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Immune Modulation by Vitamin D: Special Emphasis on Its Role in Prevention and Treatment of Cancer

      Abstract

      Purpose

      Vitamin D has been known to be involved in mineral and bone homeostasis for many years. In the past its main use was in treating osteoporosis and rickets. In recent years it was found that vitamin D is an immune-modulating agent and may also have a role in several diseases, including autoimmune diseases. The immune-modulating effects appear to be mediated by vitamin D interaction with the vitamin D receptor (VDR) that has transcriptional effects and is expressed on various cell types, especially those of the immune system. Immunologic and rheumatologic diseases were the first to be studied, but at the moment the spotlight is on the interactions between tumor cells and vitamin D. This review focuses on four forms of cancer that apparently benefit from a vitamin D supplementation during treatment: prostate, breast, and colorectal cancers and melanoma. Several studies reported that differences exist between white and black patients, which we discuss in the review.

      Methods

      We systematically searched PubMed for studies published in English. The search terms included vitamin D, cancer, breast, colorectal, prostate, and melanoma.

      Findings and implications

      Our findings show that vitamin D has the potential to become a valid coadjuvant in the treatment of cancer.

      Chemical compounds studied in this article

      Key words

      Introduction

      With the term vitamin D we usually refer to a group of 3 fat-soluble secosteroids, of which the D2 (ergocalciferol) and D3 (cholecarciferol) forms are extremely important in the human body. Not many foods contain vitamin D; most of it is produced in the skin after ultraviolet B (UVB) exposure and then activated through the kidney and the liver. Because of its being produced by human skin, vitamin D is to some extent considered a hormone.
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      International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor.
      The initial vitamin D compound is inactive and is hydroxylated in the liver to form 25-OH vitamin D3 (25 D). 25 D is also an inactive compound, but it is the most reliable measurement of an individual’s vitamin D status. It is converted in the kidney to the active compound 1,25 dihydroxy vitamin D (1,25 D) or calcidiol by 1-α-hydroxylase (CYP27B1), an enzyme that is stimulated by the parathyroid hormone. 1,25 D may be further metabolized to the inactive 1,24,25 vitamin D by 24-hydroxylase (CYP24). 1,25 D levels are tightly regulated in a negative feedback loop. 1,25 D both inhibits renal 1-α-hydroxylase and stimulates the 24-hydroxylase enzymes, thus maintaining circulating levels within limited boundaries and preventing excessive vitamin D activity/signaling.
      Vitamin D in its active form increases the absorption of calcium in the small intestine and the absorption of calcium and phosphate in the kidney; it also helps correctly deposit calcium in the bones. Thus, vitamin D was originally considered important only for bone metabolism and was used to treat rickets, osteomalacia, and osteoporosis in postmenopausal women, to reduce bone fragility.
      More recent evidence has found that vitamin D has not only a role in mineral homeostasis but also on other pathways, such as thyroid function and oxidative stress. Different studies have reported the existence of interactions between mineral bone homeostasis, oxidative stress, vitamin D, and thyroid function.
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      Thyroid function and its implications in oxidative stress influencing the pathogenesis of osteoporosis in adults with Down syndrome: a cohort study.
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      • Qazi M.H.
      1, 25-dihydroxyvitamin D3, a potential role player in the development of thyroid disorders in schizophrenics.
      In addition, vitamin D plays a role in immune modulation.
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      Vitamin D: modulator of the immune system.
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      Dr Michaels® product family (also branded as Soratinex®) versus Methylprednisolone aceponate - a comparative study of the effectiveness for the treatment of plaque psoriasis.
      This discovery was the result of the seminal observation that vitamin D can act on different cell types through the action of vitamin D receptor (VDR), in a similar way to other steroid vitamins such as vitamin A. Consequently, vitamin D was recognized as an immune modulator, and the presence of VDR was found in virtually all cells of the immune system.
      • Provvedini D.M.
      • Tsoukas C.D.
      • Deftos L.J.
      • Manolagas S.C.
      1,25-dihydroxyvitamin D3 receptors in human leukocytes.
      • Bikle D.
      Nonclassic actions of vitamin D.
      Vitamin D defect is associated with autoimmune diseases,
      • Altieri B.
      • Muscogiuri G.
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      • et al.
      Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept.
      • Eloi M.
      • Horvath D.V.
      • Ortega J.C.
      • et al.
      25-Hydroxivitamin D serum concentration, not free and bioavailable vitamin D, is associated with disease activity in systemic lupus erythematosus patients.
      and its supplementation has positive effects on autoimmune disorders, resulting in an upregulation of interleukin (IL)-10 and T regulatory lymphocytes while blocking T helper cytokines such IL-2,
      • Felaco P.
      • Castellani M.L.
      • De Lutiis M.A.
      • et al.
      IL-32: a newly-discovered proinflammatory cytokine.
      IL-32, interferon-γ, and IL-17,
      • Cantorna M.T.
      • Snyder L.
      • Lin Y.D.
      • Yang L.
      Vitamin D and 1,25(OH)2D regulation of T cells.
      which leads also to a modification in damage-associated molecular pattern signaling that is implied in various diseases.
      • Pandolfi F.
      • Altamura S.
      • Frosali S.
      • Conti P.
      Key role of DAMP in inflammation, cancer, and tissue repair.
      Such discovery prompted observations on the role of vitamin D in immunologic disorders and cancer. It was observed that in countries receiving less UVB radiation not only was there a higher incidence of bone metabolic disorders but also of autoimmune diseases.
      • Munger K.L.
      • Levin L.I.
      • Hollis B.W.
      • et al.
      Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.
      • Kamen D.
      • Aranow C.
      Vitamin D in systemic lupus erythematosus.
      • Merlino L.A.
      • Curtis J.
      • Mikuls T.R.
      • et al.
      Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women׳s Health Study.
      • Littorin B.
      • Blom P.
      • Scholin A.
      • et al.
      Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS).
      Taken together, data suggest the beneficial effects of vitamin D in autoimmune diseases.
      • Pludowski P.
      • Holick M.F.
      • Pilz S.
      • et al.
      Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence.
      • Trummer C.
      • Pandis M.
      • Verheyen N.
      • et al.
      Beneficial effects of UV-radiation: vitamin D and beyond.
      Vitamin D has shown potent anticancer activities, as hypothesized by Garland and Garland,
      • Garland C.F.
      • Garland F.C.
      Do sunlight and vitamin D reduce the likelihood of colon cancer?.
      who suggested that vitamin D could have a protective role against colorectal cancer (CRC). The geographic distribution of colon cancer deaths in the United States revealed that colon cancer mortality rates were higher in places where populations were exposed to the least amounts of natural light such as major cities and rural areas at high latitudes.
      Other studies found that vitamin D inhibits the growth of malignant melanoma cells
      • Colston K.
      • Colston M.J.
      • Feldman D.
      1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture.
      and causes the differentiation of human promyelocytic leukemia cells (HL60) toward the macrophage lineage. Since then, the antineoplastic actions of calcitriol (vitamin D3) have been shown both in vitro and in vivo, in various malignancies.
      • Feldman D.
      • Krishnan A.V.
      • Swami S.
      • et al.
      The role of vitamin D in reducing cancer risk and progression.
      Vitamin D and its analogues inhibit cell cycle progression and tumor cell growth in several cancer cell lines. Such mechanisms range from preventing cell proliferation to inducing apoptosis or suppressing the expression of cell adhesion molecules and growth factors that contribute to cancer metastasis.
      • Moukayed M.
      • Grant W.B.
      Molecular link between vitamin D and cancer prevention.
      Moreover, vitamin D exerts anticancer effects trough several mechanisms: antiproliferative effects, induction of apoptosis, inhibition of invasion and metastasis, and inhibition of angiogenesis.

