Two peptides derived from the nerve growth factor precursor are biologically active.

This report provides evidence that the proregion of the NGF precursor protein contains two novel bioactive peptides. The presence of pairs of basic amino acid (aa) residues in the NGF proregion suggests that two or three peptides other than NGF may be generated by proteolytic cleavage. Synthetic peptides of 29 aa (LIP1) and 38aa (LIP2) corresponding to the sequences -71 to -43 and -40 to -3 of the proNGF, respectively, were used in this study. ELISA specific for these two peptides revealed their presence in the rat intestine. LIP1 was localized by immunohistochemistry in endocrine cells of the intestinal epithelium, and LIP2 was immunoprecipitated from an intestinal extract. We also provide evidence for the presence of specific receptors for LIP2 in several cell lines. Scatchard analysis indicated the presence of a low affinity binding site with a Kd of approximately 10(-7) M and a high affinity binding site of 10(-9) M. Cross-linking studies revealed receptor forms of about 140 kD and 93 kD in a prostatic adenocarcinoma cell line. LIP1 and LIP2 induced rapid F-actin redistribution in PC12 cells within 2 min of incubation, which suggests a role of LIP1 and LIP2 in the process of neurite outgrowth. Furthermore, both propeptides induced rapid tyrosine phosphorylation of the Trk protein in both prostatic adenocarcinoma cells and PC12 cells, thus implicating trk in their mechanism of action. These results support our hypothesis that two peptides within the NGF precursor protein are biologically active.

Reduced expression of the low affinity nerve growth factor receptor in benign and malignant human prostate tissue and loss of expression in four human metastatic prostate tumor cell lines.

In the human prostate, a low affinity (p75) nerve growth factor (NGF) receptor (NGF-R) localizes to the epithelia while a NGF-like protein localizes to the stroma. This NGF-like ligand, derived from prostate stromal cell cultures, has been shown to participate in paracrine mediated growth of a human tumor epithelial cell line (TSU-prl) in vitro. In order to investigate the role of the NGF-R in neoplastic growth we have examined the expression of the NGF-R in normal prostate tissues, benign prostatic hyperplasia tissues, adenocarcinoma tissues, and four metastatic tumor cell lines of the human prostate. In primary epithelial cell cultures of normal human prostate the p75 NGF-R was localized by immunocytochemistry to cytoplasmic vesicles. Furthermore, Western blot analysis of the NGF-R in subcellular fractions of normal prostate tissue identified an M(r) 75,000 immunoreactive protein in the microsomal fraction under nonreducing conditions of sodium dodecyl sulfatepolyacrylamide gel electrophoresis. However, microsomal preparations of five prostatic adenocarcinoma and five benign prostatic hyperplasia specimens showed varying immunoreactivity among samples, all of which expressed less of the p75 NGF-R than the normal tissue. Interestingly, microsomal preparations of the human prostatic epithelial cell lines, TSU-prl, DU-145, PC-3, and LNCaP did not show NGF-R expression by immunoblot analysis. Hence, expression of the p75 NGF-R in normal prostate tissue, partial loss of NGF-R expression in benign and malignant prostate tissue, and complete loss of NGF-R expression in the four metastatic tumor cell lines, suggests an inverse association of p75 NGF-R expression with the neoplastic progression of the human prostate.

Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells.

In this study, a panel of normal human prostate cells (HPCs) and tumor cells derived from metastases were studied by (1)H NMR spectroscopy to determine whether the malignant transformation of HPCs results in the elevation of choline compounds. Although an elevated choline signal has been observed previously in clinical studies, the contribution of the different Cho compounds to this elevation, as well as their quantification, has not been established until now. Here we have shown that HPCs derived from metastases exhibit significantly higher phosphocholine as well as glycerophosphocholine levels compared with normal prostate epithelial and stromal cells. Thus the elevation of the choline peak observed clinically in prostate cancer is attributable to an alteration of phospholipid metabolism and not simply to increased cell density, doubling time, or other nonspecific effects. Androgen deprivation of the androgen receptor-positive cell lines resulted in a significant increase of choline compounds after chronic androgen deprivation of the LNCaP cell line and in a decrease of choline compounds after a more acute androgen deprivation of the LAPC-4 cell line. These data strongly support the use of proton magnetic resonance spectroscopic imaging to detect the presence of prostate cancer for diagnosis, to detect response subsequent to androgen ablation therapy, and to detect recurrence.

