Sympathetic signaling facilitates progression of neuroendocrine prostate cancer

Shubham Dwivedi,Sanskriti Shrestha,Anand Krishnan,Maricris Bautista,Tanaya Chaphekar,Hussain Elhasasna,Frederick S Vizeacoumar

doi:10.1038/s41420-021-00752-1

Abstract

The progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to promote PC. However, their contribution to NEPC was not studied well. In this study, we explored whether sympathetic neurosignaling contributes to NED. We found that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC), a stage preceding to NEPC, have high sympathetic innervations. Our work revealed that high concentrations of the sympathetic neurotransmitter norepinephrine (NE) induces NED-like changes in PC cells in vitro, evident by their characteristic cellular and molecular changes. The NE-mediated NED was effectively inhibited by the Adrβ2 blocker propranolol. Strikingly, propranolol along with castration also significantly inhibited the development and progression of NEPC in vivo in an orthotopic NEPC model. Altogether, our results indicate that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC.

Highlights

Prostate cancer (PC) is the second leading cancer diagnosed and the fifth leading cause of cancer-related deaths in men worldwide [1]
Understanding whether NE has any direct contribution to neuroendocrine differentiation (NED) would expand potential therapeutic intervention points for neuroendocrine PC (NEPC) spanning around NE biosynthesis, metabolism and NE-adrenergic β-receptors (Adrβs) axis
Human prostate tumors are densely innervated by sympathetic nerves We examined the sympathetic nerve distribution in eight human prostate adenocarcinoma and corresponding normal adjacent tissues to understand whether sympathetic axonogenesis occurs in prostate tumors

Summary

Introduction

Prostate cancer (PC) is the second leading cancer diagnosed and the fifth leading cause of cancer-related deaths in men worldwide [1]. The mortality associated with PC often results from the development of treatment-resistant neuroendocrine PC (NEPC) [2]. In NEPC, prostate adenocarcinoma cells transdifferentiate into neuroendocrine cells [3, 4]. Recent studies demonstrated that peripheral nerves promote PC [5,6,7]. A recent study demonstrated that Adrβ promotes NED [10]. Understanding whether NE has any direct contribution to NED would expand potential therapeutic intervention points for NEPC spanning around NE biosynthesis, metabolism and NE-Adrβ axis. We explored whether NE has any direct potential to induce NED. Our study indicates that targeting the NE-Adrβ axis may prevent NEPC development and progression

Methods

Results

Conclusion