Tumour innervation and neurosignalling in prostate cancer

Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosignalling that is necessary in early stages of tumour progression and for initiating an angiogenic switch, whereas parasympathetic nerves activate cholinergic neurosignalling resulting in tumour dissemination and metastasis. The innervation of prostate cancer seems to be initiated by neurotrophic growth factors, such as the precursor to nerve growth factor secreted by tumour cells, and the contribution of brain-derived neural progenitor cells has also been reported. Current experimental, epidemiological and clinical evidence shows the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. Using nerves and neurosignalling could have value in the management of prostate cancer by predicting aggressive disease, treating localized disease through denervation and relieving cancer-associated pain in bone metastases. In this Review, the authors describe the current evidence showing the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. They discuss the clinical and epidemiological evidence and the potential of using nerves and neurosignalling for diagnosis, prognosis and treatment of prostate cancer. Key points Prostate cancer is infiltrated by autonomic nerves that actively stimulate cancer progression. Autonomic nerves infiltrate the tumour microenvironment in response to tumour-derived neurotrophins and axon guidance molecules. Animal models have demonstrated that adrenergic and cholinergic neurosignalling stimulates prostate cancer progression, angiogenesis, invasion and metastasis. Chemical or surgical denervation, as well as genetic or pharmacological blockade, completely inhibit these effects. Attenuated tumour neurosignalling might be a key factor in the decreased incidence of prostate cancer observed in patients with spinal cord injuries or those taking β-blockers. Nerves and neurotrophic growth factors could be used as biomarkers of clinically aggressive prostate cancer, or as therapeutic targets to prevent cancer progression, dissemination and cancer-induced pain.