      VDR Structure

      VDR belongs to the super family of steroid/thyroid hormone/retinoid nuclear receptors and is made up of two different domains, one binding to the DNA and the other binding to the vitamin D. The two domains are held together by a hinge region, which is thought to be flexible to allow the receptor homodimers and heterodimers to bind to various DNA response element types (eg, direct repeats and inverted repeats).
      • Orlov I.
      • Rochel N.
      • Moras D.
      • Klaholz B.P.
      Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA.
      VDR is highly polymorphic with at least 618 reported variants, but most of them are not detectable. Single nucleotide polymorphisms (SNPs) in the VDR gene have been related to a higher incidence in breast cancer (BC) and prostate cancer (PCa), but findings are not consistent. Two SNPs, ApaI and BsmI, are located in intron 8, whereas TaqI is located in exon 9. FokI is located in exon 2 and leads to a C/T substitution; if not present, it leads to an increased protein luciferase activity. A G/A polymorphism in the promoter region of the VDR gene seems to interact with the caudal-related homeodomain transcription factor (CDX2); the common CDX2 G allele has 30% less of the transcriptional activity compared with the A allele.
      • Jingwi E.Y.
      • Abbas M.
      • Ricks-Santi L.
      • et al.
      Vitamin D receptor genetic polymorphisms are associated with PSA level, Gleason score and prostate cancer risk in African-American men.

