Role of Nuclear Hormone Receptor Peroxisome Proliferator-Activated Receptor Delta in Colorectal Cancer
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths in the U.S. CRC is also the second most common cancer among U.S. Veterans. Certain lifestyles such as high intake of the Western pattern diet (WPD) is also a risk factor for cancer, including CRC. WPD often contains high saturated fat, red and processed meat, with an excess of total calories. It is well established from observational studies that consumption of a high-fat diet is a risk factor for developing obesity, cardiovascular disease, and diabetes. Obesity is associated with increased risks of various cancers including CRC. More than two-thirds of all adults and nearly one-third of all children and youth in the U.S. are either overweight or obese according to the 2015-2020 Dietary Guidelines for Americans. Being overweight and obese, as well as CRC, significantly reduces U.S. military personnel health, readiness, and their family health in recent decades. Specifically, the percentage of military personnel with obesity increased from 5% in 1995 to nearly 15% in 2015. This could be due to Army campus-style environments with an abundance of fast-food and snack-food options and lack of physically available healthy nutritious options. Fast- and snack-food are typical WPD. In addition, one cohort study showed that Veterans (aged 45-74 years) are more likely to be heavier consumers of red and processed meat, overweight, and obese as compared to non-Veterans. Although it is not clear which components of the Western-style diet contribute to CRC, one prospective cohort study showed that dietary fat is positively associated with the risk of CRC among women. In addition, several animal studies have provided direct evidence demonstrating that high-fat diets increase intestinal tumor burden. However, how dietary fat intake contributes to CRC remains elusive. It is also unknown whether dietary fats suppress host’s immune response against tumor cells. In this proposal, we will address these challenging questions and discover potential new targets for treatment and/or prevention of CRC. Immune response is regulated by a balance between co-stimulatory and inhibitory (checkpoint) pathways. Immune checkpoints put brakes on the immune system that are crucial to maintaining self-tolerance, and keeps a proper balance of the immune system which prevents inflammatory tissue damage and autoimmune diseases. Immune checkpoint pathways are activated by interaction of immune checkpoint receptors such as PD-1 with their ligands such as PD-L1. Ideally, our immune system must kill tumor cells; however, tumor cells can hijack immune checkpoint pathways to shut down immune response against tumor cells under certain conditions. In this proposal, we investigate whether dietary fats suppress host’s immune response against tumor cells via immune checkpoint pathways. Nuclear hormone receptors, such as peroxisome proliferator-activated receptor delta (PPARdelta), play a central role in regulating storage and metabolism of fatty fats. Although it appears that PPARdelta is a focal point of cross-talk between oncogenic signaling pathways, the role of PPARdelta in CRC needs to be more clearly understood. Very little is known about the role of PPARdelta in allowing the tumor to evade the immune system, much like a “cloaking device.” Tumor immune evasion is a strategy used by tumors to evade a host’s immune response and continue growing. Tumor immune evasion can occur through several mechanisms, such as tumor cell resistance to immune attack and activation of immune checkpoint pathways in immune cells within the tumor microenvironment. For example, PD-1 (an immune checkpoint receptor) is often increased on immune cells within the tumor and its expression is associated with poor clinical outcomes in a variety of human cancers. Moreover, PD-L1 (a PD-1 ligand) expression is also elevated in a variety of human cancers, including CRC and its expression
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110322
Entities
People
- Raymond Dubois
Organizations
- Medical University of South Carolina
- United States Army