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PubMed1999

Characterization of nerve growth factor precursor protein expression by human prostate stromal cells: a role in selective neurotrophin stimulation of prostate epithelial cell growth.

BACKGROUND: Nerve growth factor (NGF) immunoreactive proteins derived from human prostatic stromal cells (hPS) have been implicated in the paracrine regulation of prostate epithelial cell growth. However, mature NGFbeta does not appear to be expressed by these cells. In order to determine whether NGF precursors are expressed by these cells, we investigated the potential processing and expression of precursor forms of NGF by human prostatic stromal cells, and examined the effects of NGF precursor moieties along with the other members of the neurotrophin family of gene products on soft agar colony formation of prostate epithelial cells. METHODS: Specific antibodies to the peptide domains defined as N4 and L38, and the NGFbeta moiety of prepro-NGF, were used in immunoblot assays to characterize the molecular weight forms of precursor NGF secreted by human prostatic stromal cells. The potential processing of NGF precursors with two enzymes, NGFgamma and trypsin, was performed by incubation with stromal cell secretory protein containing precursor NGF. The selective effects of the N4, L38, and NGFbeta peptide domains of precursor NGF, along with the remaining members of the neurotrophin family, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), were examined for their ability to stimulate growth of prostate tumor epithelial cells in an assay of soft agar colony formation. RESULTS: Immunoblot analysis of stromal cell secretory protein identified NGF precursors of 35 kDa and 27 kDa, along with the partially processed 22-kDa form of pro-NGF, whereas mature NGFbeta was not observed. Treatment of precursor NGF with NGFgamma and trypsin did not produce the large intermediate forms of pro-NGF, although these two enzymes did appear to cleave the N-terminal peptide from NGFbeta. Of the N4, L38, and NGFbeta peptide domains of precursor NGF, only NGFbeta significantly stimulated the anchorage-independent growth of TSU-pr1 prostate epithelial cells in soft agar. The other members of the neurotrophin family of gene products had no effect on the anchorage-independent growth of prostate tumor cells. CONCLUSIONS: Human prostate stromal cells secrete the 35-kDa and 27-kDa precursor forms of NGF arising from alternate start sites, and the partially processed 22-kDa form of pro-NGF. Whereas the N4, L38, and NGFbeta peptide domains present within pro-NGF were previously shown to induce phosphorylation of the high-affinity NGF receptor, tropomyosin receptor kinase (Trk), only the NGFbeta moiety was able to stimulate anchorage-independent growth of prostate tumor cells. Likewise, the other neurotrophin family members did not stimulate anchorage-independent growth of prostate tumor cells. Hence, it would appear that NGF may be the predominant neurotrophic growth factor for prostate growth, albeit via precursor forms of NGF, and that its effect appears to be selectively mediated via the NGFbeta moiety of these NGF precursors.

3T3 Cells↗
PubMed2005

cAMP induced modifications of HOX D gene expression in prostate cells allow the identification of a chromosomal area involved in vivo with neuroendocrine differentiation of human advanced prostate cancers.

The acquisition of epithelial-neuroendocrine differentiation (ND) is a peculiarity of human advanced, androgen-independent, prostate cancers. The HOX genes are a network of transcription factors controlling embryonal development and playing an important role in crucial adult eukaryotic cell functions. The molecular organization of this 39-gene network is unique in the genome and probably acts by regulating phenotype cell identity. The expression patterns of the HOX gene network in human prostate cell phenotypes, representing different stages of prostate physiology and prostate cancer progression, make it possible to discriminate between different human prostate cell lines and to identify loci and paralogous groups harboring the HOX genes mostly involved in prostate organogenesis and cancerogenesis. Exposure of prostate epithelial phenotypes to cAMP alters the expression of lumbo-sacral HOX D genes located on the chromosomal region 2q31-33 where the cAMP effector genes CREB1, CREB2, and cAMP-GEFII are present. Interestingly, this same chromosomal area harbors: (i) a global cis-regulatory DNA control region able to coordinate the expression of HOX D and contiguous phylogenetically unrelated genes; (ii) a prostate specific ncRNA gene associated with high-risk prostate cancer (PCGEM1); (iii) a series of neurogenic-related genes involved with epithelial-neuronal cell conversion. We report the expression of neurexin 1, Neuro D1, dlx1, and dlx2 in untreated and cAMP treated epithelial prostate cells. The in vivo expression of Neuro D1 in human advanced prostate cancers correlate with the state of tumor differentiation as measured by Gleason score. Thus, we suggest that the chromosomal area 2q 31-33 might be involved in the epithelial-ND characteristic of human advanced prostate cancers.

