Beneficial role of Vitamin D in common cancers: Is the evidence compelling enough?

Abstract

Vitamin D is a fat-soluble vitamin having well known effects on bone health and calcium homeostasis. Vitamin D3 (cholecalciferol) is the chemical form of vitamin D in humans, synthesized from photochemical conversion of 7-dehydrocholesterol in the skin. It is activated by hydroxylation in the liver and kidney to form 1,25-dihydroxyvitamin D3 (calcitriol), which exerts its biochemical and physiological effects through the vitamin D receptor (VDR). In addition to maintenance of skeletal mineral balance, vitamin D has multiple other roles in the body including regulation of cell cycle, cellular differentiation and immune functions, neuroprotection, antioxidant action, xenobiotic metabolism as well as antimicrobial, anti-inflammatory and antitumor effects. Vitamin D is involved in the expression of several genes having oncogenic potential. The anti-cancer effects of vitamin D are mediated via its stimulation of apoptosis and cell differentiation and inhibition of invasion, metastasis and angiogenesis.

In the last two decades, numerous studies have addressed the potential of vitamin D in curtailing development and progression of multiple malignancies and/or improving their prognosis. Most of the data accumulated over this time has linked lack of exposure to sunlight and deficiency of vitamin D to an increased risk of several cancer types but a few studies have yielded conflicting results particularly on the therapeutic role of vitamin D supplementation. Recent findings have provided detailed insights into the mechanism of anti-cancer actions of vitamin D. Disruption of the VDR signalling pathway at multiple levels seems to be at the core of oncologic transformation in various types of cancers. Based on the available mechanistic evidence, future research trials using novel pharmacological interventions targeting the vitamin D pathway need to be instituted in order to derive conclusive clinical recommendations. At present, adequacy of vitamin D status appears to be a pertinent factor in mitigating the risk of cancer development, thus maintenance of vitamin D levels through appropriate sun exposure and dietary intake is advisable.

Full text

1
BENEFICIAL ROLE OF VITAMIN D
IN COMMON CANCERS:
IS THE EVIDENCE COMPELLING ENOUGH?
WCRJ 2020; 7: e1574
Corresponding Author: Syed Imran Ali Shah, PhD; e-mail: s.shah10@alumni.imperial.ac.uk
Abst ract – Vitamin D is a fat-soluble vitamin having well known effects on bone health and
calcium homeostasis. Vitamin D3 (cholecalciferol) is the chemical form of vitamin D in humans,
synthesized from photochemical conversion of 7-dehydrocholesterol in the skin. It is activated by
hydroxylation in the liver and kidney to form 1,25-dihydroxyvitamin D3 (calcitriol), which exerts its
biochemical and physiological effects through the vitamin D receptor (VDR). In addition to main-
tenance of skeletal mineral balance, vitamin D has multiple other roles in the body including reg-
ulation of cell cycle, cellular differentiation and immune functions, neuroprotection, antioxidant
action, xenobiotic metabolism as well as antimicrobial, anti-inflammatory and antitumor effects.
Vitamin D is involved in the expression of several genes having oncogenic potential. The anti-can-
cer effects of vitamin D are mediated via its stimulation of apoptosis and cell differentiation and
inhibition of invasion, metastasis and angiogenesis.
In the last two decades, numerous studies have addressed the potential of vitamin D in cur-
tailing development and progression of multiple malignancies and/or improving their prognosis.
Most of the data accumulated over this time has linked lack of exposure to sunlight and deficiency
of vitamin D to an increased risk of several cancer types but a few studies have yielded conflicting
results particularly on the therapeutic role of vitamin D supplementation. Recent findings have
provided detailed insights into the mechanism of anti-cancer actions of vitamin D. Disruption of
the VDR signalling pathway at multiple levels seems to be at the core of oncologic transformation
in various types of cancers. Based on the available mechanistic evidence, future research trials us-
ing novel pharmacological interventions targeting the vitamin D pathway need to be instituted
in order to derive conclusive clinical recommendations. At present, adequacy of vitamin D status
appears to be a pertinent factor in mitigating the risk of cancer development, thus maintenance of
vitamin D levels through appropriate sun exposure and dietary intake is advisable.
KEYWORDS: Vitamin D, Anti-cancer, Supplementation, Hypovitaminosis D.
Department of Biochemistry, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia.
S. IMRAN ALI SHAH
INTRODUCTION
The Nobel Prize winning chemist Adolf Windaus
discovered vitamin D which was subsequently iden-
tied as a remedy for prevention and reversal of the
bone disease rickets1. Vitamin D is a fat-soluble sec-
osterol occurring in two principal forms, vitamin
D2 (ergocalciferol) and vitamin D3 (cholecalciferol),
of which vitamin D3 is the prohormone having mul-
tiple roles in human physiology. The predominant
source of vitamin D3 is ultraviolet radiation-in-
duced photochemical conversion of its precursor
7-dehydrocholestrol in the skin2. Vitamin D3 is bi-
ologically inert and two successive hepatic and re-
nal hydroxylation steps produce its active hormonal
form 1,25-dihydroxyvitam in D3, also known as cal-
citriol. 25-hydroxyvitamin D3, or calcidiol, formed
after hydroxylation of vitamin D3 in the liver is the
serum marker typically employed for estimation of
vitamin D status in routine clinical practice2. 85-
90% of circulating 25-hydroxyvitamin D3 is tightly
bound to vitamin D-binding protein (DBP), 10-15%
is loosely bound to albumin and less than 0.03% is
free3. Vitamin D plays pivotal roles in skeletal min-

