicated in
Figure 1 and supported the
hypothesis that vitamin D plays additional roles in cellular differentiation
and the control of proliferation in a variety of cell types. These results
have bolstered at a biochemical level what epidemiologists have been
witnessing in observational studies: that vitamin D status may protect against
certain cancers, as well as some autoimmune conditions.
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Vitamin D and Cancer Prevention
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Epidemiologic Studies
Geography, sunlight, and cancer risk. Most of the information
about vitamin D and cancer prevention has been based on observational,
case-control, or cohort studies linking sunlight exposure to cancer incidence
or survival. The first of these studies was documented nearly a half century
ago, when it was reported that individuals living in the northeast regions of
the United States had an approximately 2-fold higher risk of dying of cancer
than those living in southern
regions.7 Recently,
several more studies found a similar association between latitude and the risk
of developing prostate, breast, and colon cancer in the United States and
Europe.8–10
Colon cancer mortality was subsequently found to be higher among people from
the Northeastern United States compared with people living in southern
states.11 It is now
well established that the risk of developing and dying of prostate, breast,
colon, ovarian, esophageal, non-Hodgkin's lymphoma, and a number of other
lethal cancers correlated with living at higher
latitudes.11–24
Several investigators have confirmed the reciprocal relationship of
sunlight exposure and cancer. Most recently,
Grant24,25
reported that increased sun exposure decreases mortality from common cancers
in both white men and
women.7
Grant17 suggested
that 25% of breast cancer mortality in Europe was related to living at a
higher latitude and being vitamin D deficient.
These observations are also supported by a report of men who had little sun
exposure and developed prostate cancer 3–5 years earlier than men who
had optimal sun
exposure.26 Vitamin
D deficiency was reported to increase the risk for prostate cancer, and
sunlight exposure is inversely proportional to prostate cancer mortality.
Colon cancer incidence was evaluated in California because the state has a
wide range of latitudes. Living in San Diego was reported to significantly
decrease the risk of developing colon cancer compared with living in San
Francisco or further
north.27
There has been speculation that subjects living further north synthesized
less vitamin D and that therefore vitamin D seems to be protective against
tumor development or growth. The sunlight effect therefore seems to attenuate
the risk of numerous cancers, such as prostate, breast, colon, ovarian,
non-Hodgkin's lymphoma, esophageal, stomach, pancreatic, rectal, kidney,
corpus uteri, lung, and bladder. These studies, which controlled for other
important variables such as smoking and lifestyle, provide indirect evidence
of a possible causal relation between low vitamin D status and cancer
risk.
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Figure 2. 1,25(OH)2D3 regulates prostate cell growth.
Vitamin D can influence the regulation of key genetic elements of cell
differentiation and proliferation by either
1,25(OH)2D3 entering the nucleus of the prostate
cell or via conversion of 25 (OH)D3 by 1,25-OHase in the
mitochondrion. Adapted from Progress in Biophysics & Molecular Biology
Volume 62, Holick MF. Vitamin D: its role in cancer prevention and treatment,
pp 49–59, © 2006 with permission from Elsevier. AR, androgen
receptor; BAG 1L, Bcl-2 associated athanogene-1; BCL-2/BCL-XL,
B-cell leukemia/lymphoma family; CDK2, cyclin-dependent kinase 2; cIAP1 and
cIAP2, cIAP1 and cIAP2 are members of a protein family; Mc1-1, Myeloid Cell
Leukemia 1; p21, p27, and p53, tumor proteins 21, 27, and 53; PSA, prostate
specific antigen; RXR, retinoic X receptors; VDR, vitamin D receptor; XIAP,
X-linked mammalian inhibitor of apoptosis protein.
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Studies have looked more specifically at quantitative estimates of sunlight
exposure and cancer risk or mortality. Men with elevated levels of sunlight
exposure had a later onset of prostate cancer than those with low levels of
sunlight
exposure.18 Solar
ultraviolet (UV)-B exposure was inversely related to the risk of dying of
cancer in men and women in the United
States.28
Putative mechanisms for vitamin D protection against cancer. The
original hypothesis for why exposure to sunlight decreased the risk of common
cancers was that increased production of vitamin D3 in the skin
resulted in higher circulating levels of 25(OH)D3, which could be
metabolized by the kidneys to 1,25(OH)2D3. The
discovery that VDRs existed in tissues that were not involved in calcium
metabolism (ie, prostate, breast) reinforced the possibility that enhanced
production of renal 1,25(OH)2D3 could influence
noncalcemic tissues. Studies demonstrated that
1,25(OH)2D3 markedly inhibited a variety of genes
responsible for cellular proliferation, including p21 and p27, and was also
responsible for enhancing apoptotic activities and a variety of genes that
regulate cellular
differentiation.29
However, because the kidney's production of
1,25(OH)2D3 is exquisitely regulated, it could
not serve as the source of the active 1,25(OH)2D3
responsible for the newly recognized cellular functions. Thus, another
hypothesis to explain the observations that sunlight provided a protective
effect via vitamin D was
needed.1–4
Another possibility was that the "target" cells of interest were
themselves converting 25(OH)D to 1,25(OH)2D3.
