title: Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer.
abstract: 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.
  
  
  
  Expression of vitamin D receptor (VDR) and two 1,25(OH)2D3target genes was analysed in 658 patients with CRC with prolonged clinical follow-up. 1,25(OH)2D3effects 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.
  
  
  
  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)2D3inhibited 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.
  
  
  
  1,25(OH)2D3has 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.
authors.affiliation: Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Ferrer-Mayorga
authors.affiliation: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.affiliation: Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Barbáchano
authors.affiliation: Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Asunción
authors.initials: A
authors.lastname: Fernández-Barral
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.affiliation: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.affiliation: Colorectal Unit, Department of Surgery, La Paz University Hospital, IdiPAZ, Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Cantero
authors.affiliation: Department of Pathology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.affiliation: Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.affiliation: Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Larriba
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D002277:Carcinoma / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018572:Disease-Free Survival; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051861:Kangai-1 Protein / Q000235:genetics; D018167:Receptors, Calcitriol / Q000032:analysis / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4 / Q000235:genetics; D015996:Survival Rate; D059467:Transcriptome; D014815:Vitamins / Q000494:pharmacology*
chemical_list: C497688:CD82 protein, human; D051861:Kangai-1 Protein; D018167:Receptors, Calcitriol; D000071999:S100 Calcium-Binding Protein A4; D014815:Vitamins; C077591:S100A4 protein, human; D003094:Collagen; D002117:Calcitriol
keywords: COLORECTAL CANCER; MYOFIBROBLASTS; VITAMIN D RECEPTOR GENE