Sympathetic Signaling Mediator, Norepinephrine, Re-Activates Prostate Cancer Bone Metastases through Direct and Indirect Mechanisms

Abstract

Metastatic prostate cancer can recur months or years after clearance of the primary disease and is associated with poor clinical outcomes. The bone marrow represents the preferred sire for metastasis, with disseminated tumor cells (DTCs) able to establish residency and remain dormant until some outside stimulus leads to their reactivation. A number of signaling factors in the bone marrow such as growth arrest specific 6 (GAS6) have been identified to elicit dormancy (reviewed in Chapter 2), however less is known about signals that might trigger reactivation. This dissertation explores the hypothesis that signaling from the sympathetic nervous system may lead to reactivation of dormant prostate cancer cells. This hypothesis is motivated by clinical observations of a correlation between stressful life events and recurrence as well as mechanistic observations linking adrenergic signaling to the mobilization of bone marrow resident stem cells. Chapter 3 establishes a causal link between norepinephrine (NE) and reactivation of dormant prostate cancer cells in a variety of models for prostate cancer dormancy. These experiments establish a direct effect of NE on prostate cancer cells that can lead to cell cycle re-entry. Chapter 4 examines the effects of NE on the bone marrow microenvironment and identifies downregulation of GAS6 as the primary indirect factor mediating re-entry. Chapter 5 establishes a mechanism through which adrenergic signaling downregulates GAS6 expression in order to suggest clinical strategies to target this interaction. Finally, Chapter 6 suggests future directions for this project, focused on the role of GAS6 in long-term bone homeostasis, another key factor leading to recurrence. Overall, this dissertation provides a new mechanism for DTC reactivation and establishes a potential new direction for clinicians to treat patients at risk for recurrence.