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