Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells

Abstract

Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity of obesity, 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 pathologic severity of colorectal neoplasia in two independent mouse models. Hypocholesterolemia induced an oxidant stress-dependent increase in miR101c, which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T-cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metabolic disorder induces epigenetic changes to reduce lineage priming of HSC toward immune cells, thereby compromising immunosur-veillance against cancer.

Lipolysis-stimulated lipoprotein receptor overexpression is a novel predictor of poor clinical prognosis and a potential therapeutic target in gastric cancer

“…However, there are several reports on the association between tumorigenesis and lipid uptake in various types of cancers [ 23 , 24 ]. Hypercholesterolaemia, which is a common metabolic disorder in obese people, has been shown to increase the risk of gastroenterological cancers, and substantial epidemiologic evidence links hypercholesterolaemia to an increased risk of colorectal cancer [ 25 – 29 ]. However, the association between hypercholesterolaemia and prognosis in patients with GC has not been investigated adequately, although a previous study found that serum total cholesterol levels were inversely associated with the risk of stomach cancer in men [ 30 ].…”

Hypercholesterolemia Accelerates the Aging Phenotypes of Hematopoietic Stem Cells by a Tet1-Dependent Pathway

“…3a,b). Our previous studies had shown that Tet1 deficiency decreased their differentiation towards natural killer T cells and γδT cells 17 and increased the differentiation towards pro-inflammatory monocytes and macrophages. These results indicate that Tet1 deficiency alters the differentiation of HSCs to multiple cell lineages.…”

“…The lentiviral particles were prepared according to the kit instructions. Freshly isolated KTSL cells were transduced with lentivirus for 24 hours and then selected with puromycin (2 μg/ml) (Santa Cruz Biotechnology, CA, USA) for 72 hours 17 .…”

“…The ten-eleven translocation (Tet) family, including Tet1, Tet2 and Tet3, oxidizes 5-mC and initiates the demethylation of DNA [14][15][16] . Tet1 and Tet2 have been shown to regulate the self-renewal, proliferation and differentiation of HSCs 14,17,18 . The expression of Tet1 is significantly decreased in HSCs of aged mice, suggesting that Tet1 participates in the regulation of HSC aging phenotypes 19 .…”

The emerging role of γδ T cells in cancer immunotherapy

“…This increase in malignant events is not shared by mice that lack αβ T cells [11]. Similar protective effects by γδ T cells have been validated in models of colorectal cancer [12], malignant melanoma [13], B cell lymphoma [14] and prostate cancer [15]. These important contributions to tissue homeostasis and cancer immunosurveillance [16] have fuelled scientific interest to further explore the biology of γδ T cells and their potential for clinical translation [17,18].…”