Along these lines, cultured keratinocytes and prostate cells obtained from
nondiseased prostate biopsies converted 25(OH)D to
1,25(OH)2D318,27,30
(Figure 2). Following these
observations, it has been noted that the colon, lung, breast, and other
tissues all express the 25(OH)D-1-hydroxylase (1-OHase; cyp 27
B1).31 Thus, it has
been suggested that raising blood levels of 25(OH)D provides an adequate
substrate for the prostate, colon, and breast to produce their own local
1,25(OH)2D3, which, in turn, is capable of
regulating a variety of cellular processes that help control cellular growth
and prevent malignancy.
Animal models. Although the epidemiologic evidence linking sun
exposure to cancer risk seems strong, whether vitamin D deficiency per
se promotes tumor growth remained unclear. To this end, a study evaluated
the growth of a mouse colon cancer cell line MC-26 in Balb/c mice that were
either vitamin D deficient or vitamin D
sufficient.32 The
tumors grew much more rapidly in the vitamin D–deficient mice. By the
end of the study on day 19, tumors in the vitamin D–deficient mice were
on average 80% larger than in the vitamin D–sufficient mice. The 25(OH)D
levels in the vitamin D–deficient mice at the end of the study were
<5 ng/mL, whereas the vitamin D–sufficient mice maintained a 25(OH)D
level of 35 ng/mL. This observation provides strong corroborating data
supporting the concept that vitamin D sufficiency is important for reducing
tumor cell growth. There is now emerging data that vitamin D may play a role
in altering colon cancer cell growth. Spina et
al33 performed
studies using murine models of colon cancer to demonstrate that those mice who
were sufficient in vitamin D had a significantly lower (p < .05)
tumor burden compared with vitamin D–deficient mice. Furthermore, using
Gemini analog A in the same mouse model of colon cancer, these investigators
demonstrated that the tumor burden was decreased by 50% in the treatment group
when compared with placebo or 1,25(OH)2D3
(p < .05; Figure
3).
Dietary intake of vitamin D and cancer risk. Aside from sun
exposure, others sources of vitamin D are in the form of diet and supplements.
There are several epidemiologic studies of the association between vitamin D
and breast cancer risk. Studies reporting dietary and supplemental intake
demonstrate inconsistent results (Table
1).20,35–38,41
Three case-controlled studies demonstrated no association between dietary
vitamin D intake and breast cancer
risk35,39,40;
however, small sample size and selection bias may have skewed the results. On
the other hand, the Nurses Health Study demonstrated an inverse association
between vitamin D intake and breast cancer risk among premenopausal women but
no association among postmenopausal
women.41 Along
these lines, the Cancer Prevention Study II Nutrition Cohort found no
correlation between dietary intake of vitamin D and development of breast
cancer in postmenopausal
women,38 and 2
additional studies determined that the dietary intake of vitamin D in the
female adolescent had no bearing in determining future breast cancer
risk.36,37
However, researchers provided additional preliminary evidence demonstrating a
potential role of vitamin D in decreasing breast cancer risk. In a
population-based, case-controlled study in Ontario, women with breast cancer
(identified through the Ontario Cancer Registry) and controls were interviewed
about their past and present diets and sun exposure.
The investigators' preliminary analysis suggests that earlier exposures to
vitamin D during breast development in adolescence may be more significant for
reducing breast cancer risk than recent
exposures.42,43
A recent study seeking to estimate the amount of vitamin D required to reduce
the incidence of breast cancer was performed via a meta-analysis of 2
large previously published studies that measured vitamin D concentrations in
the blood [as serum 25(OH)D] and subsequent breast cancer development. The
results demonstrated that women who consumed 1000 IU a day of vitamin D in
addition to the normal background amount had a 10% reduced risk of breast
cancer.43 Garland
and colleagues44
plotted a dose-response gradient and found that as quintiles of serum 25(OH)D
(0–11 ng/mL, 12–25 ng/mL, 26–31 ng/mL, 32–42 ng/mL,
and >42 ng/mL) increased, the risk of breast cancer significantly
decreased. A serum 25(OH)D concentration exceeding 52 ng/mL (which would
require intake of >2700 IU/d of vitamin D3 in an individual
weighing 70 kg) was associated with 50% lower risk of breast cancer compared
with a serum concentration of <12 ng/mL. The authors noted that the US
median intake of 320 IU/d of vitamin D is only about one-tenth of the amount
found to be associated with a 50% reduction of breast cancer incidence. They
concluded that increasing daily intake of vitamin D, perhaps by fortification
of foods, should be considered. Studies analyzing endogenous circulating
vitamin D levels and breast cancer risk are shown in
Table
2.12,19,34,45,46
Biochemical indicators of vitamin D status and cancer risk. There
has been considerable debate recently about concentrations of circulating
25(OH)D that can be viewed as optimal for preventing vitamin D deficiency and,
in particular, promoting health. Prospective and retrospective studies have
shown that circulating levels of 25(OH)D above 50 nmol/L (20 ng/mL) were
associated with a 30%–50% decreased risk of developing prostate, breast,
and colon
cancer.47
A recent study by Dr Walter Willett's group from Harvard University found
that higher serum vitamin D levels correlated with reduced risk for certain
forms of cancers in a population of middle-aged to elderly men in a
