Sympathetic signaling facilitates progression of neuroendocrine prostate cancer

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.

Association of β-Blocker Use at Time of Radical Prostatectomy With Rate of Treatment for Prostate Cancer Recurrence

“… 34 The β 2 -AR has been identified as the key adrenergic receptor over β 1 -AR, promoting catecholamine-induced tumorigenesis. 35 In addition, an increasing amount of preclinical evidence supports that perioperative use of nsBBs has a beneficial effect on oncological outcome. 6 , 7 , 8 This finding could explain why an association with prostate cancer progression was only observed for nsBBs, which act on both β 1 - and β 2 -ARs, and not for sBBs, which target mainly β 1 -AR.…”

“…34 The β 2 -AR has been identified as the key adrenergic receptor over β 1 -AR, promoting catecholamine-induced tumorigenesis. 35 In addition, an increasing amount of preclinical evidence supports that perioperative use of nsBBs has a beneficial effect on oncological [6][7][8] This finding could explain why an association with prostate cancer progression was only observed for nsBBs, which act on both β 1 -and β 2 -ARs, and not for sBBs, which target mainly β 1 -AR. Indeed, randomized clinical trials have been performed assessing perioperative use of nsBBs alone, in breast and ovarian cancer, and in combination with cyclooxygenase 2 inhibition in colorectal cancer.…”

Endocrine and paracrine characteristics of neuroendocrine prostate cancer

“…Another recent study reported that patients who subsequently developed metastatic CRPC had elevated adrenergic nerve fiber innervation in the primary prostate tumors. High levels of the neurotransmitter norepinephrine, which is produced by sympathetic nerves, was shown to induce NE-like alterations in PC cells, and these effects were effectively inhibited by b 2 -adrenenergic receptor blocker propranolol (159).…”

Sympathetic nervous signaling dictates prostate cancer progression

“…The authors showed that sympathetic axons were present within the tumor microenvironment and interacted with neoplastic cells [ 2 ]. They found the increased innervation in half of the examined tumors, interpreting that as the evidence of active axonogenesis.…”

“…In this study, propranolol led to the inhibition of the morphological features of neuroendocrine differentiation, and inhibited the progression of PCa. Moreover, in the orthotopic tumor model, treatment with propranolol and castration significantly reduced tumor growth compared to castration alone or the control group [ 2 ]. Propranolol also affects cellular proliferation, apoptosis, inhibits angiogenesis, and regulates the immune system.…”