Journal of Microscopy and Ultrastructure 2 (2014) 1–6
Contents lists available at ScienceDirect
Journal of Microscopy and Ultrastructure
journal homepage: www.elsevier.com/locate/jmau
Review
Chemopreventive role of vitamin D in colorectal carcinoma
Salman Yousuf Guraya ∗
College of Medicine Taibah University, Almadinah Almunawwarah, Saudi Arabia
a r t i c l e
i n f o
Article history:
Received 12 September 2013
Received in revised form
25 September 2013
Accepted 25 September 2013
Available online 13 October 2013
Keywords:
Vitamin D
Colorectal carcinoma
25(OH)D
Apoptosis
Calcitriol
a b s t r a c t
Historically, the predominant function of vitamin D is well recognized in calcium and phosphate homeostasis. Recently, plenty of observational and epidemiological studies have
suggested the pro-active role of vitamin D in colorectal, prostate, breast, ovarian, and skin
cancers. The protective role of vitamin D against cancer has been attributed to its influence
on cell proliferation, differentiation, apoptosis, DNA repair mechanisms, and inflammation
and immune function. Latest research has identified that vitamin D exerts antiproliferative and prodifferentiating effects in many malignant cells, and inhibits the proliferation of
malignant cells in animal models raising the possibility of its therapeutic application as an
anticancer agent. The developed genomic models of vitamin D receptors clearly illustrate
the anti-cancer effects of Vitamin D but till date, the simultaneous hypercalcemic effect of
vitamin D could not be removed from these analogs. This review presents various dimensions of anti-cancer actions of vitamin D by elaborating its lead role in preventing colorectal
carcinoma, and sets future goals for establishing its therapeutic actions.
© 2013 Saudi Society of Microscopes. Published by Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Physiological role and metabolism of vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.
Dietary and supplemental vitamin D and colorectal carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.
Sunlight, vitamin D and colorectal carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4.
Genetic basis of colorectal carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Colorectal carcinoma and vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Colorectal adenomas and vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Anti-cancer roles of vitamin D in colorectal carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1.
Preventive role of vitamin D in colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2.
Therapeutic role of vitamin D in colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author. Tel.: +966 553375969; fax: +966 48461407.
E-mail addresses: drsyg7@yahoo.com, syousuf@taibahu.edu.sa
2213-879X/$ – see front matter © 2013 Saudi Society of Microscopes. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jmau.2013.09.001
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S.Y. Guraya / Journal of Microscopy and Ultrastructure 2 (2014) 1–6
1. Introduction
The relation between vitamin D status and colorectal cancer (CRC) risk has been coined since 1980 [1]
and researchers have investigated this hypothesis by
various means including direct measures of circulating 25-hydroxyvitamin D [25(OH)D] levels, surrogates or
determinants of 25(OH)D, covering region of residence,
intake, and sun exposure estimates, or a combination [2–4].
Most epidemiological studies have reported that higher
serum 25(OH)D levels are associated with lower incidence
rates of colon, breast, and ovarian cancers [5–9] and higher
25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] with
lower incidence rates of aggressive prostate cancer [10].
CRC is the fourth most common human malignant neoplasia worldwide, after lung, breast and prostate cancers,
estimating 1,000,000 new cases (9.4% of total cancer
cases) and 500,000 deaths annually [11]. The general incidence rates are higher in economically developed countries
of North America, Australia, Eastern Asia, and Western
Europe, whereas Africa, Latin America and Asia have a
lower incidence. The incidence of CRC in Kingdom of Saudi
Arabia is escalating with significant rightward shift demonstrating a higher prevalence of advanced lesions in young
patients [12]. This profound change in the trends and biological behavior of CRC may be associated with dietary and
environmental factors including suboptimal exposure to
sunlight and low dietary intake of vitamin D. The current
review extensively explores the carcinogenic effects of low
serum levels of vitamin D in the development of CRC and
illustrates its preventive role against CRC.
