MOLECULAR CHARACTERIZATION OF NEUROTROPHIN EXPRESSION AND THE CORRESPONDING TROPOMYOSIN RECEPTOR KINASES (TRKS) IN EPITHELIAL AND STROMAL CELLS OF THE HUMAN PROSTATE

The prostate is one of the most abundant sources of nerve growth facto r (NGF) outside of the nervous system. NGF is a member of the neurotro phin family of growth factors which in mammals also includes brain der ived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophi n-4/5 (NT-4/5). These neurotrophins can bind with high affinity to a f amily of tropomyosin receptor kinases (trks). These receptors are trkA , which binds NGF; trkB, which binds both BDNF and NT-4/5; and trkC, w hich binds NT-3. In order to characterize the molecular expression of the neurotrophins and their corresponding trk receptors in the prostat e we performed Northern blot analysis for the neurotrophins and revers e transcription-polymerase chain reaction (RT-PCR) coupled with Southe rn blot analysis for the trk family of receptors on smooth muscle stro mal cells from the prostate, the androgen responsive LNCaP prostate tu mor cell line and the androgen refractory TSU-pr1 prostate tumor cell line. The results show that smooth muscle stromal cells expressed NGF, BDNF and trkC, whereas both epithelial cell lines expressed trkA, trk B and trkC to various degrees. NT-3 was not detected in either the smo oth muscle stromal cells or in both epithelial cell lines. This sugges ts that the stromal cell derived NGF and BDNF may interact via paracri ne mechanisms with trkA and trkB receptors, respectively, on the adjac ent epithelial cells. Interestingly, the androgen responsive LNCaP cel l line did not express any of the neurotrophins, whereas the androgen refractory TSU-pr1 cell line expressed NGF, BDNF and NT-4/5. This sugg ests that the autocrine expression of NGF, BDNF and NT-4/5 is up-regul ated in prostate epithelial cells following their transformation to an androgen refractory pathology. Hence, the malignant transformation of prostate epithelial tumor cells may facilitate their escape from a pa racrine dependence on stromal cell derived neurotrophins by the acquis ition of the autocrine expression of neurotrophins. Since the patholog y of malignant cell migration within the prostate is predominantly by direct extension around prostatic nerves the upregulation of autocrine neurotrophin expression within prostate epithelial tumor cells may be concomitant with transformation to a malignant phenotype capable of i nvasion along the perineural space and extracapsular metastasis to dis tant sites of tumor formation. (C) 1997 Elsevier Science Ireland Ltd.