Bucladesine↗
PubMed2003

Stromal/epithelial interactions of murine prostatic cell lines in vivo: a model for benign prostatic hyperplasia and the effect of doxazosin on tissue size.

BACKGROUND: One of the major constraints in elucidating the mechanisms involved in the etiology of benign prostatic hyperplasia (BPH) is the lack of suitable model systems that are readily manipulable in vitro and in vivo. To address this issue, we have used murine prostatic cell lines to establish a novel in vivo model for studying prostatic cell interactions. METHODS: Luminal, basal, and smooth muscle (SM) cell lines were inoculated alone or in combinations under the renal capsule of intact or castrated male mice, and the growth and composition of prostatic tissue in the absence or presence of doxazosin was determined. RESULTS: Both the luminal and basal cell lines reconstituted prostatic tissue if co-inoculated under the renal capsule with normal SM cells, whereas none of the lines formed significant tissue when inoculated alone. Luminal cells produced and secreted prostatic secretory products. The growth of prostatic tissue formed from co-inoculation of basal and SM cells was androgen responsive. In addition, a significant reduction in prostatic tissue was noted in animals treated with doxazosin. CONCLUSION: We have established an in vivo model that uses prostatic epithelial and SM cell lines for investigating cellular interactions between epithelial and SM cells that regulate prostatic growth and function. This model will be useful for delineating the mechanisms by which prostatic cells interact and in determining the efficacy of new approaches aimed at interfering with prostatic stromal/epithelial interactions that result in abnormal cellular proliferation.

Adrenergic alpha-Antagonists↗
PubMed1987

Quantal relationship between prostatic dihydrotestosterone and prostatic cell content: critical threshold concept.

The shape of the prostatic dihydrotestosterone (DHT) dose vs prostatic cell number response curve can be used to determine if the androgen-induced increase in prostatic cell number occurs as a continuous graded process increasing with all levels of prostatic DHT, or whether the process is quantal, beginning to occur only when a critical threshold of prostatic DHT is reached. To make this determination, castrated-adrenalectomized rats, castrated rats given no treatment, and castrated rats given testosterone-filled silastic implants of varying lengths were used to construct such a prostatic DHT dose/prostatic cell number response curve ranging from undetectable to pharmacologically high levels of prostatic DHT. The shape of this dose-response curve was found not to be continuously hyperbolic, but instead, to be discontinuously sigmoidal. This demonstrates that, in the rat, androgen-induced increase in prostatic cell number occurs as a quantal process which can only begin when the concentration of prostatic DHT is above a critical threshold value (ie, 0.4 ng/10(8) cells for the rat ventral prostate). Thus, in order to completely prevent this androgenic stimulation of prostatic cell number, the prostatic DHT level has to be lowered to below this critical threshold but does not have to be completely eliminated.

Adrenalectomy↗
PubMed1992

Randomized double-blind study comparing the effectiveness of balloon dilation of the prostate and cystoscopy for the treatment of symptomatic benign prostatic hyperplasia.