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BENEFICIAL ROLE OF VITAMIN D IN COMMON CANCERS: IS THE EVIDENCE COMPELLING ENOUGH?
SKIN CANCER
Skin is the primary tissue involved in the metabo-
lism of vitamin D. Vitamin D synthesis in the skin
is dependent upon ultraviolet exposure. However,
exposure to the sun is also known to predispose to
skin cancer as evident from geographical variations
in incidence and a higher risk in fair-skinned peo-
ple12. Skin cancer, including both melanoma and
non-melanoma, is one of the most common type of
malignancies13, 14 . In vitro studies have shown an in-
hibitory role of vitamin D in the development of sev-
eral skin cancer types including melanoma, basal
cell carcinoma and squamous cell carcinoma. Dis-
ruption of molecular signalling pathways involving
vitamin D and calcium receptors has been linked to
epidermal tumorigenesis in murine models. Clini-
cal studies, however, have yielded inconsistent re-
sults with some showing lower vitamin D levels as
a risk factor for skin cancer, while others suggesting
the opposite15-17. Eid et al18 showed increased base-
line serum vitamin D levels to be associated with
an elevated risk of non-melanoma skin cancer but
ultraviolet exposure was stated to be a potentially
strong confounder. In another study, increased inci-
dence of basal cell carcinoma and melanoma and a
non-statistically signicant decreased incidence of
squamous cell carcinoma was observed with high
baseline serum vitamin D levels19. These conicting
observations suggest a role of complex factors in-
cluding ultraviolet sun exposure and skin color.
Data generated from a meta-analysis evalu-
ating the association of blood vitamin D levels
and dietary intake with the risk of melanoma and
non-melanoma skin cancers suggested an inverse
association between circulating vitamin D and mel-
anoma thickness at the time of diagnosis but dietary
or supplemental vitamin D was not associated with
the incidence of skin cancer20. Another large Amer-
ican study by Park et al21 did not nd a protective
eral homeostasis, including intestinal absorption of
calcium and phosphate, skeletal mobilization of cal-
cium and renal reabsorption of calcium4. Vitamin D
is also involved in several noncalcemic extraskeletal
functions in the body including cellular prolifera-
tion and differentiation, immunomodulation, neu-
roprotection, antioxidant defense, xenobiotic de-
toxication, antimicrobial, anti-inammatory and
anticancer actions (Figure 1) 2,5.
The effects of vitamin D are exerted through a
single vitamin D receptor (VDR), which is a member
of the class II steroid hormones. It has a C-domain
(DNA-binding), an E-domain (ligand-binding), and
an F-domain, which is one of the activating domains6.
Calcitriol (activated vitamin D) binds to VDR in the
cytosol forming a dimer that gets translocated into the
nucleus. The nuclear retinoid X receptor (RXR) binds
to the calcitriol-VDR dimer and then the complex trig-
gers gene expression by binding to the vitamin D re-
sponsive element (VDRE) (Figu re 2). Vitamin D regu-
lates the expression of nearly two hundred genes, some
of which are implicated in oncogenic mechanisms.
Vitamin D exerts antineoplastic effects by inducing
cell differentiation, promoting apoptosis, decreasing
angiogenesis, preventing invasion and inhibiting me-
tastasis. Additionally, the gene for CYP24A1, the pri-
mary enzyme for the metabolic degradation of active
Vitamin D3, is considered a putative oncogene7, 8.
Numerous studies have attempted to explore
the role of vitamin D in oncological transforma-
tion. Low sunlight exposure and hypovitaminosis
D have been linked, albeit somewhat inconsistently,
with the increased risk of cancers through scientic
evidence gathered over the past few decades9. Vita-
min D supplementation, in particular, has yielded
variable results across different types of cancers10,
11. The current review summarizes the recent work
on the antitumor potential of vitamin D in common
malignancies including skin, lung, breast, prostate,
colorectal and hepatocellular cancers.
Fig. 1. Functions of activated vitamin D (calcitriol)
signalling pathway.

