Special Issue "Vitamin D: Role in Cancer Causation, Progression and Therapy"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 August 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Donald L. Trump (Website)

President & CEO, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo New York, 14263 ,USA
Phone: 7168458501
Fax: +1 716 845 8261
Interests: calcitriol; cholecalciferol; vitamin D; CYP24A1; cancer and vitamin D; prostate cancer; bladder cancer

Special Issue Information

Dear Colleagues,

Considerable environmental, ecologic, epidemiologic and laboratory data support the hypothesis that the vitamin D signaling system is important in the genesis and progression of human cancers. This hypothesis is not supported by prospective intervention trials in human populations (primarily because such trials have not been initiated),hence the hypothesis remains largely untested and the data are primarily correlative. This issue of Cancers, "Vitamin D and Cancer" seeks articles which will shed new light on this hypothesis. Careful prospective clinical studies and well controlled laboratory investigations which seek to advance the understanding of the role of vitamin D in the causation or progression of cancer are especially sought.

Prof. Dr. Donald L. Trump
Guest Editor

Submission

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

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Keywords

  • calcitriol
  • cholecalciferol
  • vitamin D
  • CYP24A1
  • CYP27B1
  • CYP2R1
  • cancer and vitamin D

Published Papers (11 papers)

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Research

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Open AccessArticle Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status
Cancers 2014, 6(1), 211-225; doi:10.3390/cancers6010211
Received: 25 November 2013 / Revised: 23 December 2013 / Accepted: 9 January 2014 / Published: 27 January 2014
Cited by 2 | PDF Full-text (539 KB) | HTML Full-text | XML Full-text
Abstract
Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there [...] Read more.
Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44−21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessArticle 26,26,26,27,27,27-Hexadeuterated-1,25-Dihydroxyvitamin D3 (1,25D-d6) As Adjuvant of Chemotherapy in Breast Cancer Cell Lines
Cancers 2014, 6(1), 67-78; doi:10.3390/cancers6010067
Received: 28 October 2013 / Revised: 2 December 2013 / Accepted: 16 December 2013 / Published: 27 December 2013
PDF Full-text (652 KB) | HTML Full-text | XML Full-text
Abstract
It has been demonstrated that 1,25-dihydroxyvitamin D3 (1,25D) and some of its analogues have antitumor activity. 1,25D labeled with deuterium (26,26,26,27,27,27-hexadeuterated 1a,25-dihydroxyvitamin D3, or 1,25D-d6) is commonly used as internal standard for 1,25D liquid chromatography-mass spectrometry (LC-MS) [...] Read more.
It has been demonstrated that 1,25-dihydroxyvitamin D3 (1,25D) and some of its analogues have antitumor activity. 1,25D labeled with deuterium (26,26,26,27,27,27-hexadeuterated 1a,25-dihydroxyvitamin D3, or 1,25D-d6) is commonly used as internal standard for 1,25D liquid chromatography-mass spectrometry (LC-MS) quantification. In the present study using human breast cancer cell lines, the biological activity of 1,25D-d6 administered alone and in combination with two commonly used antineoplastic agents, 5-fluorouracil and etoposide, was evaluated. Using an MTT assay, flow cytometry, and western blots, our data demonstrated that 1,25D-d6 has effects similar to the natural hormone on cell proliferation, cell cycle, and apoptosis. Furthermore, the combination of 1,25D-d6 and etoposide enhances the antitumoral effects of both compounds. Interestingly, the antitumoral effect is higher in the more aggressive MDA-MB-231 breast cancer cell line. Our data indicate that 1,25D-d6 administered alone or in combination with chemotherapy could be a good experimental method for accurately quantifying active 1,25D levels in cultures or in biological fluids, on both in vitro breast cancer cell lines and in vivo animal experimental models. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessArticle Surrogates of Long-Term Vitamin D Exposure and Ovarian Cancer Risk in Two Prospective Cohort Studies
Cancers 2013, 5(4), 1577-1600; doi:10.3390/cancers5041577
Received: 29 September 2013 / Revised: 13 November 2013 / Accepted: 15 November 2013 / Published: 22 November 2013
Cited by 2 | PDF Full-text (680 KB) | HTML Full-text | XML Full-text
Abstract
Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term [...] Read more.
Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term surrogates of vitamin D exposure within the Nurses’ Health Study (NHS) and NHSII. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of overall ovarian cancer and by histologic subtype using Cox proportional hazards models. Between 1976 and 2010 in NHS and 1989 and 2011 in NHSII, we identified a total of 1,225 incident epithelial ovarian cancer cases (NHS: 970, NHSII: 255) over 4,628,648 person-years of follow-up. Cumulative average UV-B exposure was not associated with ovarian cancer risk in NHS (Ptrend = 0.08), but was associated with reduced risk in NHSII (highest vs. lowest category RR = 0.67; 95% CI: 0.50, 0.89; Ptrend < 0.01). When stratified by histologic subtype, UV-B flux was positively associated with risk of serous tumors in NHS (Ptrend < 0.01), but inversely associated in NHSII (Ptrend = 0.01). Adjusted for confounders, ovarian cancer risk was not associated with vitamin D intake from food or supplements or with predicted 25(OH)D levels. Our study does not strongly support a protective role for vitamin D in ovarian cancer risk. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessArticle 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment
Cancers 2013, 5(4), 1504-1521; doi:10.3390/cancers5041504
Received: 5 September 2013 / Revised: 22 October 2013 / Accepted: 31 October 2013 / Published: 8 November 2013
Cited by 4 | PDF Full-text (833 KB) | HTML Full-text | XML Full-text
Abstract
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) [...] Read more.
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDRhigh) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDRlow and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH)2D3 sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH)2D3 induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH)2D3-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH)2D3 opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH)2D3 may prevent lung cancer progression in a molecularly defined subset of NSCLC patients. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessArticle Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells
Cancers 2013, 5(4), 1355-1378; doi:10.3390/cancers5041355
Received: 7 August 2013 / Revised: 17 September 2013 / Accepted: 12 October 2013 / Published: 31 October 2013
Cited by 8 | PDF Full-text (676 KB) | HTML Full-text | XML Full-text
Abstract
Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series [...] Read more.
Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series of tested analogs the diastereomeric analog PRI-2202 showed the strongest antiproliferative activity on the human breast cancer cell line MCF-7, whereas the geometric analog PRI-2205 was the weakest. Both analogs were less potent in antiproliferative activity against HL-60 cells compared to the reference compounds. The ability to potentiate antiproliferative effect of cisplatin or doxorubicin against HL-60 cells or that of tamoxifen against the MCF-7 cell line was observed at higher doses of PRI-2202 or PRI-2205 than those of the reference compounds. The proapoptotic activity of tamoxifen, expressed as the diminished mitochondrial membrane potential, as well as the increased phosphatidylserine expression, was partially attenuated by calcitriol, PRI-2191, PRI-2201 and PRI-2205. The treatment of the MCF-7 cells with tamoxifen alone resulted in an increase in VDR expression. Moreover, a further increase in VDR expression was observed when the analogs PRI-2201 or PRI-2205, but not PRI-2191, were used in combination with tamoxifen. This observation could partially explain the potentiation of the antiproliferative effect of tamoxifen by vitamin D analogs. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessArticle Gene Regulatory Scenarios of Primary 1,25-Dihydroxyvitamin D3 Target Genes in a Human Myeloid Leukemia Cell Line
Cancers 2013, 5(4), 1221-1241; doi:10.3390/cancers5041221
Received: 28 August 2013 / Revised: 19 September 2013 / Accepted: 26 September 2013 / Published: 16 October 2013
Cited by 5 | PDF Full-text (1001 KB) | HTML Full-text | XML Full-text
Abstract
Genome- and transcriptome-wide data has significantly increased the amount of available information about primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes in cancer cell models, such as human THP-1 myelomonocytic leukemia cells. In this study, we investigated the genes [...] Read more.
Genome- and transcriptome-wide data has significantly increased the amount of available information about primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes in cancer cell models, such as human THP-1 myelomonocytic leukemia cells. In this study, we investigated the genes G0S2, CDKN1A and MYC as master examples of primary vitamin D receptor (VDR) targets being involved in the control of cellular proliferation. The chromosomal domains of G0S2 and CDKN1A are 140–170 kb in size and contain one and three VDR binding sites, respectively. This is rather compact compared to the MYC locus that is 15 times larger and accommodates four VDR binding sites. All eight VDR binding sites were studied by chromatin immunoprecipitation in THP-1 cells. Interestingly, the site closest to the transcription start site of the down-regulated MYC gene showed 1,25(OH)2D3-dependent reduction of VDR binding and is not associated with open chromatin. Four of the other seven VDR binding regions contain a typical DR3-type VDR binding sequence, three of which are also occupied with VDR in macrophage-like cells. In conclusion, the three examples suggest that each VDR target gene has an individual regulatory scenario. However, some general components of these scenarios may be useful for the development of new therapy regimens. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)

