Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Fernández‐Barral, Asunción; Bustamante-Madrid, Pilar; Ferrer-Mayorga, Gemma; Barbáchano, Antonio; Larriba, María Jesús; Múñoz, Alberto

doi:10.3390/cancers12092413

Cited by 45 publications

(23 citation statements)

References 137 publications

(171 reference statements)

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“…Looking beyond the box of autoimmune diseases to the mounting evidence of Vitamin D as a player in tumor development ( 81 , 82 ), significant associations between SNPs of vitamin D system genes and common types of cancer (prostate, breast, colorectal and skin cancer) have been reported ( 83 , 84 ), suggesting a similar predisposing role of SNPs for cancer as for autoimmune diseases. In these cases, a partial blockade of the VDR by pathogens could be another pathway within the established infectious etiology of cancer ( 85 , 86 ).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol

et al. 2021

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Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol

et al. 2021

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“…Four decades ago, an epidemiological study hinted at the protective effects of vitamin D 3 against CRC by indicating that high UVB exposure or life at lower latitudes, both of which result in higher vitamin D 3 synthesis, lead to lower incidence of CRC [ 38 ]. Since then, a large number of epidemiological studies, experimental work performed in cultured cells and animal models, and also some, but not all, vitamin D 3 supplementation human clinical trials have strongly suggested that 1,25(OH) 2 D 3 has anticancer effects, particularly in CRC [ 31 , 37 , 39 , 40 , 41 , 42 , 43 , 44 ].…”

Section: Antagonism Of Wnt/β-catenin Signaling By 125(oh)mentioning

confidence: 99%

“…VDR is expressed in most normal human cell types and tissues, but also in cancer cell lines and tumors of diverse origins. In line with the antitumor effects of 1,25(OH) 2 D 3 observed in several neoplasias, high VDR expression in human cancer is usually a hallmark of good prognosis [ 29 , 31 , 36 , 37 , 124 ]. VDR expression and activity is regulated transcriptionally, posttranscriptionally by several microRNAs (miRs), and posttranslationally (via phosphorylation, ubiquitination, acetylation, and sumoylation) [ 125 ].…”

Section: Antagonism Of 125(oh) 2 Dmentioning

confidence: 99%

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Wnt and Vitamin D at the Crossroads in Solid Cancer

González‐Sancho

Larriba

Múñoz

2020

Cancers

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Abnormal activation of the Wnt/β-catenin pathway is common in many types of solid cancers. Likewise, a large proportion of cancer patients have vitamin D deficiency. In line with these observations, Wnt/β-catenin signaling and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active vitamin D metabolite, usually have opposite effects on cancer cell proliferation and phenotype. In recent years, an increasing number of studies performed in a variety of cancer types have revealed a complex crosstalk between Wnt/β-catenin signaling and 1,25(OH)2D3. Here we review the mechanisms by which 1,25(OH)2D3 inhibits Wnt/β-catenin signaling and, conversely, how the activated Wnt/β-catenin pathway may abrogate vitamin D action. The available data suggest that interaction between Wnt/β-catenin signaling and the vitamin D system is at the crossroads in solid cancers and may have therapeutic applications.

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“…( 89 ) Actions of 1,25(OH) 2 D on tumor‐associated stromal cells may include decreasing extracellular matrix remodeling, and decreasing promigratory effects on carcinoma cells, and in cancer stem cells, increasing cell–cell adhesion, increasing heterochromatization, and increasing organelles such as rough endoplasmic reticulum and Golgi, while decreasing tumorigenic cells. ( 90 ) Additionally other anti‐tumor calcitriol actions may include enhancing DNA repair, and influencing activity of endothelial cells and cells of the immune system. ( 91 )…”

Section: Selected Actions Beyond Mineral and Skeletal Homeostasismentioning

confidence: 99%

Probing the Scope and Mechanisms of Calcitriol Actions Using Genetically Modified Mouse Models

Miao

Goltzman

2020

JBMR Plus

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Genetically modified mice have provided novel insights into the mechanisms of activation and inactivation of vitamin D, and in the process have provided phenocopies of acquired human disease such as rickets and osteomalacia and inherited diseases such as pseudovitamin D deficiency rickets, hereditary vitamin D resistant rickets, and idiopathic infantile hypercalcemia. Both global and tissue‐specific deletion studies leading to decreases of the active form of vitamin D, calcitriol [1,25(OH)2D], and/or of the vitamin D receptor (VDR), have demonstrated the primary role of calcitriol and VDR in bone, cartilage and tooth development and in the regulation of mineral metabolism and of parathyroid hormone (PTH) and FGF23, which modulate calcium and phosphate fluxes. They have also, however, extended the spectrum of actions of calcitriol and the VDR to include, among others: modulation, jointly and independently, of skin metabolism; joint regulation of adipose tissue metabolism; cardiovascular function; and immune function. Genetic studies in older mice have also shed light on the molecular mechanisms underlying the important role of the calcitriol/VDR pathway in diseases of aging such as osteoporosis and cancer. In the course of these studies in diverse tissues, important upstream and downstream, often tissue‐selective, pathways have been illuminated, and intracrine, as well as endocrine actions have been described. Human studies to date have focused on acquired or genetic deficiencies of the prohormone vitamin D or the (generally inactive) precursor metabolite 25‐hyrodxyvitamin D, but have yet to probe the pleiotropic aspects of deficiency of the active form of vitamin D, calcitriol, in human disease. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Cited by 45 publications

References 137 publications

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol

Wnt and Vitamin D at the Crossroads in Solid Cancer

Probing the Scope and Mechanisms of Calcitriol Actions Using Genetically Modified Mouse Models

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