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Table of Contents
Year : 2014  |  Volume : 2  |  Issue : 1  |  Page : 1-6

Chemopreventive role of vitamin D in colorectal carcinoma

College of Medicine Taibah University, Almadinah Almunawwarah, Saudi Arabia

Date of Web Publication29-Jan-2018

Correspondence Address:
Salman Yousuf Guraya
College of Medicine Taibah University, Almadinah Almunawwarah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.jmau.2013.09.001

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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.

Keywords: Vitamin D, Colorectal carcinoma, 25(OH)D, Apoptosis, Calcitriol

How to cite this article:
Guraya SY. Chemopreventive role of vitamin D in colorectal carcinoma. J Microsc Ultrastruct 2014;2:1-6

How to cite this URL:
Guraya SY. Chemopreventive role of vitamin D in colorectal carcinoma. J Microsc Ultrastruct [serial online] 2014 [cited 2019 Mar 22];2:1-6. Available from: http://www.jmau.org/text.asp?2014/2/1/1/224202

  1. Introduction Top

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],[3],[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],[6],[7],[8],[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 α-hydroxylase (CYP27B1) to the main biologically active hormone, 1α,25-dihydroxycholecalciferol (1α,25-(OH)2D3 or calcitriol) takes place in the proximal renal tubule [13]. Sufficient renal production of 1 α,25-(OH)2D3 leads to activation of the catabolic pathway by 24-hydroxylation of 1 a,25(OH)-D3, or of 25(OH)-D3. A major part of 25(OH)-D3 and of 1α,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 7-dehydrocholesterol 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],[22],[23] found inverse associations for colon or rectal cancer, or both [24]. Most of the biological actions of 1α,25(OH)2D3 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 1α,25(OH)2D3 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 1α,25(OH)2D3 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 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 Top

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 1000IU 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 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

  1. Proliferation inhibition action by 1α,25(OH)2D3 and its analogs in human colon cancer cells contributes to the anti-cancer mechanisms of vitamin D [40]. The anti-proliferative effect of vitamin D is attained by inducing G1 cell-cycle arrest, which is probably mediated by up-regulation 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.
  2. Vitamin D interferes with the synthesis of growth factors and cytokines by modulating their signaling pathways. Normal colonic epithelial proliferation is inhibited by TGF-ß signaling and this disruption of TGF-β signaling is involved in CRC malignant progression. In some models, vitamin D can restore sensitivity to TGF-ß by inducing the expression of the TGF-ß1 receptor [41].
  3. Vitamin D modulates the differentiation of colon cancer cells. In Caco-2 and HT-29 cells, treatment with 1α,25(OH)2D3 enhances morphological differentiation parameters, such as the number of desmosomes, inter-mediate filaments and microvilli length and density. Moreover, 1α,25(OH)2D3 markedly enhances the expression and activity of alkaline phosphatase, a marker of colonic differentiation.
  4. Induction of apoptosis is directly linked with the anti-cancer 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 [Figure 1] [45].
  5. 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 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].
  6. 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].
  7. 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.
  8. 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].
  9. 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].
Figure 1: Intrinsic and extrinsic cascades of vitamin D-induced apoptosis. 1α,25-Dihydroxy vitamin D3 [1α,25-(OH)2D3] up-regulates the pro-apoptotic 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 (tBlD), 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, 1α,25-(OH)2D3 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.

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A summary of the chemopreventive effects of vitamin D in CRC is presented in [Table 1].
Table 1: Chemopreventive effects of vitamin D in colorectal carcinomas.

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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 1α,25(OH)2D3 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.

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 Top

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.


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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