Review

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Open AccessReview The Protective Role of Vitamin D Signaling in Non-Melanoma Skin Cancer
Cancers 2013, 5(4), 1426-1438; doi:10.3390/cancers5041426
Received: 2 September 2013 / Revised: 18 September 2013 / Accepted: 30 September 2013 / Published: 5 November 2013
Cited by 1 | PDF Full-text (309 KB) | HTML Full-text | XML Full-text
Abstract
Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting the proliferation while promoting the [...] Read more.
Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting the proliferation while promoting the differentiation of keratinocytes, the major cell in the epidermis from which NMSC are derived, is well known. However, recent findings that mice lacking the VDR are predisposed to skin cancer has brought to the fore the question of how the VDR is protective. In this review we will look first at the role of vitamin D signaling in regulating the proliferation and differentiation of keratinocytes. We will examine two pathways, β-catenin (CTNNB) and hedgehog (HH), that are regulated by vitamin D signaling and may contribute to the dysregulated proliferation and differentiation in the absence of VDR. We will then examine the failure of VDR deficient keratinocytes to repair DNA damaged by UVB. Finally we will examine the change in long non-coding RNA (LncRNA) expression in VDR null keratinocytes that in other cells is associated with malignant transformation, a potential newly appreciated mechanism by which vitamin D signaling is protective against NMSC. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessReview Vitamin D Is a Multilevel Repressor of Wnt/b-Catenin Signaling in Cancer Cells
Cancers 2013, 5(4), 1242-1260; doi:10.3390/cancers5041242
Received: 20 August 2013 / Revised: 2 October 2013 / Accepted: 10 October 2013 / Published: 21 October 2013
Cited by 19 | PDF Full-text (604 KB) | HTML Full-text | XML Full-text
Abstract
The Wnt/b-catenin signaling pathway is abnormally activated in most colorectal cancers and in a proportion of other neoplasias. This activation initiates or contributes to carcinogenesis by regulating the expression of a large number of genes in tumor cells. The active vitamin D [...] Read more.
The Wnt/b-catenin signaling pathway is abnormally activated in most colorectal cancers and in a proportion of other neoplasias. This activation initiates or contributes to carcinogenesis by regulating the expression of a large number of genes in tumor cells. The active vitamin D metabolite 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits Wnt/b-catenin signaling by several mechanisms at different points along the pathway. Additionally, paracrine actions of 1,25(OH)2D3 on stromal cells may also repress this pathway in neighbouring tumor cells. Here we review the molecular basis for the various mechanisms by which 1,25(OH)2D3 antagonizes Wnt/b-catenin signaling, preferentially in human colon carcinoma cells, and the consequences of this inhibition for the phenotype and proliferation rate. The effect of the vitamin D system on Wnt/b-catenin signaling and tumor growth in animal models will also be commented in detail. Finally, we revise existing data on the relation between vitamin D receptor expression and vitamin D status and the expression of Wnt/b-catenin pathway genes and targets in cancer patients. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessReview Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells
Cancers 2013, 5(4), 1261-1270; doi:10.3390/cancers5041261
Received: 2 September 2013 / Revised: 1 October 2013 / Accepted: 10 October 2013 / Published: 21 October 2013
Cited by 4 | PDF Full-text (557 KB) | HTML Full-text | XML Full-text
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)
Open AccessReview Immune Regulatory Activity of Vitamin D3 in Head and Neck Cancer
Cancers 2013, 5(3), 1072-1085; doi:10.3390/cancers5031072
Received: 24 May 2013 / Revised: 2 July 2013 / Accepted: 29 July 2013 / Published: 14 August 2013
Cited by 5 | PDF Full-text (1811 KB) | HTML Full-text | XML Full-text
Abstract
While vitamin D exhibits a multitude of cellular effects that can impact on cancer development and progression, this review focuses on its immune modulatory effects. These immune modulatory effects can be both direct and indirect. Compared to other cancer types, head and [...] Read more.
While vitamin D exhibits a multitude of cellular effects that can impact on cancer development and progression, this review focuses on its immune modulatory effects. These immune modulatory effects can be both direct and indirect. Compared to other cancer types, head and neck squamous cell carcinomas (HNSCC) have received less attention, but are a fascination immunologically because of the profound extent to which they inhibit immune defenses. This review describes the mechanisms of some of these immune inhibitory processes and how vitamin D can help overcome aspects of this immune suppression. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)

