Manipulation of the nerve growth factor network in prostate cancer

Autocrine and paracrine events regulated by nerve growth factor (NGF) and relevant receptors (low- and high affinity; p75 neurotrophin receptor [p75(NTR)] and TrkA, respectively) seem to play a significant role in prostate carcinogenesis. Studies reveal that p75NTR is both a tumor suppressor of growth and a metastasis suppressor of human prostate cancer cells. Furthermore, p75NTR is progressively lost during prostate carcinogenesis. An imbalance between p75NTR and tropomyosin receptor kinase A (TrkA)-mediated signals may be involved in the progression of prostate cancer through increased proliferation and reduced apoptosis. The anti proliferative and apoptotic effects of GnRH analogs in prostate cancer cells may be mediated by altering the TrkA:p75NTR NGF receptor ratio. Administration of NGF induces a reversion of the androgen-independent/androgen receptor-negative prostate cancer cell lines to a less malignant phenotype. Finally, Trk inhibition is a novel, attractive and rational approach for prostate cancer therapy. This review unravels the NGF 'circuitry' in prostate cancinogenesis for relevant pharmacologic manipulation to lead to the development of novel therapeutic agents.