The nervous system in prostate cancer: A basic science and clinical perspective.

Prostate cancer (PCa) constitutes an important health challenge worldwide. The nervous system, in a complex and multimodal manner, regulates prostate physiology and PCa development and affects the course of the disease. The phenomena of axonogenesis and neurogenesis, first described in PCa, were a breakthrough discovery that changed our understanding of cancer-nerve crosstalk. Different nerve types within the cancer stroma and tumor surroundings create complex interactions between the cancer microenvironment elements based on neurotransmission, affecting the hallmarks of cancer. The most common form of PCa and nerve interaction is the perineural invasion (PNI), which recently has been suggested as a driver of metastases. Additionally, many preclinical discoveries depict the molecular mechanisms of altered nerve activity, showing the pivotal role of sympathetic and parasympathetic signaling systems in localized and advanced PCa, axon-guidance molecules and neurotrophin. The neuroendocrine switch in advanced PCa is one of reasons of lethal, castration-resistant phase of the disease. Knowledge about the infiltration status of the periprostatic nerves present in radiological imaging is important for urologists in planning the treatment. Although some studies suggest that PNI and nerve density may be prognostic factors in PCa, it is necessary to evaluate these indicators better and apply them to practice. The neural-based therapeutic application in PCa is limited currently. Some studies showed that β blockers reduce PCa-specific mortality and neuroendocrine differentiation potential. This review provides a comprehensive, up-to date synthesis of PCa neurobiology, uniquely integrating both preclinial and clinical perspectives.