retrospective analysis of data from a major study of health
professionals.48
Giovannucci and
colleagues48
analyzed prospective data from Harvard's Health Professionals Follow-up Study,
which includes >50,000 men aged 40–75 years. Higher serum levels of
vitamin D were associated with a significantly lower incidence of colorectal,
pancreatic, esophageal, and oral/pharyngeal cancers. An increase of 25 nmol/L
in serum vitamin D level was associated with a 17% decline in overall cancer
incidence and a 29% drop in total cancer deaths. For cancers involving the
digestive system, a 25 nmol/L increase in vitamin D reduced cancer incidence
by 43% and mortality by 45%. This study was the first to examine total cancer
incidence and mortality by using a comprehensive assessment of factors that
determine 25(OH)D levels. The authors estimated that cancer mortality for US
men could be reduced by 29% if serum vitamin D levels were increased by 25
nmol/L throughout the male population. The findings from this cohort study are
the latest of
several49–52
linking vitamin D status with reduced cancer risk, and are some of the most
compelling yet. The results, with lower risks of most (but not all) forms of
cancer, are also some of the most broad-based, and they indicate that vitamin
D may have a role in most human tumors. Factors associated with higher serum
levels of vitamin D were white race, residence in the southern United States,
higher intakes of vitamin D, body mass index <22 kg/m2, and more
physical activity. Vitamin D supplements (as opposed to dietary vitamin D) had
only a slight effect on serum vitamin D. The investigators noted that
increasing one's serum vitamin D by 25 nmol/L (the basis of their
relative-risk calculation) might mean adding at least 1500 IU/d of vitamin D,
far exceeding the US Department of Agriculture's recommended dietary allowance
(RDA) of vitamin D currently set at 200–400 IU for people aged
1–70 years. A glass of milk contains only 100 IU and would increase
serum vitamin D by only 2–3 nmol/L, they noted, but "a
fair-skinned individual can produce 20,000 IU of vitamin D in the skin through
20–30 minutes of sun exposure." A recent editorial also noted that
"the amount of sun needed to produce adequate levels of vitamin D, at
least for bone health, is modest and can be obtained in a light-skinned person
by a brief summertime afternoon
stroll."53
Other previous reports support a role for vitamin D in the prevention of
colorectal
cancer.15,22,54
Giovannucci55 has
recently published a review of the data on colon cancer risk and vitamin
D.
Other cancers where vitamin D plays a protective role. Polesel et
al56 reported that
vitamin D also serves a protective role against the development of
non-Hodgkin's lymphoma. Vitamin D (chiefly contained in fish) provided
protection against non-Hodgkin's lymphoma that was stronger in women, whereas
no differences emerged according to age (odds ratio [OR] = 0.4; 95% confidence
interval [CI], 0.2–0.9). Vitamin D also seems to play a protective role
in pancreatic
cancer.57 In 2 US
cohorts, increased intakes of vitamin D were associated with reduced risks for
pancreatic cancer, suggesting a potential role for vitamin D in the
pathogenesis and prevention of this malignancy.
Melanoma, on the other hand, has been linked to sun exposure. Thus, the
risk of excessive sun exposure needs to be weighed against the benefit of
sun-derived vitamin D. Li et
al58 reported that
genetic variants (ie, TaqI t protective allele and FokI f risk allele) in VDR
may alter risk of cutaneous melanoma. Thus, genetic alternations in VDRs may
in part determine the risk for developing cutaneous melanoma from sun
exposure.
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Mechanisms Involved in the Anticancer Effects of Vitamin D
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Over the past quarter century, evidence for the anticancer properties of
vitamin D and its analogs has been emerging in the literature. The volume of
data supports a multipronged attack that involves growth arrest at the G1
phase of the cell cycle, apoptosis, tumor-cell differentiation, disruption of
growth-factor-mediated cell survival signals, and inhibition of angiogenesis
and cell adhesion (Figure 2).
Processes involved in the tumor suppressive activity of vitamin D analogues
include inhibition of cell proliferation, induction of apoptosis, inhibition
of cell adhesion, G1-phase cell-cycle arrest, promotion of cell
differentiation, inhibition of angiogenesis, alteration of growth factors, and
inhibition of
metastasis.59,60
Thus, VDR-mediated pathways constitute potential therapeutic targets for
cancer prevention and treatment.
Proposed Cellular Mechanisms
Cell cycle regulators. Direct regulation of the cell cycle by
1,25(OH)2D3 has been studied predominantly in
in vitro systems. The 1,25(OH)2D3-VDR
system arrests the cancerous cell cycle at the G0-G1
transition through multiple
mechanisms.59 In
the monomyelocytic cell line U937,
1,25(OH)2D3-activated VDR directly binds to the
promoter of p21 and induces its expression. Furthermore,
1,25(OH)2D3 increases the expression of p27 as
well as p15, p16, and p18, which effectively inhibits the G1-to-S phase
transition (Figure
4).60
Furthermore, in the MCF-7 breast cancer cell line, treatment with
1,25(OH)2D3 inhibits cellular proliferation, and
microarray analysis demonstrated an up-regulation of a number of cell cycle
regulatory genes, including p21-activated kinase 1 and
p53.61 Thus,
vitamin D is a potent regulator of cellular differentiation and proliferation
through direct regulation of cell cycle proteins.
