Prostate Cancer & Autonomic Nerves
In the July 2013 issue of Science magazine, Claire Magnon et al. provide evidence that autonomic nerves contribute to prostate cancer development, where the sympathetic nervous system (SNS) via the activation of β2 and β3-adrenergic receptor pathway participate in the early phase of tumor development. On the other hand, the parasympathetic (cholinergic) nervous system plays a role in the dissemination of tumour metastases via M1 muscarinic receptors.
Previous or more recent research has shown that sympathetic/noradrenergic nerves and their mediators contribute to ovarian cancer, breast cancer metastasis, myeloproliferative neoplasms and melanoma. Importantly, another 2013 study demonstrates that immobilization stress, via the activation of an adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway promotes prostate carcinogenesis in mice.
In the Science study, Claire Magnon and colleagues from from the Albert Einstein College of Medicine, the Mount Sinai School of Medicine, the Durham VA Medical Centre and Duke University, USA employed in mice orthotopic injection of human PC-3 prostate cancer cells directly into the ventral prostate gland.
Stemming from recent data that patients using beta-blockers have lower recurrence rates and mortality from certain cancers and the finding that perineural invasion is associated with a worse prognosis in prostate cancer; the authors’ hypothesis was that autonomic nerves infiltrate and affect cancer development.
The authors found tumor-infiltrating sympathetic nerve fibers arising from the surrounding normal tissue (as characterized by positive staining for the noradrenaline-synthesizing enzyme tyrosine hydroxylase); parasympathetic nerve fibers were verified as well.
Of note, both chemically-induced sympathectomy using 6-hydroxydopamine, or surgical sympathetic denervation, prevented tumors expansion, whereas recipient mice with genetic deletion of β2/β3-adrenoceptors prevented the tumor development in the mice model of prostate cancer.
Furthermore, the acetylcholine receptor agonist carbachol that activates cholinergic pathways promoted metastasis rather than the tumor development.
Importantly, the histological examination of human tissues, using prostatectomy samples, demonstrated that the prostate tissue surrounding the cancers in high-risk patients had increased noradrenergic fiber density; while a high density of noradrenergic or cholinergic fibers correlated with a higher proliferative index.
The authors conclude that autonomic nerves infiltrates the prostatic tumor, and sympathetic/noradrenergic fibers are implicated in the initial stages of tumor development, while parasympathetic cholinergic nerves contribute to the later stages of cell invasion, migration and distant metastases.
The study sheds light on the exciting potential of using already available and widely used therapeutics such as beta-blockers and anti-cholinergics to impact cancer prognosis.
This is substantiated by a recent study with a cohort of 3561 prostate cancer patients, where the use of β-blockers was associated with reduced prostate cancer-specific mortality in patients with high-risk or metastatic disease.
Source: Science, 2013, 341:1236361. doi: 10.1126/science.1236361.
Read More: PubMed.gov
Updates
2015
Antonio Barbieri et al. reported that treatment with norepinephrine induces an increased in vitro and in vivo migration of DU145 human hormone-independent prostate cancer cell line. Moreover, in norepinephrine treated mice the increased expression of MMP2 and MMP9 in tumor tissues is paralleled by the presence of metastasis in lymph nodes proximal to the tumor.
These effects were antagonized by the β2AR antagonist propranolol.
Thus, norepinephrine initiates and drives migration providing a rationale for both the development and localization of metastases and that β-blockers such as propranolol could be used for chemoprevention of metastasis development.
2017
Ali H. Zahalka et al. reported in Science that that endothelial β-adrenergic receptor signaling via adrenergic nerve–derived noradrenaline in the prostate stroma
is critical for activation of an angiogenic switch that fuels exponential tumor growth.
Mechanistically, this occurs through alteration of endothelial cell metabolism. Furthermore, the loss of endothelial Adrb2, the gene encoding the β2-adrenergic receptor, leads to inhibition of angiogenesis through enhancement of endothelial oxidative phosphorylation
2019
Peder R. Braadland et al. demonstrated that
the β2-adrenergic receptor (ADRB2) is a luminal marker associated with a well-differentiated growth pattern in hormone-sensitive tumors.
ADRB2 expression was progressively downregulated upon treatment-related resistance development, and the level of ADRB2 in hormone-naïve prostate cancer determines whether or not the cells are able to undergo neuroendocrine transdifferentiation (NEtD) upon androgen deprivation both in cell lines and a mouse xenograft model.
