Vitamin D and the nutritional environment in functions of intestinal stem cells: implications for tumorigenesis and prevention

Publication date: Available online 26 November 2019Source: The Journal of Steroid Biochemistry and Molecular BiologyAuthor(s): Wenge Li, Karina Peregrina, Michele Houston, Leonard H. AugenlichtAbstractSporadic colon cancer accounts for ∼80% of CRC, with high incidence in western societies strongly linked to dietary patterns. The only mouse model for sporadic CRC results from feeding mice a purified rodent western-style diet (NWD1), establishing mouse intake of several common nutrients that mimic for each its level consumed in western populations at higher risk for colon cancer (higher fat, lower vitamin D3, calcium, methyl donors and fiber). This causes sporadic colon and small intestinal tumors at an incidence and frequency similar to that of humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts before tumors are detected. Surprisingly, feeding NWD1 decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumorigenesis, associated with extensive Lgr5hi cell transcriptional reprogramming, with nutrient levels interactive in these effects. There is a key impact of the lower vitamin D3 in NWD1 and its signaling through the Vdr. The DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, reducing accumulation of relevant somatic mutations detected by single cell exome sequencing. There are also alterations in metabolic pathways, including down-regulation of oxidative...
Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research