Regulation of growth by a nerve growth factor-like protein which modulates paracrine interactions between a neoplastic epithelial cell line and stromal cells of the human prostate.

Nerve growth factor-like substance(s) were identified in both conditioned media of a human prostatic tumor epithelial cell line (TSU-pr1) and a human prostatic stromal cell line (HPS) by Western blot analysis and bioassay of neurite outgrowth of PC12 cells. Nerve growth factor-beta (NGF) immunofluorescence was also localized to secretory vesicles in the cytoplasm of both the TSU-pr1 and HPS cells. Western blot of the TSU-pr1 and HPS cell-secreted protein identified an Mr 65,000 major protein which immunoreacted with murine NGF antibody. NGF Western blot of HPS cell-secreted protein also identified an Mr 42,000 minor band under reduced and nonreduced conditions and an Mr 61,000 minor band under reduced conditions. The secreted protein from the TSU-pr1 cells (50 micrograms/ml) and HPS (50 micrograms/ml), as well as murine NGF (50 ng/ml) or human recombinant NGF (50 ng/ml), stimulated neurite outgrowth from PC12 cells. This neurite outgrowth activity was partially inhibited by treatment with NGF antibody. Neither the serum containing growth medium nor bovine serum albumin (50 micrograms/ml) stimulated neurite outgrowth. The NGF-like secretory protein appeared to play a role in the paracrine regulation of prostatic growth between TSU-pr1 cells and HPS cells. The relative growth of TSU-pr1 cells, as indicated by [3H]thymidine incorporation, in response to HPS secretory protein was stimulated 2.8-fold in a dose-dependent manner. In the converse interaction, the relative growth of HPS cells in response to TSU-pr1 secretory protein was stimulated 1.8-fold in a dose-dependent manner. Immunoneutralization of TSU-pr1 and HPS secretory protein was performed with antibody against NGF, acidic fibroblast growth factor, and basic fibroblast growth factor. Removal of the NGF-like protein from the maximal stimulatory dose of TSU-pr1 secretory protein (100 micrograms/ml) with NGF antibody reduced HPS proliferation to 52% of maximal levels, and immunoneutralization of the NGF-like protein in the maximal stimulatory dose of HPS secretory protein (20 micrograms/ml) also reduced TSU-pr1 proliferation to 16% of maximal levels. Addition of normal rabbit serum or prior immunoprecipitation of either TSU-pr1 or HPS secretory protein with antibody against acidic fibroblast growth factor and basic fibroblast growth factor did not inhibit the proliferation of either cell type. These results suggest that TSU-pr1 tumor cells and HPS cells secrete NGF-like protein(s) which modulate their paracrine interactive growth in vitro.

Chemotaxis and chemokinesis of human prostate tumor cell lines in response to human prostate stromal cell secretory proteins containing a nerve growth factor-like protein.

The migration of three human prostate tumor epithelial cell lines (TSU-pr1, PC-3, DU-145) in response to secreted protein from a human prostate stromal cell line was investigated by using the modified blind-well Boyden chamber assay. Migrated cells were quantified by spectrophotometrically measuring the concentration of crystal violet stain extracted from their nuclei. Cell number was correlated linearly with the concentration of extracted crystal violet stain. All three tumor cell lines showed intrinsic migratory ability in the absence of chemoattractants, such that approximately 1-7% of plated cells migrated across the filter of the Boyden chambers during a 5-h incubation period. Prostate tumor cell migration was significantly enhanced (3-13-fold) in response to stromal cell secretory protein in a dose-dependent manner, whereas bovine serum albumin had no effect on stimulating tumor cell migration. Immunoprecipitation of the stromal cell secreted protein with a nerve growth factor antibody partially and significantly reduced its stimulatory activity for tumor cell migration. A Zigmond-Hirsch matrix assay of tumor cell migration in response to various concentration gradients of stromal cell secreted protein demonstrated both chemotaxis and chemokinesis by all three cell lines. These results are consistent with the stromal cell secretory protein stimulation of chemokinetic tumor cell migration through the capsule of the prostate. Outside of the prostate gland metastasis of tumor cells may occur by chemotaxis to preferential sites containing chemoattractants similar to or related to maintenance factors that can substitute for components of stromal cell secretory protein.

Expression of a Trk high affinity nerve growth factor receptor in the human prostate.