High ADRB2 cells had longer neurite outgrowth and higher expression of neuron differentiation and neuroendocrine genes than low ADRB2 cells. Overexpression of ADRB2 in low ADRB2 cells induced growth of neurite protrusions, and ADRB2 expression was associated with low canonical WNT signaling activity.
2021
Shubham Dwivedi et al. reported that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC)
a stage preceding to neuroendocrine prostate cancer (NEPC), have high sympathetic innervation.
This 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. Overall this indicates that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC.
2024
A 2024 study of 218 men with T3a prostate cancer and negative surgical margins after radical prostatectomy (RP), patients with autonomic nerve invasion had a significant 1.9-fold increased risk for biochemical recurrence (BCR) or early adjuvant therapy compared to patients without nerve invasion, Ronald J. Cohen, MBBCh, PhD, of Uropath Pty Ltd in West Leederville, Australia, and colleagues reported in Urology.
For patients with extraprostatic spread (EPS), (T3a) and negative margins, autonomic nerve invasion (ANI) significantly and independently increases the chances of biochemical recurrence (BCR) or early adjuvant therapy for intermediate-risk disease, but it is not an independent predictor for high-risk disease. This provides
a simple cost-effective method to further stratify margin negative intermediate-risk T3a prostate cancer.
Thus, autonomic nerve invasion may be simple method of identifying which patients with intermediate-risk T3a prostate cancer who have negative surgical margins after radical prostatectomy are at increased risk for biochemical recurrence.
A 2024 review by David Benzaquen et al. entitled: The Crosstalk between Nerves and Cancer-A Poorly Understood Phenomenon and New Possibilities outlines the present knowledge on the interaction between cancer and nerves with a special focus on prostate and pancreas cancer, cancers that are richly innervated and therefore called neurotrophic.
The authors believe that the neural axis influences cancer progression via the autonomous nervous system, and that this interaction plays a crucial role as a regulator of the cancer microenvironment.
The authors discuss the following topics:
- A short historical view of the interaction between the NGF and cancer
- The crosstalk between nerves and cancer
- What we know now about the interaction between the NGF and cancer
- Can nerve–cancer interactions help explain the connection between stress and cancer?
- What is known about the interaction between nerves and cancers in prostate cancer (PCa) and pancreatic ductal adenocarcinoma (PDAC)?
- Crosstalk in Prostate Cancer
- Beta-Blockers as a Therapeutic Approach
- Crosstalk in Pancreatic Cancer
2025
A 2025 study Malin Hagberg Thulin et al. uncovers the potential of combining beta-blockers (BB) with androgen deprivation therapy (ADT) to delay the progression to castration-resistant prostate cancer.
To explore the causal effect of BB, the authors employed an orthotopic xenograft model that replicates the early stages of local castration-resistant prostate cancer (CRPC). In this model, BB treatment triggered a temporary inflammatory response, potentially aiding in the destruction of cancer cells.
Figure 1. An illustration depicting the molecular changes linked to beta-blocker treatment of prostate cancer xenograft mice undergoing androgen deprivation therapy. Androgen deprivation therapy (ADT) is recognized for inducing apoptosis and growth arrest in prostate tumour cells. Over time, however, growth arrested cancer cells can reactivate leading to proliferation of castration-resistant prostate cancer (CRPC) cells. The study showed that beta-blocker (BB) treatment amplified molecular effects typically regulated by ADT, resulting in delayed progression to castration-resistant prostate cancer (CRPC). Beta-blockers (BBs) inhibit the effects of sympathetic nerve activation by acting as antagonists for beta-2 adrenergic receptors (ADRB2) and beta-3 adrenergic receptors (ADRB3). The underlying mechanism involved the activation of the proinflammatory IL23/IL17 axis and reduced expression of genes associated with signalling pathways known to promote CRPC, such as AR- and PI3K/AKT/mTOR components. From Malin Hagberg Thulin et al.
Furthermore, beta-blockers (BB) promoted a tumour phenotype where cancer cells became less dependent on the AR and PI3K/AKT/mTOR signalling pathways, while shifting their energy metabolism from fatty acid synthesis to ATP production via OXPHOS.
Additionally, beta-blockers treatment increased serum pro-inflammatory cytokines, such as the IL23/IL17 axis, in both xenografted mice and in patient samples. Together, these effects could enhance the efficacy of ADT by suppressing pathways involved in tumour growth and therapy resistance. Overall, according to the authors their study suggests that
beta-blockers combined with androgen deprivation therapy delay the progression to castration-resistant prostate cancer.
This may be achieved by influencing androgen receptor activity, adjusting energy metabolism and fostering a pro-inflammatory antitumoral microenvironment.
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