      Mechanism of Action

      In the past, studies found that the asset of vitamin D was modified in patients with various forms of cancer, but it was not until recent that it was found that vitamin D actually has a modulating effect on cancer cells
      • Marcinkowska E.
      • Wallace G.R.
      • Brown G.
      The use of 1α,25-dihydroxyvitamin D(3) as an anticancer agent.
      : 1,25(OH)2 D stimulates the expression of cell cycle inhibitors p21 and p27
      • Ingraham B.A.
      • Bragdon B.
      • Nohe A.
      Molecular basis of the potential of vitamin D to prevent cancer.
      and the expression of the cell adhesion molecule E-cadherin, while inhibiting transcriptional activity of β-catenin.
      • Palmer H.G.
      • Gonzalez-Sancho J.M.
      • Espada J.
      • et al.
      Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling.
      • Shah S.
      • Islam M.N.
      • Dakshanamurthy S.
      • et al.
      The molecular basis of vitamin D receptor and beta-catenin crossregulation.
      These actions should block the proliferative potential of these cells.
      In keratinocytes 1,25(OH)2 D promotes the repair of DNA damage induced by ultraviolet radiation and increases p53 expression in damaged cells.
      • Gupta R.
      • Dixon K.M.
      • Deo S.S.
      • et al.
      Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products.
      Epidemiologic evidence supports the importance of adequate vitamin D administration (including sunlight exposure) for the prevention of different types of cancer is extensive, as shown in recent studies.
      • Shui I.
      • Giovannucci E.
      Vitamin D status and cancer incidence and mortality.
      Vitamin D exerts anticancer activities by targeting key molecules involved in cell cycle regulation.
      • Feldman D.
      • Krishnan A.V.
      • Swami S.
      • et al.
      The role of vitamin D in reducing cancer risk and progression.
      • Jensen S.S.
      • Madsen M.W.
      • Lukas J.
      • et al.
      Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery.
      These include c-Myc and c-Fos, two known proto-oncogenes involved in the cell cycle regulatory machinery
      • Rohan J.N.
      • Weigel N.L.
      1Alpha,25-dihydroxyvitamin D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells.
      and overexpressed in several tumors. It has been found that vitamin D suppresses the expression of the oncogene c-Myc and, thus, promotes the increased expression of its antagonist, the transcriptional repressor MAD1/MXD1, an effect mediated by a cellular regulator referred to as F-box protein.
      • Salehi-Tabar R.
      • Nguyen-Yamamoto L.
      • Tavera-Mendoza L.E.
      • et al.
      Vitamin D receptor as a master regulator of the c-MYC/MXD1 network.
      However, as reviewed by Farlandin,
      • Feldman D.
      • Krishnan A.V.
      • Swami S.
      • et al.
      The role of vitamin D in reducing cancer risk and progression.
      there appear to be more mechanisms through which vitamin D could have an anticancer effect. It has strong antiproliferative effects, increasing the expression of insulin-like growth factor–binding protein 3, thus inhibiting mitogenic signaling by growth factors such as insulin-like growth factor-1
      • Boyle B.J.
      • Zhao X.Y.
      • Cohen P.
      • Feldman D.
      Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1.
      and inducing apoptosis by suppressing antiapoptotic genes such as BCL2.
      • Blutt S.E.
      • McDonnell T.J.
      • Polek T.C.
      • Weigel N.L.
      Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2.
      It also has anti-inflammatory effects, which explains why vitamin D is capable of having positive effects in both tumors and autoimmune diseases.
      Vitamin D stimulates differentiation and inhibits invasion and metastasis through increased expression of E-cadherin, a gene inversely correlated to tumor’s metastatic capacity.
      • Campbell M.J.
      • Elstner E.
      • Holden S.
      • et al.
      Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin.
      In addition, inhibition of angiogenesis, through suppression of vascular endothelial growth factor,
      • Bao B.Y.
      • Yao J.
      • Lee Y.F.
      1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis.
      reduces invasion and growth potential of the tumor.
      The biological actions of vitamin D are mediated by the VDR, mostly by genomic actions.
      • Colston K.
      • Colston M.J.
      • Feldman D.
      1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture.
      • Rohan J.N.
      • Weigel N.L.
      1Alpha,25-dihydroxyvitamin D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells.
      • Salehi-Tabar R.
      • Nguyen-Yamamoto L.
      • Tavera-Mendoza L.E.
      • et al.
      Vitamin D receptor as a master regulator of the c-MYC/MXD1 network.
      • Abe E.
      • Miyaura C.
      • Sakagami H.
      • et al.
      Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3.
      • Deschasaux M.
      • Souberbielle J.C.
      • Latino-Martel P.
      • et al.
      A prospective study of plasma 25-hydroxyvitamin D concentration and prostate cancer risk.
      Vitamin D binds to the VDR, thereby causing its dimerization with the retinoid X receptor, binding of the complex to vitamin D response elements in multiple regulatory regions located at promoters and distal sites of target genes, and the recruitment of co-modulators.
      • Feldman D.
      • Krishnan A.V.
      • Swami S.
      • et al.
      The role of vitamin D in reducing cancer risk and progression.
      Overall, mechanisms through which vitamin D works are still not totally understood, but it appears that vitamin D levels have a positive impact on the type and outcome of the tumor,
      • Shirazi L.
      • Almquist M.
      • Borgquist S.
      • et al.
      Serum vitamin D (25OHD3) levels and the risk of different subtypes of breast cancer: a nested case-control study.
      and they may even have a positive effect in preventing the development of BC.
      • Shekarriz-Foumani R.
      • Khodaie F.
      The correlation of plasma 25-hydroxyvitamin D deficiency with risk of breast neoplasms: a systematic review.
      • Janbabai G.
      • Shekarriz R.
      • Hassanzadeh H.
      • et al.
      A survey on the relationship between serum 25-hydroxy vitamin D level and tumor characteristics in patients with breast cancer.
      However, note that some of the mechanisms summarized above have been observed only in particular forms of cancer: that is, Bcl-2 and E-cadherin in PCa and differentiation in leukemic cells. Thus, it appears that there is not a single common underlying mechanism through which vitamin D is an anticancer agent.

