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Título: | Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer |
Autor: | Ferrer-Mayorga, Gemma CSIC; Gómez-López, Gonzalo; Barbáchano, Antonio CSIC ORCID; Fernández-Barral, Asunción CSIC ORCID; Peña, Cristina; Pisano, David G.; Cantero, Marta; Rojo, Federico; Muñoz Terol, Alberto CSIC ORCID; Larriba, María Jesús CSIC ORCID | Fecha de publicación: | 2017 | Editor: | BMJ Publishing Group | Citación: | Gut 66(8): 1449-1462 (2017) | Resumen: | [Objective]: Colorectal cancer (CRC) is a major health concern. Vitamin D deficiency is associated with high CRC incidence and mortality, suggesting a protective effect of vitamin D against this disease. Given the strong influence of tumour stroma on cancer progression, we investigated the potential effects of the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on CRC stroma. [Design]: Expression of vitamin D receptor (VDR) and two 1,25(OH)2D3 target genes was analysed in 658 patients with CRC with prolonged clinical follow-up. 1,25(OH)2D3 effects on primary cultures of patient-derived colon normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were studied using collagen gel contraction and migration assays and global gene expression analyses. Publicly available data sets (n=877) were used to correlate the 1,25(OH)2D3-associated gene signature in CAFs with CRC outcome. [Results]: High VDR expression in tumour stromal fibroblasts was associated with better overall survival (OS) and progression-free survival in CRC, independently of its expression in carcinoma cells. 1,25(OH)2D3 inhibited the protumoural activation of NFs and CAFs and imposed in CAFs a 1,25(OH)2D3-associated gene signature that correlated with longer OS and disease-free survival in CRC. Furthermore, expression of two genes from the signature, CD82 and S100A4, correlated with stromal VDR expression and clinical outcome in our cohort of patients with CRC. [Conclusions]: 1,25(OH)2D3 has protective effects against CRC through the regulation of stromal fibroblasts. Accordingly, expression of VDR and 1,25(OH)2D3-associated gene signature in stromal fibroblasts predicts a favourable clinical outcome in CRC. Therefore, treatment of patients with CRC with VDR agonists could be explored even in the absence of VDR expression in carcinoma cells. |
Versión del editor: | https://doi.org/10.1136/gutjnl-2015-310977 | URI: | http://hdl.handle.net/10261/187999 | DOI: | 10.1136/gutjnl-2015-310977 | ISSN: | 0017-5749 | E-ISSN: | 1468-3288 |
Aparece en las colecciones: | (IIBM) Artículos |
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vitamcolorec.pdf | 10,84 MB | Adobe PDF | Visualizar/Abrir |
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