1.1. Physiological role and metabolism of vitamin D
The prohormone (cholecalciferol), derived from skin
or diet, is hydroxylated to 25-hydroxycholecalciferol
[25(OH)D3 ] by the hepatic 25-hydroxylase. Although
25(OH)D is the most abundant form of vitamin D in the
blood, it has limited capability to bind to the vitamin D
receptor (VDR) for its final action. Further hydroxylation by
1␣-hydroxylase (CYP27B1) to the main biologically active
hormone, 1␣,25-dihydroxycholecalciferol (1␣,25-(OH)2 D3
or calcitriol) takes place in the proximal renal tubule [13].
Sufficient renal production of 1␣,25-(OH)2 D3 leads to activation of the catabolic pathway by 24-hydroxylation of
1␣,25(OH)-D3 , or of 25(OH)-D3 . A major part of 25(OH)-D3
and of 1␣,25-(OH)2 -D3 is bound in plasma to a vitamin D
binding protein (DBP, 85–87%), which modulates bioavailability and influences responsiveness in some end-organs
or to albumin (12%).
1.2. Dietary and supplemental vitamin D and colorectal
carcinoma
The secosteroid hormone vitamin D can be obtained
from either nutritional origin or it can be produced
in the skin by a photochemical conversion of 7dehydrocholesterol to previtamin D and subsequently
to vitamin D under the influence of ultraviolet rays in
sunlight [14]. The evidence to date suggests that daily
intake of 1000–2000 IU/day of vitamin D3 could reduce
the incidence of CRC with minimal risk [15]. The Women’s
Health Initiative reported that a low dose of vitamin D
did not protect against colorectal cancer within 7 years of
follow-up; however, a meta-analysis indicates that a higher
dose may reduce its incidence [16].
Majority of the cohort studies explored the association
between CRC risk and dietary or supplementary vitamin D
in men [17,18] and women [19] or both sexes [16,20], and
several case–control studies [21–23] found inverse associations for colon or rectal cancer, or both [24]. Most of the
biological actions of 1␣,25(OH)2 D3 are transduced by VDR,
which is a member of the nuclear receptor superfamily
of ligand-dependent transcription factors. VDR specifically
acts as a heterodimer with retinoid X receptor by binding to specific genomic DNA sequences known as vitamin
D response elements, located at the regulatory regions of
target genes. The interaction of 1␣,25(OH)2 D3 with VDR
induces allosteric changes in its ligand-binding domain
and enables the recruitment of co-activators which induce
chromatin decondensation, RNA polymerase II recruitment
and transcriptional activation [25]. Although the main
physiological role of 1␣,25(OH)2 D3 is the control of calcium homeostasis, however, compelling epidemiological,
animal and molecular reports suggest unique regulatory
actions of vitamin D in preventing a wide range of cancers
including CRC.
1.3. Sunlight, vitamin D and colorectal carcinoma
The geographic distribution of CRC deaths has reported
that CRC mortality rates were higher in the northern
regions of United States and Europe. Additional research
pointed out a high correlation between latitude and risk
of CRC in the United States and Europe. People living at
higher latitudes, presumably by synthesizing less vitamin
D, have a higher risk of dying from many common cancers
including CRC. These observations are in line with those
which revealed that CRC mortality in the United States was
higher in places where people were exposed to the lowest
mean solar radiation, suggesting that vitamin D may play a
protective role in CRC [1]. On the same note, published literature is replete with epidemiologic studies showing that
high vitamin D intake and high plasma levels of 25(OH)D3
were associated with a substantial reduction of CRC incidence [26].
1.4. Genetic basis of colorectal carcinoma
CRC originates from the neoplastic transformation of
epithelial cells of the colon and rectum, leading to the accumulation of genetic and epigenetic aberrations [27]. CRC is
thought to be a result of a series of genetic mutations, which
parallel histopathologic and molecular changes, from normal colonic epithelium to invasive carcinoma. At least four
sequential genetic changes, affecting one oncogen (KRAS)
and three tumor suppressor genes (APC, SMAD4 and TP53),
are required for the development of CRC. Mutation of apc
is often the initiating genetic lesion in CRCs that develop
along the chromosomal instability pathway. Depending on
the cellular context, loss of apc activates the signaling pathway causing immediate widespread apoptosis of colorectal
S.Y. Guraya / Journal of Microscopy and Ultrastructure 2 (2014) 1–6
epithelial cells and defects in differentiation and cell migration. Only cells that are inherently resistant to apoptosis
survive this initial wave of apoptosis. These surviving cells
constitute the epithelial population that develops into adenomas [28].
