Targeting Racial Disparities in Stromal DGAT to Suppress Aggressive Prostate Cancer
Abstract
Scientific Objective and Rationale: African American men develop prostate cancer at a younger age, and when the cancer is diagnosed in this population, it is more likely to be more aggressive compared to other racial groups. Although socioeconomic factors and access to health care clearly affect the racial disparity in prostate cancer, recent evidence suggests that biological factors may also be critical for the racial differences in incidence and outcome. The aggressive nature of cancer cells is directly influenced by a group of cells immediately adjacent that collectively constitute the tumor microenvironment or tumor stroma. Factors produced by tumor stroma in prostate cancer have been shown to increase tumor progression to metastatic disease. Despite this overwhelming evidence of tumor stroma as key regulators of aggressive disease, a very limited number of studies have been focused in the area of racial disparities. The major limitation is the lack of appropriate basic research tools (cell lines and mouse models) in prostate cancer research that can be used to identify key players responsible for the racial disparity. To overcome this limitation, we have recently developed a new model to study the effects of the tumor stroma in African American men using stromal cells isolated directly from prostate cancer patients and implanted in mice. This approach represents a significant advance in prostate cancer research in health disparity because it mimics the interactions of the tumor stroma with cancer cells found in patients. Using these stromal cells, we discovered that the tumor stroma from African American patients has a more robust effect on the growth of prostate cancer cell lines compared to the stroma from Caucasians. We also identified a panel of molecules involved in an abnormal storage of fat within the tumor stroma of African American patients. A recent report by the Centers for Disease Control and Prevention highlights that racial disparities in adult obesity, especially in African Americans, are a public health burden. Obesity increases fat deposits in nonadipose tissues as well as the risk of developing aggressive prostate cancer. These fat deposits serve as a source of energy during cancer cells progression. We found that DGAT1, a molecule that regulates the formation of fat deposits, was significantly higher in stromal cells from African Americans. DGAT1 levels have been associated with aggressive metastatic disease in several types of cancer. However, the functional consequences of stromal DGAT1 found in African Americans on prostate cancer progression have not been previously studied. In an effort to better understand the intrinsic mechanism(s) responsible for the pro-tumorigenic effects of tumor stroma, we hypothesize that the presence of abnormal DGAT1 levels in the tumor stroma of African American patients may be responsible for a more aggressive state overall supporting cancer progression. In this proposal, we will evaluate the clinical utility of assessing DGAT1 (and or DGAT2) to identify prostate cancer patients with a higher risk of developing aggressive disease. Our preliminary observations show that the prostate tumor stroma of African American men produce significant higher levels of DGAT compared to Caucasians. Therefore, we will to determine the prognostic value of assessing DGAT levels in prostate cancer tissues from African American patients to assess aggressive disease. Next we will use our recently developed in vivo model approach to study racial disparity in prostate cancer to understand the molecular mechanisms exerted by DGAT in cells present in the tumor microenvironment in relation to tumor progression. What Types of Patients Will It Help, and How Will It Help Them? Our studies are aimed to identify African American patients with potentially progressive disease by providing new tools to aid clinicians to risk-stratify patients in the clinic more accurately. W
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010210
Entities
People
- Omar E Franco
Organizations
- NorthShore University HealthSystem
- United States Army