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Figure 4. Nutrient regulation of cell cycle proteins. Vitamin D has broad effects in
regulating the cell cycle by regulating the expression of p53, Cip/waf p21,
p27, p57, p15, p16, and p18, which effectively inhibits the G1-to-S phase
transition. Adapted with permission from Bohnsack BL, Hirschi KK. Red light,
green light: signals that control endothelial cell proliferation during
embryonic vascular development. Cell Cycle. 2004;3:1506–1511.
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Role of 1,25(OH)2D3 in Regulating Cell Growth and Terminal Differentiation
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1,25(OH)2D3 regulates proliferation and
differentiation of different kinds of cells, including keratinocytes,
osteoblasts, and hematopoietic
cells.2
1,25(OH)2D3 has been shown to inhibit cellular
growth and induced differentiation of M-1 leukemic cells and HL-60 leukemic
cells expressing
VDR.62
1,25(OH)2D3 inhibits proliferation and induces
differentiated function in osteoblasts, keratinocytes, and hematopoietic
cells.63
1,25(OH)2D3 is generally associated with
inhibiting proliferation and inducing differentiation. The growth inhibition
of cancer cells by 1,25(OH)2D3 is associated with
growth factor signaling through transforming growth factor-β
(TGF-β), which is a potent inhibitor of proliferation of many cell types
and is involved in cell cycle control and apoptosis. Vitamin D analogs induce
an autocrine TGF-β activity through increasing expression of TGF-β
isoforms or TGF-β receptors in nonmalignant and malignant
cells.64
Insulin-like growth factor (IGF)-binding protein 3 induction by
1,25(OH)2D3 seems to contribute to its
antiproliferative and proapoptotic actions in primary cancer
cells.65–67
Recent microarray studies of gene expression profiles in cancer cells have
further highlighted the capacity of 1,25(OH)2D3
analogs to drive malignant cells to a more differentiated
state.68
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Role of 1,25(OH)2D3 in Apoptosis
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1,25(OH)2D3-induced apoptosis is an important
contributor to its growth-suppressing and anticancer properties.
1,25(OH)2D3 analogs have been shown to induce
apoptosis in cancer cells by modulating B-cell leukemia/lymphoma-2 genes
(Bcl-2) and Bax proteins (which is a proapoptotic member of the Bcl-2 protein
family), tumor necrosis factor (TNF)-, and caspase-dependent and
independent
mechanisms.69
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Role of 1,25(OH)2D3 in Controlling Tumor Invasion and Metastasis
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Aside from growth inhibition, vitamin D and its analogs decrease the
invasiveness of several cell lines in vitro, and they inhibit
angiogenesis and metastasis in xenograft and transgenic mouse models in
vivo.70 In
cultured malignant cells, 1,25(OH)2D3 and its
analogs down-regulate cell-invasion-associated proteases, including matrix
metalloproteinases 2 and 9 and serine
proteinases.71 In
prostate and colon cells, 1,25(OH)2D3 and its
analogs increase the expression of E-cadherin, a tumor suppressor associated
with the metastatic potential of cells, and inhibit the oncogenic
β-catenin
signaling.72
1,25(OH)2D3 and its analogs inhibit the
proliferation of some tumor-derived endothelial cells, inhibit the expression
of vascular endothelial cell growth factor that induces angiogenesis in
tumors, and suppress tenascin-C, which promotes growth, invasion, and
angiogenesis during
tumorigenesis.73
Breast, colon, prostate, skin, lung, and a variety of other cell lines,
when exposed to 1,25(OH)2D3, showed marked
inhibition of cellular growth and induction of terminal
differentiation.74
Although vitamin D is not currently used as a chemotherapeutic agent, it shows
promise for drug development in the treatment of certain cancers. However, at
this point, it is far from a certainty.
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Vitamin D Analogs for Cancer Treatment
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As discussed earlier, the nuclear VDR has been isolated from a variety of
target cells and tissues (Table
3), suggesting that vitamin D compounds may have therapeutic
potential throughout several body systems. The major drawback of
1,25(OH)2D3, however, is its effect on calcium
metabolism, which results in hypocalcaemia and hypercalciuria. Newly developed
vitamin D analogs with lower calcemic activity have been shown to retain many
therapeutic properties of
1,25(OH)2D3.75–106
MC 903 is a vitamin D analog with low (2/0.05) ratio of cell growth inhibition
to calcemic activity. In contrast, CB 966 (6/0.2), CB 1093 (160/0.27) and KH
1060 (1000/1.3) have much higher ratios making them potentially effective
therapeutic agents without the potential risk of
toxicity.75 More
than 2000 synthetic analogs of the biologic form of vitamin D
(1,25(OH)2D3) are presently known. These analogs
interfere with the molecular switch of nuclear
1,25(OH)2D3 signaling.
Most 1,25(OH)2D3 analogs have been identified
as agonists, a few are antagonists (ie, ZK 159222), and only Gemini analogs
(analogs having additional side-chains attached) and some of its derivatives
act under restricted conditions as nonagonists.