2. Literature review
2.1. Colorectal carcinoma and vitamin D
A significant number of observational and epidemiological studies have illustrated an inverse association between
intake of vitamin D and the risk of CRC [4,15,29]. A quantitative meta-analysis by Gorham et al. suggested that a
serum 25(OH)D level of >33 ng/mL could be associated with
50% lower incidence of CRC, compared to serum 25(OH)D
<12 ng/mL [15]. The results of five serum studies were combined using standard methods for pooled analysis. The
pooled results were divided into quintiles with median
25(OH)D values of 6, 16, 22, 27, and 37 ng/mL. The pooled
odds ratio for the highest quintile versus the lowest was
0.49 (p < 0.0001, 95% confidence interval, 0.35–0.68). Daily
intake of 1000 IU would raise the median population serum
levels to 33 ng/mL, this is less than optimal because 50% of
the population would still be less than this median level. On
the contrary, an intake of 2000 IU/day, would raise the population median level to 46 ng/mL. This dose of Vitamin D is
much lower than the suggested toxic dose of 5000 IU/day,
which would lead to hypervitaminosis with consequent
toxicity.
An experimental study by Spina et al. [30] using human
colon cancer cells (MC-26) grafted into Balb/C mice found
that dietary vitamin D repletion reduced the volume
of colon cancer-derived tumors by 40%. Another report
demonstrated that dietary vitamin D repletion reduced the
volume of colon cancer xenografts in Balb/C mice by 60%
[31]. Similarly in a subset analysis of patients from the
WHI trial [16], the odd ratio for CRC was 2.5 for women
with 25OHD levels below 12 ng/mL versus women with
levels above 24 ng/mL. Unfortunately, several other studies
failed to confirm such a relation [32,33]. Such observations strongly suggest the role of interventional studies to
determine whether vitamin D supplementation can protect against CRC and if so, which dosage or 25(OH)D serum
level would suffice to provide protection.
2.2. Colorectal adenomas and vitamin D
Up to 90% of CRCs are estimated to originate from colorectal adenomas [34]. In a meta-analysis, by Wei et al.
[35], of studies published before December 2007, a statistically significant 30% lower risk of colorectal adenomas was
reported comparing highest versus lowest level of circulating 25(OH)D. In their case–control study, Takahashi et al.
[36] found that higher circulating 25(OH)D concentrations
were associated with decreased prevalence of colorectal
adenomas only during winter season of blood collection in
Japanese men. Circulating 25(OH)D levels during summer
season were positively associated with prevalence of colorectal adenomas. Further research is required to explain
3
the role of season-specific 25(OH)D levels in development
of colorectal neoplasms.
A recent meta-analysis by Yin et al. [37] demonstrated
incident colorectal adenomas according to serum 25(OH)D
in 8 studies, and colorectal adenomas recurrence in 2 studies, respectively. Results summary reported odd ratios (95%
confidence intervals) regarding incident and recurrent
colorectal adenomas, and both outcomes combined were
0.82 (0.69–0.97), 0.87 (0.56–1.35), and 0.84 (0.72–0.97),
respectively, for an increase of 25(OH)D by 20 ng/mL.
Published literature suggests that the risk of colorectal adenoma is lowest when both calcium intake and vitamin D
status are higher [32,38]. Similarly, among those with high
circulating 25(OH)D levels, those who also had low calcium intakes were at lower risk for colorectal adenoma
than those who also had high calcium intakes [39].