      Methods

      We conducted a PubMed search for articles pertaining to various issues related to Vitamin D and cancer, and we discussed the most relevant articles especially (ie, not only those published in journals with a higher impact factor).
      We reviewed the published reports and found encouraging results, even though not all agree that vitamin D is actually effective in cancer treatment/prevention.

      Vitamin D and BC

      BC is the most common malignancy in women worldwide. There are various possible molecular patterns, which need different types of treatment and which determine different outcomes for patients.
      • Molnar I.A.
      • Molnar B.A.
      • Vizkeleti L.
      • et al.
      Breast carcinoma subtypes show different patterns of metastatic behavior.
      One of the most difficult forms to treat is the triple-negative form in which tumor cells do not present estrogen or progesterone receptors and are negative for human epidermal growth factor receptor 2. This type of BC does not benefit from hormonal therapy or anti–human epidermal growth factor receptor 2 medications.
      • Tsoutsou P.G.
      • Vozenin M.C.
      • Durham A.D.
      • Bourhis J.
      How could breast cancer molecular features contribute to locoregional treatment decision making?.
      Recently, it has emerged that patients with triple-negative BC, specifically estrogen negative, have lower cathelicidin antimicrobial peptide (CAMP), an important cytotoxic and proapoptotic peptide. Patients with tumor estrogen-negative cells produce less CAMP than the others, but it appears that if the cells are stimulated with calcitriol, CAMP levels rise, leading to potential benefits for treatment.
      • García-Quiroz J.
      • García-Becerra R.
      • Santos-Martínez N.
      • et al.
      Calcitriol stimulates gene expression of cathelicidin antimicrobial peptide in breast cancer cells with different phenotype.
      Vitamin D had also interesting effects on differentiation of tumor stem cells in triple-negative BC, in particular there is a lower expression of CD44, a glycoprotein associated with tumor progression and metastasis.
      • Shah S.
      • Islam M.N.
      • Dakshanamurthy S.
      • et al.
      The molecular basis of vitamin D receptor and beta-catenin crossregulation.
      Another important negative prognostic factor in BC is the presence of Ca2+-activated K+ channel that usually characterizes high-grade tumors. Targeting Ca2+-activated K+ channel with vitamin D and its analogues has shown a significant reduction of its expression, which possibly means that the channel is downstream in the signaling pathway of VDR.
      • Khatun A.
      • Fujimoto M.
      • Kito H.
      • et al.
      Down-regulation of Ca2+-activated K(+) channel KCa1.1 in human breast cancer MDA-MB-453 cells treated with vitamin D receptor agonists.
      Further studies are needed to determine whether vitamin D supplementation could be a useful treatment in such cases.
      In general, cancer cells exposed to vitamin D and its analogue MART10 have less metastatic potential, due to a modulation of the expression of different surface proteins. There is induction of N-cadherin switching to E-cadherin and a downregulation of metalloproteinase 9, that both reduce tumor metastatic potential
      • Chiang K.-C.
      • Yeh T.-S.
      • Chen S.-C.
      • et al.
      The vitamin D analog, MART-10, attenuates triple negative breast cancer cells metastatic potential.
      ; there also is an inhibition in expression of Id1, a tumor gene involved in tumor progression and metastasis,
      • Williams J.D.
      • Aggarwal A.
      • Swami S.
      • et al.
      Tumor autonomous effects of vitamin D deficiency promote breast cancer metastasis.
      and a modification of BC cells metabolism, through downregulation of pyruvate carboxylase.
      • Wilmanski T.
      • Buhman K.
      • Donkin S.S.
      • et al.
      1alpha,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase.
      Vitamin D seems so far to have positive effects on BC, and one of the possible reasons is its interactions with the cluster of microRNA-199a/microRNA-214 (miRNA-199a/miRNA-214), a well-known tumor promoter. miRNA-199a/miRNA-214 inhibits the suppressor of fused gene, a hedgehog pathway inhibitor. VDR signaling instead determines an increase in suppressor of fused gene activity, through the inhibition of miRNA-199a/miRNA-214 clusters,
      • Alimirah F.
      • Peng X.
      • Gupta A.
      • et al.
      Crosstalk between the vitamin D receptor (VDR) and miR-214 in regulating SuFu, a hedgehog pathway inhibitor in breast cancer cells.
      and could represent the opening of a new therapeutic avenue.
      • Gupta S.
      • Takebe N.
      • LoRusso P.
      Targeting the Hedgehog pathway in cancer.
      Finally, another interesting field of research is VDR polymorphisms, which are at least four (Fok1, Bsm1, Taq1, and Apa1). Even though in the white population alone these polymorphisms do not seem to be risk factors for the development of BC,
      • Lu D.
      • Jing L.
      • Zhang S.
      Vitamin D receptor polymorphism and breast cancer risk: a meta-analysis.
      other studies suggest that the differences between incidence in BC between black and white populations could actually be related to the presence of different polymorphisms in these populations. In fact, even though vitamin D serum levels are lower in blacks than in whites, the black group had different SNPs than the white group, determining a higher expression and activity of VDR and a lower incidence of BC.
      • Amadori D.
      • Serra P.
      • Masalu N.
      • et al.
      Vitamin D receptor polymorphisms or serum levels as key drivers of breast cancer development? The question of the vitamin D pathway.