Nerve growth factor-beta (NGF beta) and a NGF beta-immunoreactive protein derived from human prostatic stromal cell secretory protein (hPS) have been shown to stimulate the growth of prostate epithelial cells. An NGF beta-immunoreactive protein has been localized to the stroma of human prostate tissues, and a low affinity NGF receptor (gp75NGFR) has been localized to the adjacent epithelia, consistent with the paracrine regulation of prostate growth. Interestingly, gp75NGFR is progressively lost during neoplastic progression of the human prostate. In this report we have characterized the expression of the signal-transducing component of the NGF receptor, the Trk tyrosine receptor kinase, in prostate epithelial cells that bind exogenous NGF beta and an endogenous NGF beta-immunoreactive protein in hPS. In this context, a pan-Trk antibody that recognizes all of the members of the Trk receptor family (TrkA, TrkB, and TrkC) specifically localized expression of the Trk receptor to the epithelial component of normal prostate tissue, benign prostatic hyperplasia, and adenocarcinoma tissue. The binding of [125I]NGF beta to the surface of primary cultures of human prostate epithelia and the TSU-pr1 human metastatic prostate tumor cell line was displaced with either excess cold NGF beta or hPS, whereas binding was not displaced by epidermal growth factor or platelet-derived growth factor. Scatchard plot analysis of [125I]NGF beta binding to these cells identified a low affinity binding site (Kd = 1.9 x 10(-9) M) and a high affinity binding site (Kd = 1.8 x 10(-11) M) on the primary prostate epithelia, whereas only a high affinity binding site (Kd = 1.3 x 10(-11) M) was observed on the TSU-pr1 tumor cells. Stimulation of TSU-pr1 cells with either NGF beta or hPS induced tyrosine phosphorylation of Trk proteins, whereas no phosphorylation was evident in untreated cells, cells treated with hPS immunoprecipitated with anti-NGF beta antibody, or brain-derived neurotrophic factor- and neurotrophin-3-treated cells. The Trk protein was also observed in these cells by immunoblot analysis with pan-Trk antibody. These results demonstrate a functional Trk receptor in the epithelia of the human prostate that is responsive to exogenous NGF beta and an endogenous NGF beta-immunoreactive protein in hPS, thereby supporting the concept of the paracrine regulation of growth in the human prostate via a stromal neurotrophin-epithelial Trk receptor interaction.

Plasma homovanillic acid concentrations in catatonia.

We investigated the dopamine metabolite plasma homovanillic acid (plasma HVA) levels in 37 catatonic patients on the day of admission before initial medication as well as in 17 healthy controls. In a prospective study catatonic syndrome was diagnosed according to criteria of Lohr and Wiesniwski (1987) and Rosebush et al (1990) whereas comorbid diagnosis was made by Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM III/R) (APA 1987). On the day of admission blood samples were taken before initial medication. Compared to controls (80.1 +/- 40.1 pmol/mliter) catatonic patients showed significantly (P = 0.0286) increased plasma HVA (140.9 +/- 53.6 pmol/mliter). Catatonic patients free of neuroleptic medication (n = 21) differed significantly (p = 0.0416) from controls whereas neuroleptically treated catatonics (n = 16) did not. Our findings of increased plasma HVA in catatonia are explained by an alteration in either mesolimbic or mesocortical dopaminergic function, as is assumed in the case of schizophrenia. As an alternative, it may be due to increased nigrostriatal function, which can lead, as shown in animal experiments with the dopamine agonist amphetamine, to hypokinetic states resembling catatonia in humans.

Effects of bright light on circadian patterns of cyclic adenosine monophosphate, melatonin and cortisol in healthy subjects.

Bright light is known as a strong zeitgeber on human circadian rhythms and influences several endocrine and neuroendocrine functions. In the present study we examined the influence of a 3-h bright light stimulus, given at different times during the day (morning or evening), on circadian patterns of cyclic adenosine monophosphate (cAMP), melatonin and cortisol. Two groups of synchronized healthy volunteers (lights on: 05.00-23.00 h) were exposed to bright light (2500 lux) for 3 h over 6 days either in the morning (05.00-08.00 h) or in the evening (18.00-21.00 h). The results showed a significant phase advance in the circadian rhythms of melatonin and cortisol when bright light was given in the morning but not when given in the evening. Rhythm in plasma cAMP basically was not affected by either light treatment.

Dexamethasone reduces the expression of p75 neurotrophin receptor and apoptosis in contused spinal cord.