3
BENEFICIAL ROLE OF VITAMIN D IN COMMON CANCERS: IS THE EVIDENCE COMPELLING ENOUGH?
It was further revealed that non-smokers had higher
vitamin D levels, which correlated negatively with
lung cancer risk. Dietary vitamin D intake was as-
sociated with a reduced risk reduction for non-small
cell lung cancer In a case-control study25.
A dose-response meta-analysis of prospective
cohort studies reported a signicant association be-
tween circulating vitamin D and lung cancer risk
and mortality, but serum vitamin D was not associ-
ated with overall lung cancer survival. It was further
shown that an increase of 10nmol/L in the circulat-
ing vitamin D levels led to 8% and 7% reduction in
the risk of lung cancer and lung cancer mortality
respectively26. Recent ndings from a randomized
double-blind trial of patients with non-small cell lung
cancer comparing vitamin D supplements (1,200 IU/
day) with placebo over a one year period suggested
improvement in survival of patients with lower vita-
min D levels receiving vitamin D supplementation27.
The current evidence suggests that high intake and
high serum levels of vitamin D may lower the risk of
lung cancer risk and improve prognosis, but further
studies are needed to illustrate the preventative poten-
tial of vitamin D supplementation in lung cancer.
BREAST CANCER
Breast cancer is the most common malignant tumor
in women and dietary factors are thought to exert
inuence in more than one-third of the diagnosed
females13, 14. Dietary measures such as reduction
in the consumption of alcohol, red meat and fats
role of oral vitamin D on cutaneous carcinogenesis.
In their prospective study assessing the association
of vitamin D intake with the risk of skin cancer,
vitamin D intake was shown to be associated with
increased risk of basal cell carcinoma, but no asso-
ciations were found with melanoma and squamous
cell carcinoma. A delicate equilibrium of intricate
factors like sun exposure, vitamin D levels and skin
color appears to determine vulnerability to skin car-
cinogenesis. The complexity of the relationship be-
tween these factors warrants more studies to derive
unambiguous clinical recommendations regarding
the role of vitamin D in skin cancer.
LUNG CANCER
Lung cancer is a major malignancy with a high dis-
ease burden, causing more than a million deaths
worldwide every year13, 14. The role of vitamin D in
lung carcinoma has been recognized relatively re-
cently. In a Czech study assessing serum vitamin D
levels in multiple cancer groups, very low vitamin
D levels were observed in patients with lung can-
cer22. Zhang et al23 showed an inverse association
between serum vitamin D and lung cancer risk. In
a meta-analysis by Liu et al24, an inverse correlation
was shown between overall risk of lung cancer and
high vitamin D (or calcium) intake and serum vita-
min D levels individually. High serum levels were
also shown to reduce lung cancer mortality while a
positive trend was observed in the relationship be-
tween serum vitamin D concentration and survival.
Fig. 2. Mechanism of action of vitamin D. Calcitriol, being lipid-soluble, enters the cell and binds to vitamin D receptor (VDR)
in the cytosol. The calcit riol-VDR dimer is translocate d into the nucleus where nucle ar retinoid X receptor (RXR) binds to it. The
resulting complex activates gene expression by binding to vitamin D responsive element (VDRE).