      Vitamin D and PCa

      In the past 20 years the incidence of PCa has been increasing, an event at least in part because of the growing ageing population.
      • Dy G.W.
      • Gore J.L.
      • Forouzanfar M.H.
      • et al.
      Global burden of urologic cancers, 1990-2013.
      In men, PCa is the most common malignancy, and, even though there are effective strategies to treat it, it still remains the third oncologic cause of death among men.
      • Torre L.A.
      • Siegel R.L.
      • Ward E.M.
      • Jemal A.
      Global cancer incidence and mortality rates and trends--an update.
      A recent study in Norway has reported that PCa patients have better outcomes when diagnosed during the summer, when the sunlight exposure is higher and so are vitamin D serum levels.
      • Robsahm T.E.
      • Tretli S.
      • Dahlback A.
      • Moan J.
      Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway).
      Thus, it has been hypothesized that vitamin D could be a tool in battling PCa. Studies found that patients’ calcitriol serum levels between 18.2 and 20 ng have a favorable prognosis in comparison with ones with lower levels.
      • Deschasaux M.
      • Souberbielle J.C.
      • Latino-Martel P.
      • et al.
      A prospective study of plasma 25-hydroxyvitamin D concentration and prostate cancer risk.
      Other studies have shown that vitamin D greater than 34 ng/mL is a negative prognostic factor,
      • Jackson M.D.
      • Tulloch-Reid M.K.
      • Lindsay C.M.
      • et al.
      Both serum 25-hydroxyvitamin D and calcium levels may increase the risk of incident prostate cancer in Caribbean men of African ancestry.
      even though this seems less true for more aggressive forms.
      • Schenk J.M.
      • Till C.A.
      • Tangen C.M.
      • et al.
      Serum 25-hydroxyvitamin D concentrations and risk of prostate cancer: results from the Prostate Cancer Prevention Trial.
      Different grade of expression and polymorphisms of VDR have been more successfully linked to differences in grade, outcome, and risk of PCa. Low levels of tumor VDR expression have been associated with worse outcome in patients with high calcium-sensing receptors, whereas high levels of calcium-sensing receptors were not a negative prognostic factor in patients with a normal/high level of tumor VDR expression.
      • Ahearn T.U.
      • Tchrakian N.
      • Wilson K.M.
      • et al.
      Calcium-sensing receptor tumor expression and lethal prostate cancer progression.
      Gilbert et al
      • Gilbert R.
      • Bonilla C.
      • Metcalfe C.
      • et al.
      Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case-control study.
      have shown that SNPs in VDR correlate with differences in grade and risk, and other studies have shown that VDR FokI polymorphism might be capable of determining susceptibility to PCa.
      • Nunes S.B.
      • de Matos Oliveira F.
      • Neves A.F.
      • et al.
      Association of vitamin D receptor variants with clinical parameters in prostate cancer.
      • Kang S.
      • Zhao Y.
      • Liu J.
      • et al.
      Association of Vitamin D receptor Fok I polymorphism with the risk of prostate cancer: a meta-analysis.
      VDR expression is involved in the regulation of miRNA-126-3p, miRNA154-5p, and miR-21-5p and of miRNA processing ribonuclease, DICER1,
      • Dambal S.
      • Giangreco A.A.
      • Acosta A.M.
      • et al.
      microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma.
      already known to play a role in ovarian Sertoli-Leydig cell tumors.
      • Wang Y.
      • Chen J.
      • Yang W.
      • et al.
      The oncogenic roles of DICER1 RNase IIIb domain mutations in ovarian Sertoli-Leydig cell tumors.
      Population studies have shown interesting results; for example, in the Pakistani and Jordanian populations it was possible to identify various VDR polymorphisms that seemed to have a protective effect and others that were associated with a worse prognosis. FokI appeared to have a protective effect in Pakistani men, but it also was linked to more aggressive forms in Jordanian men; ApaI seemed to be linked to more aggressive forms in the Pakistani population.
      • Yousaf N.
      • Afzal S.
      • Hayat T.
      • et al.
      Association of vitamin D receptor gene polymorphisms with prostate cancer risk in the Pakistani population.
      • Atoum M.F.
      • AlKateeb D.
      • AlHaj Mahmoud S.A.
      The Fok1 vitamin D receptor gene polymorphism and 25(OH) D serum levels and prostate cancer among Jordanian men.
      Similar studies in the Japanese population failed to produce any significant result.
      • Sawada N.
      • Inoue M.
      • Iwasaki M.
      • et al.
      Plasma 25-hydroxy vitamin D and subsequent prostate cancer risk in a nested Case-Control study in Japan: The JPHC study.
      Differences between black and white men with PCa have attracted considerable interest. In the US population it was noticed that men of African ancestry have a higher incidence of PCa than men of European ancestry, and PCa is usually more aggressive in the former than in the latter. In addition, in the African population it was possible to identify VDR polymorphisms associated with a poorer outcome, in particular TaqI and ApaI.
      • Jingwi E.Y.
      • Abbas M.
      • Ricks-Santi L.
      • et al.
      Vitamin D receptor genetic polymorphisms are associated with PSA level, Gleason score and prostate cancer risk in African-American men.
      • Nelson S.M.
      • Batai K.
      • Ahaghotu C.
      • et al.
      Association between serum 25-hydroxy-vitamin D and aggressive prostate cancer in African American men.
      Such differences could be linked to vitamin D deficiency
      • Batai K.
      • Murphy A.B.
      • Nonn L.
      • Kittles R.A.
      Vitamin D and immune response: implications for prostate cancer in African Americans.
      and might be overcome by correct supplementation.
      • Nelson S.M.
      • Batai K.
      • Ahaghotu C.
      • et al.
      Association between serum 25-hydroxy-vitamin D and aggressive prostate cancer in African American men.
      Paller et al
      • Paller C.J.
      • Kanaan Y.M.
      • Beyene D.A.
      • et al.
      Risk of prostate cancer in African-American men: evidence of mixed effects of dietary quercetin by serum vitamin D status.
      have suggested that quercetin supplementation may improve patients’ status, because it is reported to reduce the risk of PCa in men with lower vitamin D levels, but it seems to have a negative effect on men who are not vitamin D deficient.