Apoptosis is an important cause of secondary cell death in spinal cord injury (SCI). SCI induces the expression of the low affinity neurotrophin receptor p75 (p75NTR), that in the absence of the high affinity component, TrkA, can promote cell death by apoptosis. We therefore hypothesized that a reduction of p75NTR expression in SCI may increase tissue sparing and therefore improve recovery of function. As a tool to test our hypothesis we used the synthetic glucocorticoid dexamethasone (DEX) to down-regulate p75NTR expression. A standardized thoracic spinal cord contusion injury was produced in female rats. Laminectomized and SCI rats received various doses of DEX immediately after injury and the treatment was continued daily for 7 days. DEX, given at high doses (20 mg/kg, s.c.) but not at low doses (1 or 8 mg/kg) prevented the increase in p75NTR mRNA and protein in SCI rats, without affecting the expression of TrkA. High doses of DEX also reduced cellular apoptosis both in white and gray matters. This effect correlated with the ability of DEX to accelerate behavioral recovery of function measured by a combined behavioral score. These data suggest that reduction of p75NTR in SCI may be a therapeutic strategy to limit cell and tissue damage and therefore to improve recovery of function in SCI patients.

Catatonia: short-term response to lorazepam and dopaminergic metabolism.

Therapeutic response to lorazepam and dopaminergic metabolism were investigated in 18 neuroleptically naive acute catatonic patients. They were diagnosed as catatonic according to criteria by Lohr and Rosebush and treated exclusively with lorazepam (2-4 mg) during the first 24 h. Dopaminergic metabolism (plasma HVA, plasma MHPG), anxiety (HAM-A) and parkinsonic/dyskinetic movements (SEPS, AIMS) were measured under standard conditions before initial treatment with lorazepam (day 0) and 24 h after initial treatment (day 1). On day 0 responders to lorazepam treatment (complete remission of catatonic syndrome after 24 h according to Rosebush and Lohr) showed significantly higher (P = 0.004) plasma HVA (130.4 +/- 51.2 pmol/ml; means +/- SD) than non-responders (no remission of catatonic syndrome after 24 h; 73.2 +/- 40.5 pmol/ml; means +/- SD). On day 1 plasma HVA did not differ any more significantly between both groups Clinically, responders showed significantly higher HAM-A (P = 0.025) and AIMS (P = 0.022) scores as well as significantly lower SEPS (P = 0.049) scores than non-responders on day 0. Hence catatonic short-term responders and nonresponders to lorazepam can be distinguished with regard to plasma HVA, anxiety and dyskinetic/parkinsonic movements.

Cardiovascular risk factors in patients with peripheral vascular disease.

Cardiovascular risk factors in 566 patients with peripheral arterial disease undergoing major vascular operations were analyzed by chi-square analysis. There were 37 postoperative deaths, for a mortality rate of 8.5%. Cardiovascular complications were responsible for 23 deaths (62%). Five risk factors--congestive heart failure, prior myocardial infarction, prior stroke, arrhythmia, and abnormal electrocardiogram--showed significant individual associations with postoperative cardiovascular complications. A multivariate analysis of these five risk factors and angina led to the development of an equation which predicts the probability of a postoperative cardiovascular complication. The number of complications observed corresponded closely to that predicted by the equation. There was a significantly higher incidence of complications in patients predicted to be at high risk than in those at low risk.

Role of staging in bilateral carotid endarterectomy.

Staging of bilateral carotid endarterectomies 1 to 6 weeks apart has been recommended because of presumed excessive morbidity chiefly related to respiratory problems, hypertension, and neurological deficits. Since data regarding the timing of the second procedure are lacking, an analysis of 79 consecutive patients undergoing bilateral endarterectomies staged from 6 days to 34 months apart (median interval, 52 days) was performed. In addition to postoperative neurological deficits, however, transient perioperative mean systolic and diastolic blood pressures (SBP and DBP) were compared after each side and were correlated with the time interval between the two procedures. No significant difference existed between the two sides in terms of preoperative hypertension, administration of steroids prior to clamping, intraoperative clamp time, the use of shunts, and the duration of operation (P greater than 0.05). Seven temporary neurological deficits occurred after operation, six after the first and one after the second endarterectomy. One permanent deficit following operation on the second side led to the only death (0.6%) in this series. Both neurological deficits (one temporary and one permanent) following the second endarterectomy occurred after procedures staged more than 60 days apart. No differences in mean SBP and DBP existed between patients with and without neurological deficits. Statistical analysis of SBP and DBP recordings during and 6, 12, 24, and 36 hours after operation when the two were staged 7 days (nine patients), 8 to 14 days (five patients), 15 to 30 days (10 patients), 30 to 60 days (17 patients), and more than 60 days (38 patients) apart revealed significantly higher readings after the second procedure, only in patients staged greater than 60 days (P less than 0.05). Therefore, in our experience, neurological deficits were less common after the second endarterectomy, and, although postoperative blood pressures were higher after the second side, these were significant only in patients staged more than 60 days apart. We find no evidence to suggest that increasing the waiting period between bilateral procedures will lower the incidence of undesirable neurological sequelae.

