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Expression of vitamin D receptor and vitamin D-associated gene signature in tumour stromal fibroblasts predicts clinical outcome in colorectal cancer patients

AuthorsFerrer-Mayorga, Gemma ; Gómez-López, Gonzalo; Rojo, Federico; Muñoz Terol, Alberto ; Larriba, María Jesús
Issue Date2016
CitationEMCCC 2016
Abstract[Objective]: Colorectal cancer (CRC) is the neoplasia most strongly associated with vitamin D deficiency. Many epidemiological studies indicate that vitamin D deficiency increases the risk of CRC and thus, suggest that vitamin D has a protective effect on CRC. This is supported by preclinical studies using vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, the most active vitamin D metabolite) or analogues in cultured cells and experimental animals. 1,25(OH)2D3 inhibits the proliferation and promotes the differentiation of colon carcinoma cells by mechanisms that include cell cycle arrest at G0/G1, the blockade of the Wnt/β-catenin pathway and the induction of E-cadherin and other epithelial adhesion proteins. 1,25(OH)2D3 action is mediated by the vitamin D receptor (VDR), a member of the superfamily of nuclear receptors that upon ligand biding regulates the transcription rate of hundreds of genes. Consequently, VDR expression is the main determinant of cell responsiveness to 1,25(OH)2D3. Fibroblasts are the main cellular component of tumour stroma and upon activation by the tumour microenvironment they contribute to tumorigenesis by several mechanisms. In this study we explored VDR expression and 1,25(OH)2D3 action on CRC stromal fibroblasts. [Methods]: The expression of VDR and of two 1,25(OH)2D3 target genes was analysed in 658 metastatic CRC patients with prolonged clinical follow-up. Primary cultures of patient-derived colon normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were set up to study 1,25(OH)2D3 effects on gene expression and on two fibroblast protumoural properties: collagen gel contraction and induction of carcinoma cell migration. Publically available datasets were used to correlate the expression of the gene signature imposed by 1,25(OH)2D3 in CAFs with CRC patient clinical outcome. [Results]: High VDR expression in tumour stromal fibroblasts is associated with better overall survival and progression-free survival in CRC. Patient-derived NFs and CAFs express VDR and respond to 1,25(OH)2D3. 1,25(OH)2D3 inhibits the ability to reorganize collagen fibres and contract collagen gels of NF and CAF primary cultures. In addition, 1,25(OH)2D3 reduces the capacity of NF and CAF cultures to paracrinally promote the migration of human colon carcinoma cells in Transwell-mediated coculture assays. Remarkably, global transcriptomic analyses show that 1,25(OH)2D3 imposes in CAFs a gene signature that correlates with longer overall survival and disease-free survival of CRC patients. Moreover, expression of two 1,25(OH)2D3 target genes CD82 (upregulated) and S100A4 (downregulated) is associated directly and inversely, respectively, with stromal VDR expression and CRC patient clinical outcome. [Conclusions]: Our results indicate that CRC stromal fibroblasts express VDR and that their gene expression and physiology is modulated by 1,25(OH)2D3 in a way that may contribute to the antitumoural action of 1,25(OH)2D3 against this neoplasia. High expression of VDR and of the 1,25(OH)2D3-associated gene signature in stromal fibroblasts predicts a favourable clinical outcome in CRC. Thus, treatment of CRC patients with VDR agonists could be explored even in the absence of VDR expression in carcinoma cells.
DescriptionResumen del póster presentado al 8th European Multidisciplinary Colorectal Cancer Congress, celbrado en Amsterdam (Netherlands) del 11 al 13 de diciembre de 2016.
Appears in Collections:(IIBM) Comunicaciones congresos
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