      Vitamin D and CRC

      CRC is the third form of cancer for incidence and the fourth for mortality.
      • Marmol I.
      • Sanchez-de-Diego C.
      • Pradilla Dieste A.
      • et al.
      Colorectal carcinoma: a general overview and future perspectives in colorectal cancer.
      A large number of published reports are dedicated to the description of the oncoprotective role of vitamin D in CRC. Garland et al
      • Garland C.F.
      • Garland F.C.
      • Gorham E.D.
      • et al.
      The role of vitamin D in cancer prevention.
      were the first to hypothesize a relation between sun exposure/vitamin D production and CRC risk, highlighting that CRC incidence and mortality rates were higher in those people who had less sunlight exposure. In fact, although diverse approaches for vitamin D measurement, different case population, and risk factors were used, all the epidemiologic studies confirmed the inverse correlation between vitamin D3/vitamin D intake and CRC risk. Moreover, the International Agency of Cancer Research stated that the association is congruent and convincing. However, despite the large number of screened people (1,000,000),
      • Ma Y.
      • Zhang P.
      • Wang F.
      • et al.
      Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies.
      most of the reference list was focused on large meta-analyses without a direct measurement of vitamin D role in tumor genesis,
      • Gandini S.
      • Boniol M.
      • Haukka J.
      • et al.
      Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma.
      • Lieberman D.A.
      • Prindiville S.
      • Weiss D.G.
      • Willett W.
      Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals.
      • Bostick R.M.
      • Potter J.D.
      • Sellers T.A.
      • et al.
      Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women׳s Health Study.
      • Zheng W.
      • Anderson K.E.
      • Kushi L.H.
      • et al.
      A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women.
      leaving an open gap and the necessity of clinical trials.
      • Pereira F.
      • Larriba M.J.
      • Munoz A.
      Vitamin D and colon cancer.
      The underlying molecular mechanism through which vitamin D can exert its supposed protective function concerns the ability of calcitriol to interact with different pathways and its receptor, as well as VDR expression in normal and pathologic states. Several studies have reported that VDR is highly expressed at the beginning of the malignancy, whereas its expression is strongly decreased in advanced metastasizing CRC, suggesting the use of the vitamin D more as a chemoprotector than as a possible therapy in CRC.
      • Matusiak D.
      • Murillo G.
      • Carroll R.E.
      • et al.
      Expression of vitamin D receptor and 25-hydroxyvitamin D3-1{alpha}-hydroxylase in normal and malignant human colon.
      • Anderson M.G.
      • Nakane M.
      • Ruan X.
      • et al.
      Expression of VDR and CYP24A1 mRNA in human tumors.
      In human CRC, the transcription factor SNAIL and the Wnt/β-catenin pathway are highly dysregulated. Their overexpression is the cause of tumor proliferation, inflammation, and progression. The aberrant activation of the Wnt/β-catenin pathway, observed in 90% of CRC, can be switched off by the calcitriol/VDR interaction through the induction of β-catenin nuclear export or VDR/β-catenin sequestration, or the induction of cystatin,
      • Klampfer L.
      Vitamin D and colon cancer.
      thereby inhibiting Wnt/β-catenin–derived tumor progression. The transcriptional factor SNAIL, whose nuclear translocation is driven by the Wnt/β-catenin pathway, is a VDR repressor as observed both in cellular lines and xenograft mice. Its expression is correlated to VDR inhibition, thus causing a reduction in calcitriol/VDR interaction and in its antitumor effect. For this reason, SNAIL expression has been proposed as a predictive marker for vitamin D therapy nonresponders.
      • Larriba M.J.
      • Munoz A.
      SNAIL vs vitamin D receptor expression in colon cancer: therapeutics implications.
      Extensive studies on CRC animal models have shown positive results in CRC treatment through the use of vitamin D.
      • Lamprecht S.A.
      • Lipkin M.
      Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms.
      Mice models, in which the carcinogenesis was generated through specific diet, found amelioration after vitamin D and calcium supplementation. Instead, in xenograft mice models the administration of vitamin D or other compounds significantly reduced the incidence of colon tumors, as already reviewed elsewhere.
      • Kang W.
      • Lee S.
      • Jeon E.
      • et al.
      Emerging role of vitamin D in colorectal cancer.
      Taken together, these data suggest a potential role for the use of vitamin D in cancer treatment and to fill the gap between preclinical studies and clinical therapy some trials have started. However, as reported by Pereira et al,
      • Pereira F.
      • Larriba M.J.
      • Munoz A.
      Vitamin D and colon cancer.
      these trials failed to show a substantial impact on CRC treatment in patients.

