Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effects, but PC gradually develops resistance, relapses and spreads. Most patients who fail primary therapy and have recurrences eventually develop castration-resistant prostate cancer (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, tropomyosin receptor kinase A (TrkA). NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its crosstalk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchymal transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.

Prostate cancer is the major cause of cancer-related death among the male population of Western society, and androgen deprivation therapy represents the first line in prostate cancer treatment. However, although androgen receptor expression is maintained throughout the various stages of prostate cancer, androgen deprivation therapy frequently fails. Clinical studies have demonstrated that different androgen/androgen receptor signalling pathways operate in target tissues. Androgen receptor stimulates growth and transformation of target cells, but under certain conditions slows down their proliferation. In this review we discuss the role of androgen receptor in controlling different functions of mesenchymal and transformed mesenchymal cells. Findings here presented support the role of androgen receptor in suppressing proliferation and stimulating migration of stromal cells, with implications for current approaches to cancer therapy.

Gene expression is governed by chromatin mainly through posttranslational modifications at the N-terminal tails of nucleosomal histone proteins. According to the histone code theory, peculiar sets ...