We attempted to determine the effectiveness of balloon dilation of the prostate for the treatment of symptomatic benign prostatic hyperplasia (BPH). A total of 33 men with symptomatic BPH signed informed consent to participate in a randomized, double-blind study comparing balloon dilation of the prostate and cystoscopy. Balloon dilation of the prostate and cystoscopy were performed with the patient under intravenous sedation after intraurethral instillation of viscous lidocaine and infiltration of the autonomic neural innervation of the prostate with 1% lidocaine. Efficacy was based upon improvement in Boyarsky symptom scores, increases in peak urinary flow rates and patient global assessment of symptomatic improvement. Efficacy was assessed at 1 and 3 months after treatment. A study nurse blinded to the randomization scheme administered the symptom score questionnaires and supervised the uroflowmetry studies. The study was randomized, since the mean baseline prostate sizes, peak urine flow rates, obstructive and irritative symptoms scores, post-void residual volumes and patient ages were similar in the 2 groups. The patient perceptions of treatment rendered were similar for the 2 treatment groups, confirming that the study was double-blind. The patients undergoing cystoscopy and balloon dilation of the prostate experienced a statistically significant improvement in the mean total symptom scores at 1 and 3 months. The mean total symptom scores after balloon dilation of the prostate and cystoscopy at 1 and 3 months were not significantly different. The mean peak urinary flow rates 1 and 3 months after balloon dilation of the prostate and cystoscopy were not significantly different from the baseline mean peak urinary flow rates. We demonstrate that balloon dilation of the prostate and cystoscopy are equally effective for the treatment of BPH. Since cystoscopy is considered a diagnostic modality, our study suggests that the efficacy previously observed after balloon dilation of the prostate is primarily placebo-related. The study does not support the indication of balloon dilation of the prostate for the treatment of symptomatic BPH.

Aged↗
PubMed2000

Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia.

OBJECTIVES: Cellular senescence is a unique cellular response pathway thought to be closely associated with the aging process. The senescent phenotype is characterized by the loss of a cell's ability to respond to proliferative and apoptotic stimuli even while normal metabolic activity and vitality is maintained. Recently, a novel biomarker, senescent-associated beta-galactosidase (SA-beta-gal), was found to identify cells with the senescent phenotype. In the present study, we examined whether human prostatic epithelial cells adopt a senescence-associated phenotype after prolonged culture and analyzed a series of human benign prostatic hyperplasia (BPH) specimens to determine whether the cellular senescence process might be a factor in the development of BPH. METHODS: A primary culture of epithelial cells was established from the normal tissue of the peripheral zone of a radical prostatectomy specimen and was serially passaged until senescence. Forty-three human prostate specimens were obtained subsequent to radical prostatectomy or transrectal ultrasound-guided biopsy. The cultured cells and tissue specimens were histochemically stained to reveal the expression of SA-beta-gal, the cellular senescence biomarker. RESULTS: As has been reported for other types of cultured cells, human prostatic epithelial cells demonstrated widespread expression of the cellular senescence marker, SA-beta-gal, on prolonged culture. In our survey of hypertrophied human prostate tissues, 17 specimens (40%) of the 43 analyzed demonstrated positive staining for SA-beta-gal. In these tissues, SA-beta-gal expression was noted only in the epithelial cells. No statistical correlation (P = 0.42) between the chronologic age of the patient donor and SA-beta-gal expression was found. However, a high prostate weight (greater than 55 g) was found to correlate strongly with the expression of the SA-beta-gal biomarker (P = 0. 0001). CONCLUSIONS: Cultured prostatic epithelial cells expressed SA-beta-gal on reaching replicative senescence in vitro. The survey of human BPH specimens for the senescent marker showed that prostatic epithelial cells in patients with BPH with more advanced enlargement of the prostate (greater than 55 g prostate weight) expressed SA-beta-gal, and the prostates from patients with BPH that weighed less than 55 g tended to lack senescent epithelial cells. On the basis of these results, we propose that the accumulation of senescent epithelial cells may play a role in the development of the prostatic enlargement associated with BPH.

Aged↗
PubMed1997

Detection of intact prostate cancer cells in the blood of men with prostate cancer.

OBJECTIVES: To develop a procedure to be used to find, identify, and characterize the living prostate cancer cells in the blood of patients with prostate cancer. METHODS: The procedure is based on a negative selection approach that removes most of the blood cells and collects the remaining prostate cancer cells, which are identified and characterized by fluorescent in situ hybridization with deoxyribonucleic acid probes and by indirect fluorescent immunocytochemical staining. The blood cells are removed via density gradient centrifugation. RESULTS: Using the prostate cancer LNCaP cells as a model, the recovery rate of the added prostate cancer cells to 10 mL of blood was about 85%, with a dilution of 1 LNCaP cell to 10,000 white blood cells or more. Blood samples varying from 9 to 27 mL were collected and analyzed from 8 men aged 54 to 79 years who had varying levels of PSA in serum. In one blood sample, prostate cancer cells were not found; in the seven other samples, the number of prostate cancer cells found per milliliter of blood varied from 1 to 20. Prostate cancer cells were not found in 7.5 to 15-mL blood samples from 3 healthy younger men. The prostate cells were found to be aneuploid for chromosomes 7 and 8, highly suggestive that these cells were cancerous. CONCLUSIONS: Using a negative selection approach, prostate cells can be found in the blood of patients with prostate cancer, as identified by prostate cell-specific probes and antibodies. These cells were found to be aneuploid.