Five vitamin D analogs have been approved for clinical use in a variety of
disorders: calcipotriol (Dovonex; Leo Pharmaceuticals, Copenhagen, Denmark)
for the treatment of psoriasis, 19-nor-1,25(OH)2D2
(Zemplar; Abbott Laboratories, Abbott Park, IL) for secondary
hyperparathyroidism, doxercalciferol (Hectorol; Bone Care Int, Madison, WI)
for reduction of elevated parathyroid hormone levels, 22-oxacalcitriol
(Maxacalcitol; Chugai Pharmaceuticals, Tokyo, Japan), and alfacalcidol. Thus,
these synthetic analogs which maintain antiproliferative effects but do not
have strong calcemic activity have been developed and show promising results
(Table 4). Studies using the
human osteosarcoma cell line MG-63 demonstrated that 3 of these analogs
(KH1060, EB1089, and CB1093), have a greater antiproliferative effect than
1,25(OH)2D3. Treatment with these analogs increases p27
protein levels by increasing expression and decreasing degradation. The
analogs cause decreased levels of cyclin E, decreased CDK2 kinase activity and
hypophosphorylation of Rb, and inhibition of the G1-to-S phase
transition.105
Similar results have been seen in neuroblastoma cell lines treated with a
20-epi-1,25(OH)2D3
analog,106
suggesting that in the future, these 1,25(OH)2D3
analogs may be useful in chemotherapeutic regimens.
Several other analogs are currently being tested in preclinical and
clinical trials for the treatment of various types of cancer and osteoporosis,
as well as
immunosuppression.80
Vitamin D analogs are effective treatments and are widely used as drugs for
hyperproliferative skin disorders such as psoriasis, and in suppression of
secondary hyperparathyroidism and parathyroid hyperplasia resulting from
chronic renal
insufficiency.107–109
For instance, Gemini analogs have been recently found to be 100–1000
times more potent in their antiproliferative activity than the natural
hormone. Studies in mice suggest that they may be useful in the treatment of
some cancers, including colon
cancer.27
Understanding how analogs exert their selective actions may allow for the
design of more effective and safer vitamin D compounds for the treatment of a
wide range of clinical disorders. The promising vitamin D analogs under
development for the treatment of cancer are shown in
Table
476–88;
the in vivo effects of vitamin D analogs in animal models for breast
cancer, prostate cancer, and colon cancer are shown in
Table
589–106;
and the molecular targets for vitamin D compounds in cancer are shown in
Table 6. Optimal administration
of vitamin D analogs is only being realized, with high-dose intermittent
administration overcoming bioavailability and hypercalcemic problems.
Combination therapy with cytotoxic agents (taxols and cisplatins),
anti-resportive agents (biphosphonates), agents blocking vitamin D metabolism
(ketoconazole), ionizing radiation, antiproliferative agents (retinoic acids),
antihypercalcemic agents (dexamethasone), histone deacetylase inhibitors, or
cytochrome P450 inhibitors may achieve better results through synergy, as
shown in
vitro.110–115
Understanding how analogs exert their tissue-specific selective actions may
allow for the design of more effective and safer vitamin D compounds for the
treatment of hyperproliferative disorders, including cancer.
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Vitamin D and the Immune System
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T Cells as the Main Target
1,25(OH)2D3 seems to modulate immunity principally
via regulating T-cell function. VDR has been found to be expressed on
virtually every type of cell involved in immunity
(Table
3).110–113
The immunomodulatory actions of vitamin D are elicited through its direct
action on T-cell and antigen-presenting cell (APC) functions. Thus,
1,25(OH)2D3 may have an important physiologic role in
immunoregulation and therapeutic target in immune-mediated diseases.
Effects on T Cells and T Helper 1 Cytokine Profiles: Relevance to Autoimmunity
In autoimmune patients, T cells target tissues such as the central nervous
system (multiple sclerosis [MS]), the gut (Crohn's disease, inflammatory bowel
diseases [IBD]), the joints (rheumatoid arthritis) and the pancreas (type-1
diabetes). The common denominator between these diseases is that T-helper 1
(Th1) cells secrete a proinflammatory profile of cytokines (TNF-,
interferon [INF], IFN ) at the site of pathology, which drives the
disease process. In general, if a treatment for Th1-mediated autoimmunity
works, it suppresses the number or activity of Th1 cells or antagonizes the
cytokines (TNF- in particular) that they produce. In addition,
treatments that work for one Th1-driven disease are likely to suppress other
Th1-driven autoimmune diseases (eg, infliximab used to treat Crohn's disease
and rheumatoid arthritis).
Vitamin D regulates T cells both directly and indirectly via
APCs.120,121
When vitamin D is deficient or signals through the VDR are weakened, Th1 cell
actions are intensified, whereas regulatory T cells and Th2 cells are
diminished, thus favoring an autoimmune Th1
response.122,123
1,25(OH)2D3 increases regulatory T cells and Th2
cells (anti-inflammatory cytokines) while suppressing Th1 cell
activities.124
VDRs are required to maintain a physiologic balance of Th1 and Th2 cell
responses, and furthermore in the absence of the VDR, Th2 cell functions are
diminished.125
1,25(OH)2D3 suppresses production of the Th1
proinflammatory cytokines interleukin-2 (IL-2) by binding to the distal
nuclear factor of activated T cells (NF-AT) binding site in the promoter of
the human IL-2 gene and IFN through the interaction of VDRs, with a
vitamin D response element (VDRE) in the promoter region of the IFN
gene.126,127
Because vitamin D deficiency favors a proinflammatory Th1 immune response,
does supplementation rebalance immunity? In vitro addition of
1,25(OH)2D3 has recently been shown to enhance
and promote differentiation of type 2 T-helper (Th2) lymphocytes through a
direct effect on naïve CD4+ T cells.