      Vitamin D and Melanoma

      Melanoma is among the most immunogenic tumors.
      • Pandolfi F.
      • Cianci R.
      • Lolli S.
      • et al.
      Strategies to overcome obstacles to successful immunotherapy of melanoma.
      Although for other tumors the impact and the efficacy of vitamin D is a straightforward interrogative, in melanoma it is not as simple to study its effects. This is due to the importance of sun exposure as a risk factor in melanoma but also in vitamin D production. Gandini et al
      • Gandini S.
      • Sera F.
      • Cattaruzza M.S.
      • et al.
      Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure.
      and Hoel et al
      • Hoel D.G.
      • Berwick M.
      • de Gruijl F.R.
      • Holick M.F.
      The risks and benefits of sun exposure 2016.
      have found that, more than from sun exposure itself, risks derive from the quality and quantity of time spent in the sun; despite sunburn being a risk factor, sunlight has a protective effect, as reported by Shipman et al.
      • Shipman A.R.
      • Clark A.B.
      • Levell N.J.
      Sunnier European countries have lower melanoma mortality.
      Indeed, sun exposure in general is known to have a beneficial effect on the skin. It improves disorders such as psoriasis, eczema, vitiligo, and acne; however, several studies still emphasize the negative effects of sun exposure on skin cancer in general and melanoma in particular.
      • van der Rhee H.J.
      • de Vries E.
      • Coebergh J.W.
      Regular sun exposure benefits health.
      Berwick et al.
      • Berwick M.
      • Pestak C.
      • Thomas N.
      Solar ultraviolet exposure and mortality from skin tumors.
      have shown that there actually is a straightforward association only between sun exposure and squamous cell carcinoma and not with other forms of skin cancer. Actually, a reduced exposure to sunlight, particularly UVB, seems to increase the incidence of melanoma in populations at higher latitudes,
      • Gorham E.D.
      • Mohr S.B.
      • Garland C.F.
      • et al.
      Do sunscreens increase risk of melanoma in populations residing at higher latitudes?.
      which possibly is related to lower vitamin D production. Wyatt et al
      • Wyatt C.
      • Lucas R.M.
      • Hurst C.
      • Kimlin M.G.
      Vitamin D deficiency at melanoma diagnosis is associated with higher Breslow thickness.
      suggest that vitamin D deficiency at the diagnosis is associated with a higher Breslow score and that a correct supplementation in the general population could ensure lower scores at diagnosis. Saiag et al
      • Saiag P.
      • Aegerter P.
      • Vitoux D.
      • et al.
      Prognostic value of 25-hydroxyvitamin D3 levels at diagnosis and during follow-up in melanoma patients.
      instead hypothesized that vitamin D serum levels are prognostic during follow-up but not when melanoma is diagnosed. Moreover, results from a prospective study on 872 patients confirmed the hypothesis of Wyatt et al,
      • Wyatt C.
      • Lucas R.M.
      • Hurst C.
      • Kimlin M.G.
      Vitamin D deficiency at melanoma diagnosis is associated with higher Breslow thickness.
      suggesting that higher vitamin D serum levels can contribute to better tumor outcome and lower tumor grade at diagnosis.
      • Newton-Bishop J.A.
      • Beswick S.
      • Randerson-Moor J.
      • et al.
      Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma.
      Note that recent evidence shows that there is de facto more than one single form of vitamin D and that its interactions do not only affect VDR but also the retinoic acid orphan receptors α and γ.
      • Slominski A.T.
      • Brozyna A.A.
      • Zmijewski M.A.
      • et al.
      Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management.
      Such knowledge may help understand and improve the different outcomes for patients.
      Several studies have shown the positive effects of vitamin D both in in vitro and in vivo experiments; melanoma cancer lines exposed to vitamin D or other compounds have found a significant reduction of proliferation, migration, and survival of malignant cells, and transition from a less-differentiated stage to a more-differentiated stage.
      • Wasiewicz T.
      • Szyszka P.
      • Cichorek M.
      • et al.
      Antitumor effects of vitamin D analogs on hamster and mouse melanoma cell lines in relation to melanin pigmentation.
      • Skobowiat C.
      • Oak A.S.
      • Kim T.K.
      • et al.
      Noncalcemic 20-hydroxyvitamin D3 inhibits human melanoma growth in in vitro and in vivo models.
      However, the predictive value of the serum concentration of vitamin D on cancer risk is still elusive, as reviewed by Berwick et al.
      • Berwick M.
      • Erdei E.O.
      Vitamin D and melanoma incidence and mortality.
      As reported by Marshall and Byrne,
      • Marshall J.E.
      • Byrne S.N.
      Does sunlight protect us from cancer?.
      not all anticancer effects of sunlight exposure can be connected to vitamin D. Further studies are needed to explore the other involved pathways.
      • van der Rhee H.
      • Coebergh J.W.
      • de Vries E.
      Is prevention of cancer by sun exposure more than just the effect of vitamin D? A systematic review of epidemiological studies.

      Conclusions

      Increasing evidence supports a role of vitamin D not only in bone metabolism but also as an immune-modulator agent.
      • Lappe J.M.
      • Travers-Gustafson D.
      • Davies K.M.
      • et al.
      Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.
      • Anastasi E.
      • Capoccia D.
      • Granato T.
      • Viggiani V.
      • Tartaglione S.
      • Manganaro L.
      • Angeloni A.
      • Leonetti F.
      Assessing the association between 25-OH vitamin D levels and ROMA score in a population of obese women.
      Vitamin D and its receptor play an important role in various forms of cancer. Metastatic potential and tumor progression appear to be influenced by VDR signaling, whereas vitamin D serum levels have shown to some extent an inverse correlation with the risk of developing CRC, PCa, BC, and melanoma.
      It still is too early to know if this knowledge can be translated into clinical practice; studies are not always consistent,
      • van der Rhee H.
      • Coebergh J.W.
      • de Vries E.
      Is prevention of cancer by sun exposure more than just the effect of vitamin D? A systematic review of epidemiological studies.
      and several clinical trials are just starting (NCT02172651; NCT01516216). In this regard it is worth mentioning a 4-year population-based double-blind, randomized placebo-controlled trial by Lappe et al
      • Menghini L.
      • Ferrante C.
      • Leporini L.
      • Recinella L.
      • Chiavaroli A.
      • Leone S.
      • Pintore G.
      • Vacca M.
      • Orlando G.
      • Brunetti L.
      A natural formula containing lactoferrin, Equisetum arvensis, soy isoflavones and vitamin D3 modulates bone remodeling and inflammatory markers in young and aged rats.
      in more than 1100 postmenopausal women. The trial found that improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women.
      Other clinical trials ongoing at the present time are exploring other possible actions of vitamin D: the vitamin D and longevity trial (VIDAL) in the United Kingdom and the vitamin D and Omega-3 trial (VITAL) in the United States.
      • Pradhan A.D.
      • Manson J.E.
      Update on the vitamin D and omega-3 trial (VITAL).
      Some of the diverse results that have been seen in clinical trials with vitamin D might be due to variations in intracellular calcitriol and VDR levels, owing to miRNA regulation.
      In addition, as previously mentioned, some of the anticancer in vitro effects were observed on specific cancer cells, and further research is needed to confirm that some specific anticancer activities are taking action in every form of cancer. However, despite this note of caution, vitamin D represents a promising new frontier in the battle against cancer.

      Conflicts of Interest

      The authors have indicated that they have no conflicts of interest regarding the content of this article.

      Acknowledgments

      This work was supported in part by an internal grant from the Catholic University (linea D1), Rome, Italy. All Authors contributed equally to this paper.

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