Other

Jump to: Research, Review

Open AccessDiscussion The Inverse Relationship between 25-Hydroxyvitamin D and Cancer Survival: Discussion of Causation
Cancers 2013, 5(4), 1439-1455; doi:10.3390/cancers5041439
Received: 22 September 2013 / Revised: 22 October 2013 / Accepted: 24 October 2013 / Published: 5 November 2013
Cited by 7 | PDF Full-text (499 KB) | HTML Full-text | XML Full-text
Abstract
Cancer mortality rates vary inversely with geographic latitude and solar ultraviolet-B doses. This relationship may be due to an inhibitory role of vitamin D on cancer development. The relationship between vitamin D and cancer appears to be stronger for studies of cancer [...] Read more.
Cancer mortality rates vary inversely with geographic latitude and solar ultraviolet-B doses. This relationship may be due to an inhibitory role of vitamin D on cancer development. The relationship between vitamin D and cancer appears to be stronger for studies of cancer mortality than incidence. Because cancer mortality reflects both cancer incidence and survival, the difference may be due to effects of vitamin D on cancer survival. Here we review analytic epidemiologic studies investigating the relation between vitamin D, measured by circulating levels of 25-hydroxyvitamin D (25-OHD), and cancer survival. A relationship between low 25-OHD levels and poor survival is shown by most of the reviewed studies. This relationship is likely to be causal when viewed in light of most criteria for assessing causality (temporality, strength, exposure-response, biological plausibility and consistency). A serum level of 25-OHD around 50 nmol/L appears to be a threshold level. Conversely, there are several mechanisms whereby cancer could lower serum levels of 25-OHD. The severity of disease at the time of diagnosis and time of serum sampling are key factors to clarify the temporal aspect of these relationships. Evidence that vitamin D supplementation could retard the disease process or prolong survival time would be key evidence, but is difficult to generate. However, recent clinical trial results in prostate cancer support a role for vitamin D in this regard. Full article
(This article belongs to the Special Issue Vitamin D: Role in Cancer Causation, Progression and Therapy)

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