The nerve growth factor-delivered signals in prostate cancer and its associated microenvironment: when the dialogue replaces the monologue

Prostate cancer (PC) represents the most diagnosed and the second most lethal cancer in men worldwide. Its development and progression occur in concert with alterations in the surrounding tumor microenvironment (TME), made up of stromal cells and extracellular matrix (ECM) that dynamically interact with epithelial PC cells affecting their growth and invasiveness. PC cells, in turn, can functionally sculpt the TME through the secretion of various factors, including neurotrophins. Among them, the nerve growth factor (NGF) that is released by both epithelial PC cells and carcinoma-associated fibroblasts (CAFs) triggers the activation of various intracellular signaling cascades, thereby promoting the acquisition of a metastatic phenotype. After many years of investigation, it is indeed well established that aberrations and/or derangement of NGF signaling are involved not only in neurological disorders, but also in the pathogenesis of human proliferative diseases, including PC. Another key feature of cancer progression is the nerve outgrowth in TME and the concept of nerve dependence related to perineural invasion is currently emerging. NGF released by cancer cells can be a driver of tumor neurogenesis and nerves infiltrated in TME release neurotransmitters, which might stimulate the growth and sustainment of tumor cells.In this review, we aim to provide a snapshot of NGF action in the interactions between TME, nerves and PC cells. Understanding the molecular basis of this dialogue might expand the arsenal of therapeutic strategies against this widespread disease.

Automated summary

Prostate cancer is the most diagnosed and second most lethal cancer in men worldwide, and its development and progression are influenced by alterations in the tumor microenvironment and neurotrophins like nerve growth factor (NGF). Aberrations in NGF signaling are implicated in neurological disorders as well as the pathogenesis of proliferative diseases, including prostate cancer, by promoting a metastatic phenotype. Nerve outgrowth and perineural invasion also play important roles in cancer progression. Understanding the interactions between the tumor microenvironment, nerves, and prostate cancer cells can potentially lead to new therapeutic strategies.