4
BENEFICIAL ROLE OF VITAMIN D IN COMMON CANCERS: IS THE EVIDENCE COMPELLING ENOUGH?
association of low levels of vitamin D with a high
risk of prostate tumors for the rst time, based on
the observations of reduced PC mortality rates in
patients with more ultraviolet light exposure35. Nu-
merous studies have since been conducted eval-
uating vitamin D deciency, either due to dietary
insufciency or low ultraviolet exposure, as a risk
factor for PC36. While most of these studies have
implicated low circulating vitamin D levels in the
progression of PC, a few have borne controversial
results. Vitamin D supplementation has been shown
to confer a benecial impact on patients with low-
risk PC under active surveillance37. However, cal-
cium- rich diets have been linked to accelerated
progression of early stage PC. The opposing roles
for calcium and vitamin D in the development, pro-
gression and prognosis of PC suggest a complex in-
terplay between these nutrients38. Results from a re-
cent meta-analysis indicated a reduction in all-cause
mortality and PC-specic mortality in patients with
higher circulating vitamin D levels39. A systemic re-
view of randomized clinical trials by Petrou et al40
suggested dose-dependent clinical benets of vita-
min D supplementation in combination with stan-
dard cancer-specic therapies. Vitamin D supple-
mentation in PC has been shown to positively alter
the redox status with potential to improve disease
outcomes. However, an undesirable accumulation
of metal ions in the erythrocytes of PC patients has
also been documented which may affect the cancer
outcomes in an adverse manner41.
Therapeutic activation of vitamin D signalling,
either by vitamin D alone or in combination with
other antineoplastic agents, seems to be a plau-
sible prevention strategy but the available data do
not provide conclusive information42. Furthermore,
considering the androgen-dependent nature of PC,
it is highly pertinent to evaluate the role of testos-
terone signalling as an intermediate mechanism in
the relationship between vitamin D and PC pro-
gression43. Existing data support the need to further
demonstrate the mechanistic and therapeutic roles
of vitamin D in the pathogenesis of PC.
COLORECTAL CANCER
Colorectal cancer (CRC) is a common malignant
neoplasm and one of the leading causes of cancer re-
lated mortality the world over13,14 . Garland and Gar-
land proposed a protective role of vitamin D against
CRC in 1980 and numerous studies conducted since
then have suggested that higher circulating vitamin
D levels lower the risk of CRC44, 45. Hypovitaminosis
D is common in patients with newly diagnosed CRC.
Furthermore, chemotherapy and surgical resection of
CRC have also been shown to induce fall in serum
along with increase in the intake of vitamin D and
bre have been highlighted as potentially bene-
cial in reducing the risk of breast cancer28. VDR
found in breast epithelial cells, plays physiological
roles in the mammary gland during milk produc-
tion through regulation of calcium transport and
hormone differentiation29. Several vitamin D-re-
sponsive targets have been identied in cancerous
mammary cells through genomic proling includ-
ing the role of VDR signalling in modulation of
cell cycle events, cell differentiation and apoptosis
as well as regulation of metabolic and immune ef-
fects inuencing tumor microenvironment30. Sup-
pression of CYP24A1 gene, the enzyme product
of which causes catabolic inactivation of vitamin
D in target tissues, enhances apoptosis and inhib-
its growth in breast cancer cells by increasing the
bioavailability of active vitamin D31. Huss et al32
evaluated the covariation between expression of
VDR and prognostic factors of breast cancer in a
tissue microarray of invasive breast tumors. Both
intranuclear and cytoplasmic expression of VDR
in breast cancer cells was positively associated
with favorable prognostic characteristics such as
lower grade, smaller tumor size and positive estro-
gen and progesterone receptor expression. Positive
VDR expression was also associated with a low
risk of breast cancer deaths.
Data from most observational and epidemiologic
studies are supportive of an inverse relationship be-
tween serum vitamin D levels and the risk of breast
cancer risk29. A high incidence of hypovitamin-
osis D has been shown in breast cancer patients22.
A systematic review by Estebanez at al33 . showed
a protective effect of serum vitamin D on breast
cancer in premenopausal women. However, no as-
sociation was found between vitamin D intake and
the development of breast cancer. Pooled ndings
from a recent meta-analysis of observational studies
suggested a direct association between deciency of
circulating vitamin D and breast cancer while total
and supplemental vitamin D intake had an inverse
relationship with breast cancer34. Further research
employing the latest genomic, proteomic and me-
tabolomic techniques is required to elucidate the
possible protective mechanisms of action of vitamin
D against breast cancer development. Clinical trials
designed to denitively assess the association of vi-
tamin D levels and intake with the risk, recurrence
and survival in breast cancer are also warranted.
PROSTATE CANCER
Prostate cancer (PC) is a major malignancy afict-
ing men and one of the leading causes of cancer
mortality worldwide13, 14. A study reported that the