1,25(OH)2D3 has been shown in vitro to
inhibit the development of Th1 cells while promoting the development of Th2
cells.121,128,129
Thus, 1,25(OH)2D3 seems to modulate T-cell
differentiation, driving cells toward the Th2 phenotype and inhibiting Th1
development.
Thus, the action of 1,25(OH)2D3 in
antagonizing Th1 cytokine production while promoting Th2 function may have an
important therapeutic role in diseases whereby Th1 cytokine responses drive
the immunopathology.
Effects on APCs
The secretion of cytokines by APCs such as macrophages and dendritic cells
(DCs) is crucial for the recruitment and activation of T lymphocytes. The
actions of APCs on T cells are also influenced by
1,25(OH)2D3. Interleukin-12 (IL-12) is the
principal APC-derived cytokine that determines the direction (Th1 vs
Th2) of the immune response. Thus, Th1-stimulating cytokines are inhibited by
1,25(OH)2D3 in DCs, as well as in other
APCs.124 IL-12
stimulates the development of CD4+ Th1 lymphocytes and inhibits the
development of CD4+ Th2 lymphocytes. By inhibiting IL-12,
1,25(OH)2D3 shifts the immune response away from
a Th1 and toward a Th2 profile. Finally,
1,25(OH)2D3 stimulates DC production of the
immunosuppressive cytokine IL-10, which antagonizes the Th1 driving effects of
IL-12.130 These
observations provide a rationale for use of vitamin D and its analogs in the
prevention and treatment of autoimmune disease.
Autoimmune Disease
Autoimmune diseases occur because of an inappropriate immune-mediated
attack against self-tissue, resulting in tissue injury and disease. Both
environmental and genetic factors play a vital role in disease development.
Vitamin D availability via sun exposure or diet may contribute to the
development of both MS and IBD. In support of this view, vitamin D and
signaling through the VDR have been shown in mice to dictate the outcome of
experimental MS and IBD. Vitamin D seems to regulate T-cell development and
function, which may influence the outcome of the immune response either toward
or away from
autoimmunity.131,132
For example, in the absence of vitamin D and signals delivered through the
VDR, autoreactive T cells develop, whereas in the presence of active
1,25(OH)2D3 and a functional VDR, the balance in
the T-cell response is restored and autoimmunity
avoided.133
Vitamin D from sunlight exposure is lower in areas where IBD occurs most
often, as IBD is most prevalent in northern climates such as North America and
Northern
Europe.134,135
Vitamin D deficiency is common in patients with IBD even when the disease is
in
remission.136,137
Why vitamin D deficiency occurs more frequently in IBD is unclear. It is
probably due to the combined effects of low vitamin D intake, malabsorption of
many nutrients including vitamin D, and decreased outdoor activities in
climates that are not optimal for vitamin D synthesis in the skin.
The strongest evidence that the VDR and its ligand have important roles in
the pathogenesis of IBD comes from studies in mouse models. IL-10 knockout
mice, model for the Crohn's disease form of IBD, spontaneously develop
enterocolitis within 5–8 weeks of birth due to an uncontrolled immune
response to resident intestinal flora in conventional animal
facilities.138
Approximately 30% of mice die subsequent to the development of severe anemia
and weight loss. By contrast, IL-10 knockout mice raised in pathogen-free
facilities develop a milder form of enterocolitis that does not result in
death. Experimental IBD is induced by TNF-- and IFN-secreting
Th1 cells. Th2 or T regulatory cells inhibit both the development and function
(cytokine secretion) of Th1 cells.
Cantorna123 was
the first to establish an experimental link between vitamin D status and IBD.
The author showed that vitamin D deficiency exacerbates the symptoms of
enterocolitis and increases morbidity and mortality in IL-10 knockout mice,
whereas supplementation with vitamin D ameliorates IBD symptoms, reduces
inflammation, and improves histologic scores and
mortality.123 They
noted that 100% of the vitamin D–deficient IL-10 KO mice expressed
symptoms of IBD (diarrhea, rectal bleeding) and 60% died before 9 weeks of age
from complications of severe IBD. In contrast, vitamin D–sufficient mice
showed no outward symptoms of IBD at the same time
point.134
Supporting the vitamin D deficiency data, mice that are both IL-10 and VDR
deficient (double VDR/IL-10 KO) develop a fulminating form of experimental IBD
that leads to 100% mortality by 7 weeks of
age.123
Interestingly, the severity of IBD in the VDR/IL-10 knockout mice is the same
regardless of whether or not disease-causing microorganisms are present in the
colony. Both vitamin D deficiency and VDR deficiency render experimental IBD
more severe. These observations provide strong evidence that establishes
vitamin D and VDR as a physiologic regulator of intestinal inflammation in
IBD. The accumulating evidence for the immunomodulatory effects of VDR ligands
certainly provides a rationale for further investigation of their potential in
the treatment of IBD. A schematic depicting the potential role of vitamin D in
Crohn's disease is shown in Figure
5.
