Prostate Tissue Gene Expression Patterns Predict Prostate Tissue Inflammation, Aggressive Prostate Cancer, and a Poorer Prognosis Among Black and White Men
Abstract
A normal immune response is the first line of defense against cancer. However, an immune response that fails to turn off after removing the challenge may, over time, create regions of inflammation in the tissue. Counter to the immune system’s intended role, the creation of this inflammation may actually promote an aggressive prostate cancer. Obesity, insulin resistance, smoking, or other lifestyle factors may initiate a state of chronic inflammation by releasing signaling proteins (i.e., cytokines, chemokines, reactive oxygen specifies, others) that alter the normal balance of pro- and anti-inflammatory immune responses. As the balance between pro- vs. anti-inflammatory signaling shifts to favor a “hyperactive” pro-inflammatory and pro-cancer development, cell growth and damage due to oxidants increase within the prostate. Black men are at higher risk of an aggressive prostate cancer and have a higher prostate cancer death rate compared to white men. Black populations are also at higher risk for inflammatory-related diseases, including high blood pressure and diabetes, and blacks are also reported to have higher blood levels of pro-inflammatory markers, including C-reactive protein and interleukin-6. We believe that differences in immune system regulation between blacks and whites contribute to the race disparities in prostate cancer. Thus, the overarching goals of this proposal are to determine how prostate tissue inflammation alters prostate tissue, whether these changes in prostate tissue are the same in black and white men, and whether there is an impact of these tissue changes on prostate cancer aggressiveness and prognosis following treatment. With modern technology, we can accurately assess which exact genes are active and at what level, which can be a powerful approach to identify genes that are expressed under different conditions with prostate cancer. Only a few prior studies have compared prostate tissue gene expression profiles between black and white prostate cancer patients, and these studies reported that black men had higher expression of genes involved with an activated immune system. There were also differences with race in genes involved in the immune response, antigen presentation, T-cell function, and cytokine signaling. One study found that inflammatory gene expression differed between low-grade and high-grade prostate cancer, as well as by race, such that inflammatory gene expression was higher in prostate tissue from blacks, but only in low-grade tumors. Differences in the regulation of inflammatory pathways were found to be coupled with race differences in prostate tissue DNA copy number and cell regulatory genes, perhaps more so in the stroma than in the tumor. Thus, the limited existing literature suggests there are differences between race groups in inflammatory activation in the prostate. Which component of inflammation that causes these changes in prostate gene expression is uncertain, and whether the same processes are involved in black vs. white men is also unknown. This proposal asks what aspect of the immune system alters gene expression in prostate tissue that results in greater prostate cancer in black or white men. We are thoroughly characterizing systemic inflammatory markers and prostate tissue inflammatory markers in 150 black and 150 white men. We will investigate the race-specific link between specific immune cell patterns and the expression of inflammatory regulatory gene expression in prostate tissue. The immune system is complex, and therefore we include a broad spectrum of immune cells to investigate pro- and anti-inflammatory immune cell reactions that may affect prostate cancer outcomes and that differ with race. This analysis will help us identify those components of inflammation that are most relevant to the diagnosis of aggressive prostate cancer, or that affect the response to prostate cancer treatment, and the similarities or differences in these re
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810266
Entities
People
- Jay Fowke
Organizations
- United States Army
- University of Tennessee Health Science Center