2.3. Anti-cancer roles of vitamin D in colorectal
carcinoma
2.3.1. Preventive role of vitamin D in colorectal cancer
a. Proliferation inhibition action by 1␣,25(OH)2 D3 and its
analogs in human colon cancer cells contributes to the
anti-cancer mechanisms of vitamin D [40]. The antiproliferative effect of vitamin D is attained by inducing
G1 cell-cycle arrest, which is probably mediated by upregulation of cell-cycle inhibitors, such as p21WAF1/CIP
and p27KIP. Vitamin D modulates the activation of
these cell cycle related genes by various intricate channels. p21 contains a vitamin D response elements in its
promoter region, and therefore is susceptible of direct
transcriptional control by vitamin D.
b. Vitamin D interferes with the synthesis of growth
factors and cytokines by modulating their signaling
pathways. Normal colonic epithelial proliferation is
inhibited by TGF- signaling and this disruption of TGF signaling is involved in CRC malignant progression. In
some models, vitamin D can restore sensitivity to TGF-
by inducing the expression of the TGF-1 receptor [41].
c. Vitamin D modulates the differentiation of colon cancer cells. In Caco-2 and HT-29 cells, treatment with
1␣,25(OH)2 D3 enhances morphological differentiation
parameters, such as the number of desmosomes,
inter-mediate filaments and microvilli length and density. Moreover, 1␣,25(OH)2 D3 markedly enhances the
expression and activity of alkaline phosphatase, a
marker of colonic differentiation.
d. Induction of apoptosis is directly linked with the anticancer action of vitamin D. This mechanism is regulated
by the up-regulation of the pro-apoptotic protein bak
and the down-regulation of the anti-apoptotic protein
bcl-2 [27]. Vitamin D activates the intrinsic pathway
of apoptosis causing the disruption of mitochondrial
function, cytochrome release and production of reactive
oxygen species [42,43]. Vitamin D also directly activates
caspases to induce apoptosis [44]. A subjective algorithm of apoptosis is displayed in Fig. 1 [45].
e. In addition to vitamin D, VDR modulates the actions of a
secondary bile acid, lithocholic acid. Fat-rich diets contain high levels of lithocholic acid, which inflicts DNA
damage in normal colon cells and, therefore, increases
4
S.Y. Guraya / Journal of Microscopy and Ultrastructure 2 (2014) 1–6
Table 1
Chemopreventive effects of vitamin D in colorectal carcinomas.
No.
Effects
1.
2.
3.
4.
5.
6.
7.
8.
Anti-proliferative
Induction of differentiation
Apoptosis
Inhibition of growth factor and cytokines synthesis
Induction of hypercalcemia
Anti-inflammatory
Inhibition of tumor cell-induced angiogenesis
Induction of mitogen-activated protein kinase
cascade
Inhibition of stress-activated kinase signaling
9.
Fig. 1. Intrinsic and extrinsic cascades of vitamin D-induced apoptosis.
1␣,25-Dihydroxy vitamin D3 [1␣,25-(OH)2 D3 ] up-regulates the proapoptotic protein bak and down-regulates the anti-apoptotic protein
bacl-2. Pro-apoptotic and anti-apoptotic bcl-2 modulate the release of
cytochrome c and other pro-apoptotic factors. Cytochrome c integrates
with APAF-1 and pro-caspase 9 to form the apoptosome, which stimamulates caspase 3 activation, inducing the cleavage of different substrates
in apoptotic cells. Another bcl-2-family member, BID, when cleaved
by caspase 8 (tBID), translocates to the mitochondria membrane and
triggers the mitochondria-dependent or intrinsic death pathway. BID connects the extrinsic (death-receptor mediated cell death pathway) and
the intrinsic death pathways. In cancer cells, 1␣,25-(OH)2 D3 induces
the down-regulation of inhibitor of apoptosis proteins (IAP). APAF-1,
apoptotic protease activating factor-1; BAK, Bcl-2-antagonist killer; BAX,
Bcl-2-associated X protein; tBID, truncated BH3-interacting domain death
agonist; BCL-2, B-cell CLL/lymphoma-2 protein; BCL-XL, BCL2-related
protein, long isoform; FADD, FAS-associated death domain.
the risk of CRC. Activation of VDR by either lithocholic
acid or vitamin D up-regulates CYP3A, SULT2A1, and
MRP3 gene transcription; these proteins are involved
in the detoxification of lithocholic acid in the liver and
intestine [11].
f. Calcium intake is associated with lower risk of CRC
[46,47]. However, because 90–95% of circulating vitamin D and its metabolites result from exposure to
solar ultraviolet rays [48,49], there is little correlation
between intake of calcium and serum 25(OH)D levels.