View larger version (31K):
[in this window]
[in a new window]
|
Figure 5. Potential role of vitamin D in Crohn's disease. In Crohn's disease,
bacterial antigens drive antigen-presenting cells (DCs) to produce cytokines
such as interleukin-12 (IL-12) which drive a T-helper 1 (Th1) proinflammatory
response to induce macrophages, which produce TNF and neutrophil
chemoattractive agents, ultimately resulting in the production of noxious
agents and tissue injury. The damaged intestinal tissue is more permeable to
antigens that drive the vicious cycle of antigen-presentation, local immune
activation, and tissue injury. Anti-inflammatory cytokines such as
interleukin-10 (IL-10), made by regulatory T cells (T regs), anatagonize Th1
proinflammatory processes by stimulating T-helper 2 function. Vitamin D
anatagonizes Th1 proinflammatory responses by interfering with antigen
presentation and Th1 activation, up-regulating Th2 cytokines and
down-regulating NF B in macrophages. Ag, antigen; IFN, interferon; IL,
interleukin; TNF, tumor necrosis factor.
|
|
A large epidemiologic study showed an inverse relationship between vitamin
D status and the development of MS. The study showed that women with the
highest vitamin D intakes (including supplements) had a 40% reduction in the
risk of developing
disease.139 Like
IBD, vitamin D deficiency is common in patients with
MS.122 The cause
of low vitamin D levels in MS patients is also likely to be due to a
combination of low vitamin intakes and decreased outdoor activities in
climates that are not optimal for vitamin D synthesis in the skin. In
vivo, the immune targets of vitamin D have been defined primarily in
Th1-driven autoimmune diseases. Vitamin D deficiency accelerates the
development of experimental MS and type-1
diabetes.139–142
Conversely, 1,25(OH)2D3 treatment suppressed the
development of these Th1-mediated autoimmune
diseases.143 In
addition, 1,25(OH)2D3 treatment of mice with
ongoing MS symptoms halted the disease progression in these mice, showing that
vitamin D altered the immune response even after the disease had been
established. 1,25(OH)2D3 has been shown to
inhibit Th1-driven responses in a number of different
models.142
Vitamin D may also play a role in preventing type I diabetes mellitus.
Autoimmune type 1 diabetes can be prevented in nonobese diabetic mice by
1,25(OH)2D3 and its
analogs.144,145
Treatment of NOD mice from weaning until old age not only prevented clinical
diabetes, it also prevented the histologic lesion
insulitis.146 In
this model of autoimmune diabetes, up-regulation of regulatory immune cells
and a shift from Th1 toward Th2 lymphocytes locally in the pancreases of
treated mice can be observed. This protective Th2 population is induced not
only at the site of the β cell attack but also in the peripheral immune
system.147 After
immunization of 1,25(OH)2D3-treated NOD mice with
a diabetes-specific autoantigen (a peptide of GAD65), lymphocytes of the
draining lymph nodes showed an increased IL-4 and decreased IFN
production in vitro and in vivo. Strikingly, this immune
deviation induced by 1,25(OH)2D3 is limited to
pancreatic autoantigens and could not be seen after immunization with the
β cell-irrelevant protein ovalbumin.
Other effects on the immune system of NOD mice have been described, the
most important being a restoration of the defective apoptosis sensitivity of
lymphocytes, leading to a more efficient elimination of potentially dangerous
autoimmune effector
cells.148 This
increased apoptosis induced by 1,25(OH)2D3 and
its analogs in DCs and T lymphocytes of NOD mice has been described after
treatment with different apoptosis-inducing signals, such as corticosteroids,
and could help to explain why an early short-term treatment with these agents,
before onset of autoimmunity, confers long-term protection and promotes
tolerance restoration.
Besides preventing the onset of autoimmune diseases,
1,25(OH)2D3 and its analogs are also able to
treat ongoing autoimmune diseases. Treatment of NOD mice with analogs of
1,25(OH)2D3 can prevent the progression of an
initial β cell attack (reflected by the presence of insulitis) to
clinical overt
diabetes.149
Interestingly, in this model of ongoing autoimmune destruction, no induction
of suppressor cells by 1,25(OH)2D3 could be
demonstrated. Nevertheless, within the pancreases of protected mice, again a
shift from Th1 toward Th2 cytokines is noted. Further, analogs of
1,25(OH)2D3 are able to inhibit the recurrence of
autoimmune diabetes after syngeneic islet transplantation in NOD
mice.150,151
Development of noncalcemic vitamin D analogs could permit sustained
systemic administration without causing significant hypercalcemia, thus
allowing wider clinical applications in the future. Vitamin D supplementation,
which is an inexpensive and efficient way to prevent vitamin D deficiency,
might also help reduce the risk of autoimmune disease.
|
VDR Polymorphisms and Disease
|
|---|
Most of the biologic activities of 1,25(OH)2D3
are mediated by a high-affinity receptor that acts as a ligand-activated
transcription factor. The major steps involved in the control of gene
transcription by the VDR include ligand binding, heterodimerization with
retinoid X receptor (RXR), binding of the heterodimer to VDREs, and
recruitment of other nuclear proteins into the transcriptional preinitiation
complex. Thus, genetic alterations of the VDR gene could lead to important
defects on gene activation, affecting calcium metabolism, cell proliferation,
and immune function. For example, VDR gene mutations cause vitamin
D–resistant rickets, a rare monogenetic
disease.152 A
polymorphism is a genetic variant that appears in at least 1% of the
population. These changes can occur in noncoding parts of the gene (introns),
so they would not be seen in the protein product. Changes in these regulatory
parts of the gene would then affect the degree of expression of the gene and
thus the levels of the protein. The discovery of genetic variants linked with
susceptibility of diseases can be the key to advances in preventive medicine.
