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Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer
  1. Gemma Ferrer-Mayorga1,
  2. Gonzalo Gómez-López2,
  3. Antonio Barbáchano1,
  4. Asunción Fernández-Barral1,
  5. Cristina Peña3,
  6. David G Pisano2,
  7. Ramón Cantero4,
  8. Federico Rojo5,
  9. Alberto Muñoz1,
  10. María Jesús Larriba1
  1. 1Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain
  2. 2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain
  3. 3Department of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain
  4. 4Colorectal Unit, Department of Surgery, La Paz University Hospital, IdiPAZ, Madrid, Spain
  5. 5Department of Pathology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
  1. Correspondence to Professor Alberto Muñoz and Dr María Jesús Larriba, Instituto de Investigaciones Biomédicas “Alberto Sols”, Arturo Duperier 4, Madrid 28029, Spain; amunoz{at}iib.uam.es, mjlarriba{at}iib.uam.es

Abstract

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.

  • COLORECTAL CANCER
  • VITAMIN D RECEPTOR GENE
  • MYOFIBROBLASTS

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