Feskanich et al. [50] controlled for calcium intake and
could not identify the influence of calcium on the results
for 25(OH)D. In another study, calcium intake was identical (1300 mg/day) in cases and controls, and therefore
could not account for the inverse association of serum
25(OH)D with CRC risk [50].
g. Since inflammation plays important role in cancer development [51], vitamin D exerts a strong
anti-inflammatory role in delaying or preventing cancer development and/or progression [52]. Vitamin D
exhibits antiinflammatory actions that may contribute
to its beneficial effects in several cancers. Krishnan et al.
[53] used cDNA microarrays to discover the molecular
pathways that mediate the anticancer effects of calcitriol in PCa cells. The results showed that calcitriol
regulation of gene expression leads to the inhibition
of the synthesis and biologic actions of prostaglandins
(PGs), stress-activated kinase signaling, and production
of proinflammatory cytokines.
h. Calcitriol is a potent inhibitor of tumor cell-induced
angiogenesis in experimental models [54]. Calcitriol
inhibits vascular endothelial growth factor (VEGF)induced endothelial cell tube formation in vitro and
decreases tumor vascularization in vivo in mice bearing xenografts of BCa cells over-expressing VEGF [55].
Calcitriol and its analogs also directly inhibit the proliferation of endothelial cells leading to the inhibition of
angiogenesis [56].
i. Calcitriol induces mitogen-activated protein kinase
activitation and inhibition of stress-activated kinase
signaling and thus exerts a powerful anti-cancer effect
on all cell lines [57].
A summary of the chemopreventive effects of vitamin
D in CRC is presented in Table 1.
2.3.2. Therapeutic role of vitamin D in colorectal cancer
In the presence of sufficient preclinical evidence that
high-dose of vitamin D exerts objective anticancer effects,
a wealth of preclinical trials has been carried out to test this
hypothesis in humans [58,59]. Various vitamin D analogs
have been tried (e.g. seocalcitol, inecalcitol, paricalcitol),
but calcitriol is by far the most frequently used, both as a
single agent and as part of a combination regimen. Overall,
single agent vitamin D has not been consistently associated
with objective tumor response in phase I–II trials enrolling
cancer patients. The main hurdle in developing vitamin D
analogs for the treatment of cancer is the difficulty in separating the calcemic activity of vitamin D analogs from its
antiproliferative activity [60]. Despite the positive results
obtained with 1␣,25(OH)2 D3 analogs when analyzed with
in vitro and in vivo rodents models of colon carcinogenesis, they are shown to be of sub-optimal efficacy in clinical
assays.
S.Y. Guraya / Journal of Microscopy and Ultrastructure 2 (2014) 1–6
More than a thousand analogs of vitamin D have been
developed to date and certain analogs have been effectively used as antiproliferative agents in the treatment of
psoriasis. However, to date, there are few clinical trials testifying the therapeutic efficacy of vitamin D analogs in CRC
treatment. One promising study has reported that vitamin
D analog seocalcitol was effective in treating inoperable
hepatocellular carcinoma [61]. Serious efforts are being
made to design new VDR ligands exhibiting improved therapeutic impact, and to establish new strategies for CRC
chemoprevention based on these ligands. The combination of vitamin D analogs with other anti-tumor agents
(i.e. chemotherapeutic drugs, epigenetic drugs, etc.) may
result in enhanced anti-cancer efficiency. A big effort is
being made to develop novel synthetic VDR ligands that
can dissociate the beneficial activities from the undesired
hypercalcemic effects.
3. Conclusion
Despite the wealth of clinical trials conducted so far,
attempting to establish the therapeutic efficacy of vitamin D, there are no reported randomized controlled trials,
which can confirm the therapeutic efficacy of vitamin D for
CRC. However, the preventive role of vitamin D in CRC is
well recognized and globally accepted. There is a need to
further explore the therapeutic potential of vitamin D and
its non-calcemic analogs in CRC.
Conflict of interest
The author declares no conflict of interest.
Acknowledgement
I am highly obliged to Dr. Shaista Salman Guraya,
Assistant Professor of Radiology Taibah University, in
professional designing and crafting the figure in the
manuscript.
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