Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow
Abstract
Clinical observations have identified an association between psychologic stress and cancer relapse, suggesting that the sympathetic nervous system/norepinephrine (NE) plays a role in reactivation of dormant disseminated tumor cells (DTC) in the bone marrow niche. Here, the mechanism by which NE regulates prostate cancer DTCs in the marrow is explored. NE directly stimulated prostate cancer cell proliferation through β2-adrenergic receptors (ADRB2). NE also altered prostate cancer proliferation in the marrow niche by indirectly downregulating the secretion of the dormancy inducing molecule growth arrest specific-6 (GAS6) expressed by osteoblasts. These observations were confirmed in cocultures of prostate cancer cells expressing the fluorescent ubiquitination-based cell-cycle reporters (FUCCI) and osteoblasts isolated from GAS6-deficient (GAS6−/−) animals. A novel ex vivo model system, using femurs harvested from GAS6+/+ or GAS6−/− mice, was used to confirm these results. As in coculture, when prostate cancer cells were injected into the marrow cavities of GAS6+/+ femurs, NE altered the prostate cancer cell cycle. However, NE had less of an impact on prostate cancer cells in femur explants isolated from GAS6−/− mice. Together, this study demonstrates that NE reactivates prostate cancer cell cycling through both a direct action on prostate cancer cells and indirectly on adjacent niche cells.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 30, 2017
- Source ID
- 10.1158/1541-7786.mcr-17-0132
Entities
People
- Ann M. Decker
- Frank C Cackowski
- Jingchen Wang
- Kenji Yumoto
- Russel S. Taichman
- Younghun Jung
Organizations
- National Institutes of Health
- Prostate Cancer Foundation
- United States Department of Defense
- University of Michigan