Role of neurotrophins and neurotrophin receptors in the in vitro invasion and heparanase production of human prostate cancer cells

The role of the neurotrophins (NTs) and their corresponding receptors (NTRs ) TrkA, TrkB, TrkC, and p75(NTR) in neoplasia has received relatively littl e attention. However, because malignant cell migration within the prostate occurs predominantly by direct extension around prostatic nerves, the prese nce and possible upregulation of NTs from autocrine/paracrine sources and N TR expression within prostate epithelial tumor cells may be important in me tastasis. We have been addressing their expression and interactions in huma n prostate cancer cell lines (LNCaP, PC-3, and DU145) and their role in pro state cancer invasion. In this study, we demonstrated that nerve growth fac tor (NGF), the prototypic NT, and NT-4/5 increased in vitro invasion throug h a reconstituted basement membrane and induced time- and dose-dependent ex pression of heparanase, a heparan sulfate-specific endo-beta-D-glucuronidas e, an important molecular determinant of tumor metastasis. The NT effects w ere most marked in the DU145 brain-metastatic cells and were detected at NT concentrations sufficient to fully saturate both low- and high-affinity NT Rs. Additionally, we characterized the molecular expression of NT high-affi nity (Trk) and low-affinity (p75(NTR)) receptors in these cell lines by rev erse transcription-polymerase chain reaction. These lines had negligible tr kA and trkC expression, although trkB was expressed in the three prostatic tumor cell lines examined. The brain-metastatic DU145 cells were also posit ive for p75(NTR). Our data showed that the NTs and NTRs are important in me tastasis and that their expression coincides with transformation to a malig nant phenotype capable of invasion along the perineural space and extracaps ular metastasis to distant sites. These findings set the stage for more res earch into this area as related to prostate cancer evolution and may improv e therapy for prostate cancer metastasis.