Alcohol intake contributes to serious health issues including colorectal cancer (CRC). However, the exact mechanism(s) of ethanol-associated carcinogenesis, have remained obscure, as ethanol itself is not a carcinogen. Circadian disruption is a common feature among alcoholics. Epidemiological studies have linked non-traditional work schedules (e.g., shift work) with increased risks of cancer. The overall goal of this Project is to establish that alcohol consumption contributes to serious risk of colon cancer when combined with desynchronization of circadian rhythms and to reveal the underiying cellular immunologic mechanisms. We have evidence for inflammation driving polyposis, for mast cells orchestrating inflammation, and for regulation of mast cells and inflammation by Tregs. Alcohol fed mice whose circadian rhythms were disrupted by chronic shifting of the light/dark cycle developed overt intestinal and colonic inflammation, resulting in expanded mitotic proliferation zone and crypt elongation. We hypothesize that alcohol and desynchronization of circadian rhythms act synergistically to increase inflammation and susceptibility to colon cancer. Here we propose to test this hypothesis in a novel mouse model: mice that spontaneously develop benign polyps in their colon and distal ileum.
In Aim 1 we will establish the extent to which alcohol synergizes with environmental desynchronization of central and peripheral circadian rhythms through light/dark shift and food restriction to cause inflammation, exacerbate polyposis, and promote CRC. The role of mast cells and Tregs in this process will be addressed by genetic and pharmacologic interventions.
In Aim 2, we will use a genetic approach to establish that the circadian disruption of immune cells plays a considerable role in pathophysiology of alcohol induced colon cancer. We will generate through bone marrow chimerism mice that are predisposed to polyposis and also express a dominant negative Clock mutant in the immune compartment. The proposed studies are significantly relevant as a potential model for humans engaged in lifestyle-related disruption of proper circadian organization.Our findings will provde new paradigms for cancer prevention and targeted therapy.
Alcohol promotes cancer develoment/progression in a subset of individuals;however, it is not clear what factor(s) confer susceptibility. Identification of disrupted circadian rhythms as a predisposing factor for cancer devebpment/progression may.lead to new prevention strateges or treatment strategies (i.e., chronobiological therapy and/or pro- or pre-biotics) for alcohol-induced cancer.
|Forsyth, Christopher B; Voigt, Robin M; Keshavarzian, Ali (2014) Intestinal CYP2E1: A mediator of alcohol-induced gut leakiness. Redox Biol 3:40-6|
|Tang, Yueming; Forsyth, Christopher B; Keshavarzian, Ali (2014) The role of miRNAs in alcohol-induced endotoxemia, dysfunction of mucosal immunity, and gut leakiness. Alcohol Clin Exp Res 38:2331-4|