Calcitriol inhibits the protumoural properties of colorectal cancer-associated fibroblasts and the expression of its receptor in these cells predicts patient clinical outcome

Resumen del trabajo presentado al 41 Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Santander del 10 al 13 de septiembre de 2018.Vitamin D deficiency is associated with a higher risk of colorectal cancer (CRC). Accordingly, calcitriol, the most active vitamin D metabolite, inhibits the proliferation and promotes the epithelial differentiation of human colon carcinoma cell lines. Calcitriol action is mediated by the vitamin D receptor (VDR), a member of the superfamily of nuclear receptors that upon ligand binding regulates the transcription of target genes. Recent data indicate that fibroblasts are the principal cellular component of tumour stroma and contribute to tumourigenesis by numerous mechanisms. Thus, we have investigated calcitriol effects on primary cultures of CRC patient-derived colon normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs). NFs and CAFs express VDR and respond to calcitriol. Remarkably, calcitriol inhibits two fibroblast protumoural properties: the ability to reorganize the extracellular matrix and the capacity to paracrinally promote the migration of CRC cells. Moreover, global transcriptomic analyses show that calcitriol regulates the gene expression profile of NFs and CAFs, and imposes in CAFs a gene signature that correlates with a better outcome of CRC patients. We have also analysed the expression of VDR and of two calcitriol target genes (CD82, upregulated; and S100A4, downregulated) in 658 metastatic CRC patients. Importantly, high VDR expression in tumour stromal fibroblasts is associated with better prognosis. In addition, the expression of CD82 and S100A4 in these cells is associated directly and inversely, respectively, with that of VDR and with CRC patient clinical outcome. In summary, our results indicate that the antitumoural action of calcitriol on CRC is mediated not only by its direct action on carcinoma cells, but also by inhibiting the protumoural properties of CAFs. We propose that treatment of CRC patients with VDR agonists could be explored in those patients that express VDR in tumour stromal fibroblasts even in the absence of VDR expression in carcinoma cells.Peer Reviewe