Abstract 634: Hypercholesterolemia Increases the Incidence of Colorectal Neoplasia by Impairing Hematopoietic Stem Cell Differentiation Towards Nkt and γδ T Cells

Abstract

Rationale: Hypercholesterolemia, a co-morbidity of obesity, is one of the most common diet-related metabolic disorders and is an independent risk factor for colorectal neoplasia. As yet, no generalizable mechanism has been described to show how hypercholesterolemia increases the risk of cancer especially that of colorectal neoplasia. Objective: We hypothesized that hypercholesterolemia impaired the differentiation of hematopoietic stem cells (HSCs) toward the cellular components critical to immunosurveillance against colorectal neoplasia. Identifying the mechanisms by which hypercholesterolemia affects HSC differentiation may provide clues to understanding how hypercholesterolemia increases all-cause mortality and especially that of colorectal cancer in divergent clinical studies. Methods and Results: Two different hypercholesterolemic mice were applied in the study, including ApoE-/- mouse and high cholesterol diet fed WT mouse. Colorectal neoplasia was induced by IP injection of AOM. The incidence of colorectal neoplasia was significantly higher in these hypercholesterolemic mice. FACS analysis showed that NKT and γδT cells were significantly fewer in the thymus and colon of hypercholesterolemic mice. The infiltration of NKT and γδT cells in tumors isolated from hypercholesterolemic mice was attenuated. In agreement, in vitro differentiation assay demonstrated that the differentiation capacity of HSCs towards NKT and γδT cells was significantly impaired in the groups isolated from hypercholesterolemic mice. The deficiency in NKT or γδT cells increased the incidence of AOM-induced colorectal neoplasia. Conclusion: NKT and γδT cells are critical cellular components in the immnuosurveillance against colorectal neoplasia. Hypercholesterolemia increases the incidence of colorectal neoplasia by impairing the differentiation of HSCs towards NKT and γδT cells.