Prostate--a novel target for evaluation of FSH modulating peptides

Effects of prostatic inhibin peptide and its synthetic fragments on FSH biosynthesis by the human pituitary and prostate, were examined in vitro. The results showed that FSH biosynthesis by prostatic tissue is modulated by these peptides in a similar fashion to that observed at the pituitary level.     

Hormonal modulation of biosynthesis of prostatic specific antigen, prostate specific acid phosphatase and prostatic inhibin peptide.

Hormonal modulation of in vitro biosynthesis of three prostatic secretory proteins, prostate specific acid phosphatase (PSAP), prostate specific antigen (PSA) and prostatic inhibin peptide (PIP) by human benign hyperplasia (BPH) tissue was studied. LH and inhibins caused increase in the synthesis of all three proteins whereas FSH enhanced the synthesis of PIP and PSA only but decreased PSAP synthesis. Prolactin and thyroid releasing hormone decreased synthesis of PIP and PSAP. However, PSA synthesis was enhanced by TRH and was decreased by prolactin. Estradiol caused significant increase in PSA and PSAP but no discernible changes in PIP synthesis were noticed. Testosterone caused an increase in PIP, PSA and PSAP. These data indicate that biosynthesis of PIP, PSA and PSAP by BPH tissue is under multihormonal regulation.     

Effects of aromatase inhibition with aminoglutethimide in men with benign prostatic hypertrophy [Poster 28]

Fourteen men with benign prostatic hypertrophy were treated with the aromatase inhibitor aminoglutethimide for periods of up to 3 months. LH, FSH and testosterone levels rose within one week and remained elevated, while estradiol levels decreased. Despite significant changes in these hormones there was no change in urine flow rates or prostatic size over the study period.     

Computerized microscopic analysis of prostatic fine needle aspirates. Comparison with breast aspirates

Computerized image analysis was employed to analyze fine needle aspiration smears of the prostate and breast using both high-resolution images of individual cells and medium-resolution images of scenes and clusters (contextual analysis). A linear discriminant analysis was used to demonstrate the computer's ability to discriminate between benign and malignant categories for both types of tissue. Correct classification as benign or malignant using contextual analysis was achieved in 22 of 26 prostatic aspirates and in 15 of 18 breast aspirates, as determined by comparison with histology. The addition of high-resolution single-cell analysis resulted in correct classification of 24 of 26 prostatic aspirates and all breast aspirates. For virtually all features, the distinction between benign and malignant was more subtle for prostatic than for breast tissue. The data indicate that contextual analysis may be less effective as an adjunct to high-resolution single-cell microscopy of prostatic specimens than it is for breast specimens.     

Prostate cancer vs hyperplasia: relationships with prostatic and adipose tissue fatty acid composition

The objective of the present study was to study whether adipose tissue and prostatic tissue fatty acid composition differentiates between prostate cancer and benign hyperplasia patients. In addition, the present investigation aimed at exploring the extent to which prostatic tissue fatty acid composition differentiates between prostate-confined cancer and extraprostatic disease including possible metastasis. The subjects were 71 male patients from the island of Crete. Half the patients (n=35) had been diagnosed with benign hyperplasia of the prostate, half with prostatic malignancy (n=36). Patients were examined at the outpatient clinic of the urology unit, University Hospital, Medical School, University of Crete. Relative to benign hyperplasia patients, cancer patients had elevated adipose tissue saturated and reduced monounsaturated fatty acid levels. Cancer patients had reduced prostate tissue stearic to oleic acid ratios and stearic acid levels as opposed to hyperplasia patients. The most pronounced difference between cancer patients and hyperplasia patients was a 3-fold elevated prostatic palmitoleic acid in the former group. Relative to benign hyperplasia patients, cancer patients had reduced prostate tissue arachidonic and docosahexaenoic acid levels. Finally, there was a significantly reduced omega-3/omega-6 polyunsaturated fatty acid ratio in the prostate cancer patient as opposed to the benign hyperplasia group. The pronounced elevations in prostatic tissue palmitoleic acid in cancer patients highlight a possible role of this fatty acid in neoplastic processes. The decreased arachidonic acid levels in cancer patients possibly stem from enhanced metabolism of arachidonic acid via lipoxygenase and cyclooxygenase pathways, and the formation of derivatives such as 5-HETE, 15-HETE, 12(S)-HETE and PGE(2).     

