The role of the neurotrophins (NTs) and their corresponding receptors (NTRs) TrkA, TrkB, TrkC, and p75^NTR in neoplasia has received relatively little attention. However, because malignant cell migration within the prostate occurs predominantly by direct extension around prostatic nerves, the presence and possible upregulation of NTs from autocrine/paracrine sources and NTR expression within prostate epithelial tumor cells may be important in metastasis. We have been addressing their expression and interactions in human prostate cancer cell lines (LNCaP, PC-3, and DU145) and their role in prostate cancer invasion. In this study, we demonstrated that nerve growth factor (NGF), the prototypic NT, and NT-4/5 increased in vitro invasion through a reconstituted basement membrane and induced time- and dose-dependent expression of heparanase, a heparan sulfate-specific endo-β-d-glucuronidase, an important molecular determinant of tumor metastasis. The NT effects were most marked in the DU145 brain-metastatic cells and were detected at NT concentrations sufficient to fully saturate both low- and high-affinity NTRs. Additionally, we characterized the molecular expression of NT high-affinity (Trk) and low-affinity (p75^NTR) receptors in these cell lines by reverse transcription-polymerase chain reaction. These lines had negligible trkA and trkC expression, although trkB was expressed in the three prostatic tumor cell lines examined. The brain-metastatic DU145 cells were also positive for p75^NTR. Our data showed that the NTs and NTRs are important in metastasis and that their expression coincides with transformation to a malignant phenotype capable of invasion along the perineural space and extracapsular metastasis to distant sites. These findings set the stage for more research into this area as related to prostate cancer evolution and may improve therapy for prostate cancer metastasis.