Hypercholesterolemia Increases Colon Cancer Risk by a Tet1-dependent Reduction of Hematopoietic Stem Cell differentiation towards NKT and ?dT cells: Potential Novel ImmunotherapyWednesday, 2 November 2016 at 16:30 Add to Calendar ▼2016-11-02 16:30:002016-11-02 17:30:00Europe/LondonHypercholesterolemia Increases Colon Cancer Risk by a Tet1-dependent Reduction of Hematopoietic Stem Cell differentiation towards NKT and ?dT cells: Potential Novel ImmunotherapyCancer Immunotherapy and Biofluid Biopsies 2016 in Boston, USABoston, USASELECTBIOenquiries@selectbiosciences.com Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity in obese people, has been shown to increase cancer risk, especially colorectal cancer. However, the mechanism by which hypercholesterolemia, or any metabolic disorder, increases cancer risk remains unknown. In this study, we show that hypercholesterolemia increases the incidence and pathological severity of colorectal neoplasia in two independent mouse models by inducing an oxidant-stress dependent increase in miR101c that downregulates Tet1 in hematopoietic stem cells (HSCs) which in turn reduces the expression of genes critical to natural killer T cell (NKT) and ?dT cell differentiation. These effects reduce the number and function of terminally differentiated NKT and ??T cells in the thymus, the colon submucosa and during early tumorigenesis. These results suggest a new mechanism by which a metabolic disorder induces epigenetic mechanisms that reduce lineage priming of HSCs towards immune cells and thereby compromises immunosurveillance against cancer. |