5
BENEFICIAL ROLE OF VITAMIN D IN COMMON CANCERS: IS THE EVIDENCE COMPELLING ENOUGH?
HEPATOCELLULAR CARCINOMA
Hepatocellular carcinoma (HCC) is the primary liv-
er malignancy, accounting for more than 80% of all
patients with liver cancer. It is one of the most com-
mon cancers globally and despite the recent advance-
ments in treatment modalities, HCC is a major cause
of cancer related mortality due to its poor prognosis13,
14. Associat ion of vitamin D and HCC has been a sub-
ject of investigation for quite some time now but the
evidence garnered remains unclear56 ,57.
A recent cross-sectional study reported vitamin
D deciency, decreased VDR levels and downreg-
ulation of autophagy and host-mediated apoptosis
in HCC patients with hepatitis C viral infection,
suggesting a role of VDR axis in the development
of HCC related to viral hepatitis58. Buonomo et al59
reported hypovitaminosis D to be common in HCC
patients with a negative impact on the overall sur-
vival of patients with liver cirrhosis regardless of
the presence of HCC. In another study, higher se-
rum levels of bioavailable vitamin D (free and al-
bumin-bound fractions only), rather than total cir-
culating vitamin D, were shown to be associated
with improved survival in HCC60. Wu at al61 have
recently demonstrated that vitamin D deciency at
baseline is associated with poor tumor response in
patients receiving transarterial chemoembolization
(TACE) as rst-line therapy for advanced HCC.
Vitamin D has been shown to enhance the an-
titumor activity of 5-Fluorouracil and improve liv-
er function in a rat model of HCC by modulating
the expression of transforming growth factor beta
1 (TGF-β1), caspase-3, and nuclear factor erythroid
2-related factor 2 (NrF2)62. Another study has shown
vitamin D to be able to re-sensitize HCC cell lines
resistant to treatment with everolimus, an inhibitor
of mechanistic target of rapamycin (mTOR). Vita-
min D reverses resistance to everolimus by upregu-
lation of miR-375 and consequent down-regulation
of several oncogenes responsible for drug resistance
and epithelial mesenchymal transition in HCC63.
Genomic analysis has demonstrated association
between the single nucleotide polymorphism of
VDR gene at FokI locus and increased susceptibili-
ty of HCC in patients with chronic hepatitis B infec-
tion. The polymorphism is also useful in evaluating
the severity of HCC through its association with its
clinicopathological characteristics6 4,65. Conversely,
CYP2R1 poly morphism responsible for higher vita-
min D levels, has been associated with progression
to HCC in patients infected with hepatitis C virus66.
Recent biochemical, genomic, animal and clinical
data have highlighted the involvement of vitamin D
pathway in the pathogenesis and prognosis of HCC in
various clinical contexts. Therapeutic regimens com-
prising of vitamin D analogues in combination with
vitamin D concentration46, 47. A systematic review
of epidemiological studies assessing serum vitamin
D concentration and the risk for CRC reported an
inverse relation between the two48. A recent pooled
analysis by McCullough et al49 showed higher serum
vitamin D levels to be associated with a marked re-
duction in CRC risk in women. A lower risk was also
observed for men, but it was not statistically signi-
cant.
Mechanistic studies have shown that cal-
citriol, the active metabolite of vitamin D, mediates
a range of potential protective effects against CRC
through the VDR. These include suppressing pro-
liferation and promoting differentiation of cancer
cells, modulating immune cell function, inhibiting
gene expression and tumorigenic actions of can-
cer-associated broblasts and altering intestinal o-
ra50. In a recent analysis by Fedriko et al51, genomic
variants in the vitamin D signalling and their altered
transcriptional activity depending on the serum vi-
tamin levels were suggested to be associated with
colorectal tumorigenesis. Another genetic study
of VDR polymorphisms showed certain polymor-
phisms to be correlated with serum vitamin D and
calcium concentration in patients with CRC, there-
by suggesting a role of vitamin D in the onset of
CRC. Homozygous genotype (aa) of the rs7975232
VDR single nucleotide polymorphism was found
associated with serum vitamin D levels in CRC
patients and the heterozygous genotype (Tt) of the
rs731236VDR single nucleotide polymorphism cor-
related with serum Ca levels52. Low serum levels of
vitamin D were shown to be associated with poor-
er survival in CRC patients, particularly those with
homozygous genotype (GG) of the rs11568820 VDR
single nucleotide polymorphism47.
Recently, high-dose vitamin D was shown to
improve clinical outcomes in patients with meta-
static CRC receiving standard chemotherapy53. An
Iranian study also showed a reduced risk of CRC
with dietary vitamin D, but no such association
was observed with calcium intake54. Previously,
a meta-analysis of randomized controlled trials of
vitamin D supplementation and the incidence and
mortality of CRC showed vitamin D supplementa-
tion to be benecial in terms of reducing the risk of
mortality only55.
Epidemiologic evidence accrued over the years
is suggestive of a protective effect of vitamin D on
CRC, but supplementation does not seem to provide
benet as would be expected, particularly in terms
of reduction in the incidence of CRC. Randomised
trials of vitamin D supplementation designed to ac-
count for confounding factors like sun exposure,
seasonal inuences, skin color and dietary intake
are required to determine the preventative and ther-
apeutic potential of vitamin D in CRC.

