Clinical observations have identified an association between psychological stress and cancer relapse; suggesting that the sympathetic nervous system/norepinephrine (NE) plays a role in reactivation of dormant disseminated tumor cells (DTCs) in the bone marrow niche. Here, the mechanism by which NE regulates prostate cancer (PCa) DTCs in the marrow is explored. NE directly stimulated PCa cell proliferation through β2-adrenergic receptors (ADRB2). NE also altered PCa proliferation in the marrow niche by indirectly by downregulating the secretion of the dormancy inducing molecule growth arrest specific-6 (GAS6) expressed by osteoblasts. These observations were confirmed in co-cultures of PCa 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 co-culture, when PCa cells were injected into the marrow cavities of GAS6+/+ femurs, NE altered the PCa cell cycle. However, NE had less of an impact on PCa cells in femur explants isolated from GAS6-/- mice. Together, this study demonstrates that NE reactivates PCa cell-cycling through both a direct action on PCa cells and indirectly on adjacent niche cells.
Identification of mechanisms that target DTCs may provide novel therapeutic approaches to prevent or treat cancer metastases more effectively.
Molecular cancer research : MCR. 2017 Aug 16 [Epub ahead of print]
Ann Decker, Younghun Jung, Frank C Cackowski, Kenji Yumoto, Jingcheng Wang, Russell S Taichman
Periodontics and Oral Medicine, University of Michigan School of Dentistry., Periodontics and Oral Medicine, University of Michigan School of Dentistry .