Determination of viability of ischemic intestine by Doppler ultrasound.

Doppler ultrasound was used to determine the viability of ischemic small intestine and to select the optimum point for resection of nonviable bowel. Twenty ischemic segments of small intestine were produced in dogs by ligating the vascular supply. The Doppler ultrasound probe then was used to determine the last point of arterial flow within the bowel wall. The dogs were reexplored after 24 hours. Histological examination of full-thickness biopsies showed the intestine to be normal in all 20 segments at the last audible Doppler signal, and in 19 of the 20 segments at 1 cm distal to the last signal. Progressive degrees of necrosis were observed at 2 and 3 cm distal to the last signal. Twenty-five segments of ischemic intestine were resected in baboons. All resections performed at the last Doppler signal or 1 cm distal to it were normal 1 month later. Of 15 resections performed at 2, 3, and 4 cm distal to the last signal, 10 showed evidence of stricture or anastomotic disruption. Doppler ultrasound is a reliable method for determining the viability of ischemic intestine and for selecting the optimum point for resection of nonviable bowel.

Oral calcium tolerance and urinary cyclic AMP in urolithiasis.

Oral calcium tolerance and urinary cyclic AMP testing was used in the evaluation of 61 unselected patients with stones. The oral calcium tolerance test was easy to perform and was useful in defining several distinct metabolic abnormalities contributing to calculous formation. Oral calcium tolerance testing is more precise than twenty-four-hour urinary calcium determination and should provide a means of determining proper medical treatment of urolithiasis. Urinary cyclic AMP was disappointing as a measure of parathormone activity.

Subjective sleepiness and physiological sleep tendency in healthy young morning and evening subjects.

The Multiple Sleep Latency Test (MSLT) was performed twice after 8 h and after 4 h of night sleep in 15 healthy young subjects (mean age: 23 y). Seven subjects could be regarded as morning, 8 subjects as evening types. After 8 h of sleep significantly more evening types napped at 08.00 hours and at 12.00 hours. Evening types rated themselves more sleepy on an hourly administered visual analogous scale (VAS). Sleep onset latencies (SOL) decreased, and the amount of Stages 1 and 2 increased in all subjects dependent on the sleep restriction condition. No significant differences between morningness and eveningness concerning SOL and structure of nap structure could be observed. After 4 h of sleep there was a marked increase in subjectively rated sleepiness during the morning hours in both groups.

Dopamine D2 receptor occupancy measured by single photon emission computed tomography with 123I-Iodobenzamide in chronic schizophrenia.

Single photon emission computed tomography (SPECT) with 123I-iodobenzamide (123I-IBZM) was used to study 22 chronic schizophrenic patients. The patients, who were receiving maintenance therapy with typical neuroleptics, had not shown any significant improvement since their admission to the hospital. Basal ganglia/frontal cortex ratios of the uptake of 123I-IBZM did not show significant differences on the basis of neuroleptic dosage in chlorpromazine equivalents. There were, however, significant differences in 123I-IBZM uptake in the basal ganglia among patients characterized by negative, mixed, and positive symptoms of schizophrenia. Although only a small number of patients had shown a positive response to treatment by the time of discharge, D2 receptor blockade was significantly higher in responders than in nonresponders. In addition, there was an inverse correlation between reduced activation as measured by the Brief Psychiatric Rating Scale and the basal ganglia/frontal cortex ratio. These findings suggest a complex pathogenetic link between the blockade of dopamine D2 receptors and psychopathology in chronic schizophrenic patients. SPECT studies with 123I-IBZM appear to have prognostic value in identifying chronic schizophrenic patients who respond poorly to neuroleptic treatment.

Can response to partial sleep deprivation in depressed patients be predicted by regional changes of cerebral blood flow?

