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.
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.
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 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.
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
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.
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 innervations. 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.