Role of Unique Exosomes Secreted Under Hypoxia in Prostate Cancer Aggressiveness
Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men and displays a distinct racial disparity. We need better understanding of prostate cancer biology, especially in African Americans, to improve prognosis and treatment to lower PCa-associated deaths. Numerous clinical studies have shown that regions of low oxygen (hypoxia) in the growing tumors select for resistant clones, faster growth, treatment failure, and disease relapse. Despite that, we have limited knowledge about how hypoxia in tumors leads to aggressive disease. We have identified that, under hypoxic conditions, cancer cells start sending messages loaded in tiny membrane-bound vesicles called “exosomes.” Here onward, exosomes secreted by PCa cells under hypoxic conditions will be mentioned as “ExoHypoxic.” These ExoHypoxic educate all of the receipt cells surrounding the hypoxic areas to support the growth of only cancer cells. So far, we have identified the effect of ExoHypoxic on various cell types (fibroblasts, endothelial cells, macrophages, and naïve prostate cancer cells), but not on key immune cells. In the present application, we have proposed to do that. We believe that ExoHypoxic uptake by CD4+ and CD8+ T-cells compromises their ability to fight cancer cells, while ExoHypoxic uptake by myeloid-derived suppressor cells and macrophages causes immune escape and immunosuppression, leading to disease aggressiveness. Based on the above rationale, we propose that ExoHypoxic characterization in PCa patients could provide valuable information about the disease course (Scheme 1). If the ExoHypoxic concentration is found to be higher in blood loaded with higher amounts of proteins and RNAs associated with hypoxia, that would predict adverse prognosis, and such patients would need to be monitored constantly and treated aggressively. What Types of Patients Will It Help and How Will It Help Them? Proposed studies will help all prostate cancer patients, as hypoxia is an integral component of all primary and metastatic tumors. ExoHypoxic (concentration and cargo) will be a valuable parameter in determining whether patients have “aggressive” or “indolent” disease. What Are the Potential Clinical Applications, Benefits, and Risks? One key rationale for using exosomes for biomarker development is that these vesicles are present in biofluids such as blood and urine, so they are relatively easy to access. Therefore, ExoHypoxic could be easily isolated from the blood of patients and serve as an important prognostic biomarker. There is no risk associated with the proposed approach, as blood is almost universally obtained from patients in the clinic. What is the Projected Time It May Take to Achieve a Patient-Related Outcome? We have proposed to characterize ExoHypoxic in African American and Caucasian PCa patients with known disease status (“disease relapse” or “disease free”) 5 years after prostectomy, so outcomes will be immediately applicable in the clinic without any delay. What Are the Likely Contributions of This Study to Advancing the Field of Prostate Cancer Research? We are first to optimize the methods to “surface shave” and characterize proteins present on the surface of exosomes secreted by prostate cancer cells under hypoxic conditions. Such an approach has not only made it possible to isolate ExoHypoxic from patient’s blood, but also specific exosomes secreted by other components of the tumor microenvironment could be isolated following a similar approach.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910427
Entities
People
- Gagan Deep
Organizations
- United States Army
- Wake Forest University