Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

Abstract

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 demonstrate that NE reactivates PCa cell-cycling through both a direct action on PCa cells and indirectly on adjacent niche cells

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

“…To do this, we first explored the phenotypic consequences of p38/MAPK pathway activation. The p38/MAPK pathway is a key regulator of the stress response (Igea and Nebreda, 2015), and a regulator of tumor cell dormancy in many cancer types, including prostate cancer (Decker et al, 2017; Yu-Lee et al, 2018). Consistent with the role of p38 in a dormancy phenotype, enzaR cells exhibited a significant downregulation in the ratios of pERK:p38α, an important indicator of the shift from a proliferative (high ERK) to dormant (high p38α) phenotype ( Supplemental Fig S7A ).…”

Concise Review: Prostate Cancer Stem Cells: Current Understanding

“…Proliferative [229] Quiescent [3] Proliferative or quiescent [248,249] Dormant or quiescent [150,250] No data…”

Disseminated tumour cells in bone marrow are the source of cancer relapse after therapy

“…Preventing dormant DTCs in the bone marrow from reactivating cell cycling or kicking dormant cancer cells back into circulation may be strategies for preventing the relapse of metastatic disease. β‐adrenergic receptor antagonists, which interfere with proliferative re‐activation norepinephrine (NE) signalling, may reduce cancer relapse or slow disease progression . One potential strategy is finding a way to inhibit E‐selectin, which could limit the ability of the cancer cells to travel into the bone and resurge as metastatic cancer.…”

“…β-adrenergic receptor antagonists, which interfere with proliferative re-activation norepinephrine (NE) signalling, may reduce cancer relapse or slow disease progression. 129 One potential strategy is finding a way to inhibit E-selectin, which could limit the ability of the cancer cells to travel into the bone and resurge as metastatic cancer. A combination of the E-selectin inhibitor GMI-1271, daunorubicin and cytarabine, was shown to result in a greater depletion of AML from the bone marrow.…”