In general, association studies can be used to test whether a polymorphism
occurs more frequently in the cases studied than in the controls. If a
relationship with the disease emerges from association studies, this finding
would strongly support the idea that the candidate gene is in some way
involved in the disease. The diseases associated with VDR polymorphisms are
summarized in Table
7.153
Carling et
al154 reported a
relationship between the BsmI polymorphism and primary
hyperparathyroidism. Recently, 2 meta-analyses performed by Thakkinstian et
al155,156
demonstrated a positive association between the b allele and bone
mass density. Furthermore, it was shown that the haplotypes Bat and
BAt were significantly associated with osteoporosis.
An association has been described between VDR polymorphisms and
susceptibility to and outcome of some cancers, like breast, prostate, and
colon cancers. In 1997, Ingles et
al157 published
one of the first reports finding a relationship between the polyA polymorphism
of the VDR gene and prostate cancer in the US population. Taylor et
al158 showed the
relationship between the TaqI polymorphism and an increased risk of
prostate cancer, whereas the restriction site (tt) was associated
with a lower risk with higher levels of
1,25(OH)2D3.159
However, other investigators found no association between TaqI or
polyA and prostate
cancer.160–162
In the case of other VDR polymorphisms (FokI, BsmI),
conflicting results can be found as
well.159,162–165
In addition, a recent meta-analysis of 28 different studies was performed, and
no relationship was found between any of the former VDR polymorphisms and
prostate cancer
susceptibility.166
As with prostate cancer, conflicting results have been reported regarding
the possible relationship between breast cancer and VDR polymorphisms. The
majority of the reports present in the literature found no relationship
between the risk of breast cancer and TaqI polymorphism, but some of
them presented a link between TaqI polymorphism and risk of
metastases.167–171
The BsmI shows an opposite pattern, with a relationship detected
in 3
reports.172–174
In the case of FokI the consensus is higher, and most of the reports
showed no association with increased risk of breast
cancer.171,173,174
To date, studies investigating the relationship between polyA or
ApaI170,171
and the risk of breast cancer showed a link between these VDR polymorphisms
and the possibility of presenting a tumor. The number of papers analyzing VDR
polymorphisms in other cancer types is significantly lower. Regarding colon
carcinoma, there are reports showing an association with BsmI
polymorphism,175,176
whereas conflicting results are found regarding
FokI.177,178
VDR polymorphisms have been described in a number of autoimmune diseases. A
positive relationship between the B allele of the BsmI
polymorphism and a lack of a relationship between the FokI
polymorphism and the incidence of systemic lupus erythematosus has been
observed.179–181
In the case of Crohn's disease, a link has been suggested between the
TaqI, ApaI and FokI polymorphisms and disease
susceptibility.182
Furthermore, a link between BsmI and FokI with primary
biliary cirrhosis and autoimmune hepatitis has also been
found.183,184
In MS patients, a higher presence of the bA haplotype has been
detected,185,186
whereas
TaqI187
and
FokI188
polymorphisms were observed.
In summary, a vast amount of information has been collected through the
years regarding the association of vitamin D polymorphisms with susceptibility
to contract different diseases. Unfortunately, the results obtained so far are
conflicting, and the role of VDR polymorphisms remains obscure. Therefore, the
use of VDR polymorphisms as diagnostic tools, or even as markers for a higher
propensity toward some diseases, is still a matter of debate.
|
Recommendations and Conclusion
|
|---|
Vitamin D deficiency is a common clinical problem in the United
States.189–194
Because most patients with mild deficiency are asymptomatic, physicians should
have a high index of suspicion in populations at highest risk for deficiency.
Identification and treatment of patients with vitamin D deficiency are
important for optimal bone development and muscle strength. The major source
of vitamin D for both children and adults comes from reasonable sun exposure.
In the absence of sun exposure, most experts now agree that 1000 IU of vitamin
D is needed daily in the absence of sun exposure to maintain a healthy blood
level of 25(OH)D of between 75 and 125 nmol/L (30–50
ng/mL).194–200
However, vitamin D supplementation is not widely practiced and most
supplements only contain 400 IU of vitamin D. As reviewed in this manuscript,
in addition to bone health, there is mounting scientific evidence that
implicates vitamin D deficiency with an increased risk of autoimmune disease
and many common deadly cancers. Children over the age of 1 year and all adults
should receive 1000 IU of vitamin D per day, or have judicious sun exposure to
satisfy their vitamin D requirement. Measurement of 25(OH)D should be
encouraged. The risks and potential benefits of vitamin D supplementation
should be further studied for use in patients who either have or are at high
risk for breast, colon, and prostate cancer and autoimmune diseases.
The authors acknowledge Kerry Schulze, PhD, Johns Hopkins School of Public
Health, Department of Human Nutrition, and Susan Kreimer, MS, a freelance
medical writer in New York, for their editorial contributions. The work was
supported in part by grant number AT00437 from the National Center for
Complementary & Alternative Medicine of the National Institutes of Health
(Adrian S. Dobs, MD, MHS, principal investigator).
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305-322 (2007)
DOI: 10.1177/0115426507022003305
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