Adult↗
PubMed2000

A comparison of complications between ultrasound-guided prostate brachytherapy and open prostate brachytherapy.

PURPOSE: Prostate brachytherapy has reemerged during the 1990s as a treatment for clinically localized prostate cancer. The renewed popularity of prostate brachytherapy is largely due to the use of transrectal ultrasound of the prostate, which allows for more accurate isotope placement within the prostate when compared to the open approach. The present study investigates whether this improved cancer control is at the expense of increased morbidity by comparing the morbidity after transrectal ultrasound-guided prostate brachytherapy to the morbidity after prostate brachytherapy performed via an open approach. METHODS AND MATERIALS: All men in the Medicare population who underwent prostate brachytherapy in the year 1991 were identified. These men were further stratified into those men who underwent prostate brachytherapy via an open approach and the men who underwent prostate brachytherapy with ultrasound guidance. All subsequent inpatient, outpatient, and physician (Part B) Medicare claims for these men from the years 1991-1993 were then analyzed to determine outcomes. RESULTS: In the year 1991, 2124 men in the Medicare population underwent prostate brachytherapy. An open approach was used in 715 men (33.7%), and ultrasound guidance was used in 1409 men (66.3%). Mean age for both cohorts was 73.7 years with a range of 50.7-92.8 years for the ultrasound group and 60.6-92. 1 years for the open group. A surgical procedure for the relief of bladder outlet obstruction was performed in 122 men (8.6%) in the ultrasound group and in 54 men (7.6%) in the open group. An artificial urinary sphincter was placed in 2 men (0.14%) in the ultrasound group and in 2 men (0.28%) in the open group. A penile prosthesis was implanted in 10 men (0.71%) in the ultrasound group and in 4 men (0.56%) in the open group. A diagnosis code for urinary incontinence was carried by 95 men (6.7%) in the ultrasound group and by 45 men (6.3%) in the open group. A diagnosis code for erectile dysfunction was carried by 90 men (6.3%) in the ultrasound group and by 64 men (9.0%) in the open group. CONCLUSION: Prostate brachytherapy performed with ultrasound guidance does not appear to increase significantly complications resulting from the procedure. Both techniques appear to offer similar rates of procedures performed to correct urinary incontinence, bladder outlet obstruction and erectile dysfunction. The limitations of claim information in determining patient outcomes, however, must be considered when evaluating this data.

Aged↗
PubMed2003

Development of a prostate-specific promoter for gene therapy against androgen-independent prostate cancer.

Androgen ablation has been the standard treatment for metastasized prostate cancer. In most cases, however, prostate cancer cells eventually lose androgen dependency and become refractory to the conventional endocrine therapy. Androgen-independent prostate cancer is characterized by a heterogeneous loss of androgen receptor (AR) expression among tumor cells. Prostate-specific promoters such as prostate-specific antigen and rat probasin (rPB) promoters have been examined in the development of gene therapy targeted to prostate cancer. However, those promoters require binding of the androgen-AR complex to the androgen-response element and are active only in the androgen-dependent prostate cancer cell lines and not in the androgen-independent cell lines. To target transgene expression in androgen-independent prostate cancer, we designed a prostate-specific promoter that is activated by the retinoids-retinoid receptor complex instead of the androgen-AR complex. The modified rPB promoters expressed transgenes in response to retinoid in both androgen-dependent and androgen-independent prostate cancer cells and not in other cancer cell lines or in human normal cells, in vitro and in vivo. Furthermore, the combination of retinoid treatment and adenovirus-mediated gene transfer of the modified rPB-driven HSV-tk gene resulted in a significant growth suppression of the androgen-independent prostate cancer cells in the presence of the prodrug ganciclovir. This study suggests that tailoring of the hormone-responsive elements may offer a new therapeutic opportunity against the hormone-refractory stage of prostate cancer.

Adenoviridae↗