Early Detection of Castration-Resistant Prostate Cancer by Assessing Interactions Between Circulating Tumor Cells and Accompanying Immune Cells
Abstract
Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Since the growth of the tumor depends on supply of appropriate hormones, a therapy leading to castration by hormone deprivation (androgen deprivation therapy [ADT]) halts the tumor growth and, importantly, also its metastatic spread. This stage of the PCa is hormone- or castration-sensitive (CS). Beneficial effects of ADT are apparent, even if the therapy is administered to patients with already diagnosed metastasis. Unfortunately, about 30% of these patients will fail to respond and will progress into the hormone-resistant (castration-resistant [CR]) stage, with metastasis spreading quickly and deadly. Fortunately, there are effective second-line hormone deprivation or systemic therapies to slow down metastases in this group of patients to prolong their lives and improve their lives’ quality. However, for the best survival advantage, the additional therapies need to be administered as early as possible. The problem is that the 70% of patients that remain CS will not benefit from such treatment; instead, their immune system, so far efficient in the anti-cancer fight, may be weakened by the misguided therapy. Early identification of the patients at risk of developing CR holds the key to protecting them while not harming the majority of patients remaining at the CS stage. Established markers of PCa progression, such as the level of prostate specific antigen (PSA) in serum, are not sensitive enough for early detection of CR. In this project, we want to construct a biological test based on single-cell profiling that identifies post-castration metastatic PCa patients at risk of failing the first-line anti-hormonal therapies. These patients can enormously benefit from the new therapies preventing metastatic spread, with improved survival and enhanced life quality. To reach this goal, we propose to test properties of rare cells that are responsible for spreading metastasis. These circulating tumor cells (CTCs) are shed from tumor sites to the bloodstream. The majority of CTCs die; however, the surviving “aggressive” cells travel to distant organs and seed metastases. The recently developed techniques allow isolation of CTCs from peripheral blood (“liquid biopsy”) and their investigation with single-cell technologies to determine their aggressiveness. Since CTCs have to escape from the tumor and then survive in the turbulent bloodstream, they have to be mechanically fit. Indeed, we found in retrospective studies that CTCs obtained from CR patients are much softer, deformable, and more adhesive than CTCs from CS patients. Soft and deformable cells will be less prone to damage, and stickiness may help them to invade organs. We determined these properties using atomic force microscopy (AFM). This technique “images” mechanical properties by nondestructively poking cells with a micrometer-scale stylus. We confirmed our observations by testing the expression level of specific genes that may be responsible for the invasiveness of CTCs. We hypothesize that CTCs with an “aggressive” mechanical phenotype indicate resistance to ADT. We also found that the mechanical fitness and endurance of CTCs may be related to their interactions with immune cells called macrophages. Distinct classes of macrophages can prey on CTCs (anti-cancer predators) or protect them from the environment (pro-cancer chaperones). We noticed that, indeed, many CTCs isolated from liquid biopsies by microfiltration are travelling with chaperone macrophages and show enhanced fitness. Classification and enumeration of such macrophages can provide additional indication of whether the patient is responding to or failing ADT. We hypothesize that a large number of chaperones hints at a poor outcome. Here, for this prospective study, we propose to recruit metastatic PCa patients who are initiating ADT due to the continuous increase of PSA level after prostate removal. We will is
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810519
Entities
People
- Tim H-M Huang
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio