Abstract
The Wnt/β-catenin signalling pathway is essential for intestinal epithelium homeostasis, but its aberrant activation is a hallmark of colorectal cancer (CRC). Several studies indicate that the bioactive vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits proliferation and promotes epithelial differentiation of colon carcinoma cells in part through antagonism of the Wnt/β-catenin pathway. It is now accepted that stromal fibroblasts are crucial in healthy and pathologic intestine: pericryptal myofibroblasts are constituents of the stem cell niche and cancer-associated fibroblasts (CAFs) contribute to CRC progression. However, studies on the combined action of 1,25(OH)2D3 and Wnt factors in colon fibroblasts are lacking. Here we show by global transcriptomic studies that 1,25(OH)2D3 and Wnt3A have profound, additive, partially overlapping effects on the gene expression profile of CCD-18Co human colon myofibroblasts. Moreover, 1,25(OH)2D3 and Wnt3A inhibit CCD-18Co cell proliferation and migration, while 1,25(OH)2D3 reduces, but Wnt3A increases, their capacity to contract collagen gels (a marker of fibroblast activation). These data were largely confirmed in patient-derived primary colon normal fibroblasts and CAFs, and in fibroblasts from other origins. Our results indicate that 1,25(OH)2D3 and Wnt3A are strong regulators of colon fibroblast biology and contribute to a better knowledge of intestinal homeostasis and stromal fibroblast action in CRC.
Highlights
Pericryptal myofibroblasts are constituents of the stem cell niche and cancer-associated fibroblasts (CAFs) contribute to Colorectal cancer (CRC) progression
We recently showed that primary cultures of human colon normal fibroblasts (NFs) and Cancer-associated fibroblasts (CAFs) express vitamin D receptor (VDR) and respond to 1,25(OH)2D3
Our results indicate that 1,25(OH)2D3 and Wnt3A are crucial regulators of the gene expression and phenotype of human colon fibroblasts and may contribute to a better understanding of intestinal homeostasis and more efficient treatment of intestinal pathologies such as CRC, inflammatory bowel diseases, and intestinal fibrosis
Summary
Pericryptal myofibroblasts are constituents of the stem cell niche and cancer-associated fibroblasts (CAFs) contribute to CRC progression. Several signals are required to maintain the homeostasis of intestinal stem cells, among them canonical Wnt factors have a prominent role[1,2,3] These Wnt proteins are provided by cellular components of the stem cell niche such as Paneth cells (only in the small intestine) and pericryptal myofibroblasts[3,4,5]. Extracellular canonical Wnts bind to their cell membrane receptors and promote an intracellular signalling cascade (known as the Wnt/β-catenin or canonical Wnt signalling pathway) that leads to the translocation of β-catenin to the cell nucleus There, it binds DNA-bound transcription factors of the T-cell factor (TCF) family and acts as a transcriptional co-activator for several genes that are crucial to preserve the stemness and the undifferentiated phenotype of intestinal stem cells[6]. They modulate the extracellular matrix properties and secrete molecules that act on carcinoma and other cells present in the tumour microenvironment promoting tumour growth and invasion, angiogenesis and immunosuppression[17,18,19]
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