The possible predictive value of regional cerebral perfusion patterns with respect to the response to partial sleep deprivation (PSD) was evaluated in 15 major depressive patients (mean age = 54.9 years, mean Hamilton depression score = 21.6). Patients were studied with single photon emission computed tomography with technetium-99 m-D,L-hexamethyl-propylene amine oxime. Scans were performed on the morning before and after (at 08.00 h) PSD. Responders to PSD had significantly higher perfusion in the right orbitofrontal cortex than did non-responders before PSD. Multiple regression analysis indicated that right orbitofrontal/basal cingulate perfusion (r = -0.77, P < 0.001) before PSD, and left inferior temporal perfusion (r = 0.59, P = 0.01) after PSD, were fairly accurate predictors of change in Hamilton depression scores. Thus, it appears that the orbitofrontal cortex and the cingulate are involved in PSD and may serve as predictors of therapeutic response.

Increased survival with surgery alone vs. combined therapy.

Recent investigations have questioned the efficacy of a combined therapy regimen with irradiation. The purpose of this study was to compare the survivals with surgery alone versus combined therapy (pre-op irradiation) and to analyze any apparent differences to identify the source(s) of failure. Two and five-year determinate survivals for this group identify the source(s) of failure. Two and five-year determinate survivals for this group were found to be significantly better for surgery alone. There is no instance where combination therapy is found to be statistically superior. An analysis of treatment failures showed that distant metastases occurred at a greater rate in the combined therapy patients than they did with those treated by surgery alone. The advisability of combined therapy using preoperative irradiation with its increased cost and morbidity to the patient is questioned if it does not improve survival over surgery used as a single modality.

Effect of rubidium on the course of illness and the circadian rectal temperature in a 66-year-old depressive woman.

Rubidium (Rb+) has an antidepressive effect and shortens the circadian period in animals, whereas Li+, another alcalic metal, lengthens it. When we treated a depressive Li+ nonresponder with Rb+, we found an improvement of depression as well as a phase advance of the temperature rhythm in relation to the rest-activity rhythm.

Stromal-epithelial paracrine interactions in the neoplastic rat and human prostate.

Homotypic paracrine interactions in the rat and human prostate have been investigated using prostatic stromal cells and neoplastic epithelial cells (PA-III, rat; TSU-pr1, human). Secretory proteins prepared from each cell type were used to determine the dose dependent regulation of growth (DNA synthesis) of the corresponding homotypic responder cell, as determined by 3H-thymidine incorporation. PA-III secretory protein stimulated rat stromal cell proliferation by 1.8-fold. This stimulatory activity of PA-III protein on stromal cell proliferation was partially reduced (approximately 35%) by treatment with nerve growth factor (NGF) antibody, whereas neither acidic fibroblast growth factor (aFGF) antibody nor basic fibroblast growth factor (bFGF) antibody immunoneutralized the stimulatory activity of PA-III cell protein. In the corresponding opposite interaction, rat stromal cell protein modulated PA-III growth in a biphasic manner. At lower concentrations of stromal cell protein (1.25 micrograms/ml) PA-III cell growth was stimulated by 1.6-fold, whereas at higher concentrations of protein (100 micrograms/ml) PA-III cell growth was inhibited to 60%. Treatment of the stromal cell protein (1.25 micrograms/ml and 100 micrograms/ml) with NGF antibody reduced PA-III cell relative growth to approximately 30% and 5%, respectively. bFGF antibody treatment of stromal cell protein at 1.25 micrograms/ml did not influence relative growth, whereas bFGF antibody treatment of 100 micrograms/ml stromal cell protein reduced relative growth by an additional 40%. Treatment of the stromal cell protein (1.25 micrograms/ml and 100 micrograms/ml) with aFGF antibodies reduced relative growth from that observed at these two protein concentrations by approximately 50% in both cases. Human epithelial TSU-pr1 protein stimulated human stromal cell proliferation approximately 1.7-fold. Treatment of TSU-pr1 protein with NGF antibody resulted in stimulation of human stromal cell proliferation (4-fold). In the corresponding opposite interaction, human stromal cell secretory protein stimulated TSU-pr1 epithelial cell proliferation in a dose-dependent manner up to a maximum of 2.6-fold. This stimulation of TSU-pr1 proliferation by stromal cell secretory protein was reduced to 20% of maximal levels by treatment with antibody against NGF, whereas antibodies against bFGF and aFGF did not significantly influence the stimulatory effect of stromal cell secretory protein mediated proliferation of TSU-pr1 cells. These results suggest that prostatic stromal cells and neoplastic epithelial cells secrete several paracrine factors. One of these factors is nerve growth factor-like, and appears to have a major non-neurotrophic influence on the paracrine regulation of prostatic growth.