6
minosis D has been highlighted as a risk factor for
multiple cancer types, but its therapeutic potential
has generated mixed results. The recent emergence
of biochemical and genomic evidence points to dis-
turbances in the vitamin D signalling pathway as
one of the reasons for oncogenic change. Future
work should be aimed at elaboration of these molec-
ular mechanisms of vitamin D which are likely to
offer clinically useful insights. Based on the existing
knowledge, it is reasonable to suggest maintenance
of serum vitamin D levels within normal range to
extract potential anti-cancer benets of vitamin D.
Acknowledgments
We are grateful to Dr. Farhan Alswailmy, Dean of the Col-
lege of Pharmacy, and the Deanship of Scientic Research
at University of Hafr AlBatin for supporting this work.
conflict of interest:
The authors declare no conict of interest.
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Vitamin D has been studied in various other common
cancers owing to its involvement in multiple cellular
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serum levels of vitamin D following supplementation
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does not seem to improve progression-free survival in
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D levels are associated with decreased risk of head
and neck cancers and improved survival. Inade-
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the risk of mortality and recurrence in patients with
head and neck cancers. Vitamin D has the potential
to serve as an adjuvant to traditional chemothera-
peutic agents for head and neck malignancies, lend-
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responses for improving prognosis80-83.
CONCLUSIONS
The role of vitamin D in prevention of neoplastic
transformation and progression has been debated
extensively for over two decades now. Hypovita-

7
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