Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer

Ferrer-Mayorga, Gemma; Gómez‐López, Gonzalo; Barbáchano, Antonio; Fernández‐Barral, Asunción; Peña, Cristina; Pisano, David G.; Cantero, Ramón; Rojo, Federico; Múñoz, Alberto; Larriba, María Jesús

doi:10.1136/gutjnl-2015-310977

Cited by 146 publications

(108 citation statements)

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“…Vitamin D action in human colon has classically been investigated in immortalized carcinoma cell lines, and recently in ex vivo short‐lived colon biopsy samples and primary fibroblasts from patient‐derived normal and tumor tissue . We report for the first time that human colon stem cells express VDR in vivo .…”

Section: Discussionmentioning

confidence: 93%

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

et al. 2019

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Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25‐dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids, calcitriol upregulates stemness‐related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7, and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness‐related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.

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Section: Discussionmentioning

confidence: 93%

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

et al. 2019

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“…In an elegant series of studies, Munoz and coworkers have dissected the relationships between VDR signaling and invasion in colon cancer cell lines and primary tumors. [81][82][83][84][85][86] These workers established the delicate interplay between VDR, E-cadherin, and the Wnt signaling pathway in cell lines and clinical samples. Others have examined adhesion protein expression in other cancer models, suggesting that these mechanisms may be generalizable beyond colon cancer cells.…”

Section: Tissue Invasion and Metastasismentioning

confidence: 99%

Vitamin D Receptor Signaling and Cancer

Campbell

Trump

2017

Endocrinology and Metabolism Clinics of North America

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The primary biological action of the secosteroid hormone vitamin D (1,25(OH) 2 D 3 ) is to bind to the vitamin D receptor (NR1I1/VDR) and to regulate serum calcium levels. As a downstream consequence, the actions of the receptor control bone formation and maintenance. The first clinical manifestation of insufficient VDR endocrine signaling, rickets, was discovered by Daniel Whistler in the Netherlands in the 17th century; 300 years later, the VDR gene was cloned by Bert O'Malley and coworkers. 1 Between these dates, research into vitamin D was at the forefront of areas of public health, chemistry and biochemistry including the light catalyzed synthesis of vitamin D 3 by Adolf Windaus. For this work, he received the Nobel Prize in Chemistry (1928). Work in the 1960s and 1970s led to analyses of vitamin D endocrine metabolism and led to remarkable strides describing biochemical synthesis of 1,25(OH) 2 D 3 and the diverse biology in which VDR participates.The precursor of 1,25(OH) 2 D 3 , cholecalciferol or vitamin D 3 , is produced in the skin and converted in the liver to 25-hydroxyvitamin D 3 , (25(OH)D 3 ); circulating levels of 25(OH)D 3 serve as a useful index of vitamin D total body stores. A further hydroxylation occurs in the principally in the kidney at the carbon 1 position by 25-hydroxyvitamin D-1α-hydroxylase (encoded by CYP27B1) to produce the biologically active hormone, 1,25(OH) 2 D 3 . A second mitochondrial cytochrome P450 enzyme, the 24-hydroxylase (encoded by CYP24A1), can use both 25(OH)D and 1,25(OH) 2 D 3 as substrates, and is the first step in the inactivation pathway for these metabolites. Because of the direct role 1,25(OH) 2 D 3 plays in control of serum calcium levels, elevated levels of 1,25(OH) 2 D 3 block its synthesis and induce inactivation and accelerate catabolism 2 via induction of CYP24A1, in a classical negative feedback loop.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The first report that VDR actions could control cancer cell growth were discovered partly through serendipity, and partly through logical extension of other studies. Reports in the 1970s identified purified cell fractions that bound 1,25(OH) 2 D 3 with high affinity, 14 and encouraged investigators to begin to consider what were the molecular actions of the VDR in the classic tissues involved in calcium homeostasis, for example, skin, bone, intestine, and kidney. 15 In 1981, Kay Colston and coworkers 16 were first to demonstrate that 1α,25(OH) 2 D 3 at nanomolar concentrations inhibited human melanoma cell proliferation in vitro. That the workers used a cancer cell model was serendipitous; cancer cell models are more readily available to study in cell culture experiments than nonmalignant counterparts, and in this case 16 the cells chosen were available in an adjacent laboratory. Campbell and Trump In parallel, it was also known that retinoids, which are also small lipophilic molecules that target NRs, could drive cell differentiation, for exa...

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“…We read with great interest the recent publication by Ferrer-Mayorga et al ,1 concerning Vitamin D receptor (VDR) signalling’s impacts on cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). In line with one previous publication regarding VDR in pancreatic cancer (PC),2 activation of VDR signalling in stromal fibroblasts predicts a favourable clinical outcome in CRC.…”

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confidence: 99%

VDR signaling inhibits cancer-associated-fibroblasts’ release of exosomal miR-10a-5p and limits their supportive effects on pancreatic cancer cells

Kong

Wang

et al. 2018

Gut

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Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer

Cited by 146 publications

References 54 publications

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

Vitamin D Receptor Signaling and Cancer

VDR signaling inhibits cancer-associated-fibroblasts’ release of exosomal miR-10a-5p and limits their supportive effects on pancreatic cancer cells

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