Serum bioactive and immunoreactive follicle stimulating hormone during chronic treatment with gonadotropin releasing hormone agonist in elderly men.

Chronic administration of GnRH agonists "down regulates" the pituitary and decreases LH and FSH serum levels. Changes in the bioactivity of FSH have not been adequately assessed under such treatment, for lack of a proper test. We examined serum changes under GnRH agonist treatment among 12 healthy elderly men suffering only from benign prostatic hypertrophy, for up to one year, using a modification of a granulosa cell bioassay for the determination of FSH bioactivity. While radioimmunoassay-FSH decreased, we noticed a significant increase in the bioactivity of this hormone. The clinical importance of this increase is discussed.     

Gonadotropin-releasing hormone receptors in prostate tissue

OBJECTIVE: To perform an immunohistochemical analysis of gonadotropin-releasing hormone receptors (GnRH-Rs) in archival prostate tissue. STUDY DESIGN: Thirteen benign prostatic hyperplasia (BPH) specimens from open surgery, 48 radical prostatectomy specimens (30 surgery only and 18 neoadjuvant hormone treatment and surgery) and 14 prostate needle biopsies were examined. The avidin-biotin-peroxidase technique and monoclonal antibody A9E4 against the extracellular domain of GnRH-Rs were employed. Cases with > 5% immunoreactive cells (IR) were considered positive. RESULTS: The epitheliumfrom all 13 cases of BPH was immunoreactive. Most tumor cellsfrom biopsies were IR positive. Twenty-seven of 30 surgery-only specimens were IR positive vs. 8/18 in the surgery and neoadjuvant hormone treatment group. CONCLUSION: GnRH-Rs have been histochemically demonstrated in normal lutenizing hormone/follicle-stimulating hormone pituitary cells. In cell lines LN-CaP and DU-145, Gn-RH-R was identical to that of the pituitary. GnRH-Rs in the prostate can be quite easily assessed immunohistochemically in archival tissue samples, and hormone treatment significantly decreases the immunoreactivity of GnRH-Rs in prostate cancer tissue. This strongly suggests that GnRH agonists bind to BPH and prostate cancer cells.     

Benign prostatic hyperplasia-associated prostate-specific antigen (BPSA) shows unique immunoreactivity with anti-PSA monoclonal antibodies.

We previously identified a modified molecular form of prostate-specific antigen that is significantly elevated in the nodular transition zone tissue of prostates with benign prostatic hyperplasia. This prostate-specific antigen form, designated BPSA, is inactive and contains clipped polypeptide bonds at amino-acid residues Lys145-146 and Lys182-183. BPSA is not elevated in prostate cancer tissues and may therefore be a prostate-specific antigen marker to better discriminate benign prostatic hyperplasia from early prostate cancer. In this work we characterize the immunoreactivity of BPSA in competition assays with prostate-specific antigen using anti-prostate-specific antigen mAb recognizing six different epitopes on the prostate-specific antigen molecule. One mAb showed > 50% loss of immunoreactivtiy with BPSA compared with prostate-specific antigen, while the binding of two mAbs was largely unaffected and three mAbs had intermediate reactivity. BPSA purified from prostate tissue and seminal plasma, as well as BPSA generated in vitro by mild trypsin-treatment were found to have a similar pattern of reactivity to the six mAbs. However, other forms of inactive seminal plasma prostate-specific antigen, either intact or clipped at Lys145 only, had immunoreactivity similar to total prostate-specific antigen. These results demonstrate that BPSA has unique immunological properties from other forms of prostate-specific antigen, which should allow the development of BPSA-specific mAbs for the study of benign prostatic hyperplasia. Measurement of BPSA levels in the serum may help discriminate benign prostatic hyperplasia from early prostate cancer.     

Comparative study of human steroid 5alpha-reductase isoforms in prostate and female breast skin tissues: sensitivity to inhibition by finasteride and epristeride

Steroid 5alpha-reductase (5-AR) catalyses the reduction of testosterone (T) to dihydrotestosterone (DHT). The 5alpha-reductase found in human benign prostatic hyperplasia (BPH) has been compared with that found in human breast skin tissue in respect of sensitivity to inhibition by Finasteride and Epristeride. Kinetic studies showed the presence of two isoforms of 5alpha-reductase in benign prostatic hyperplasia indicated by low and high Km isoforms for testosterone, while female breast skin tissue contained only one isoform. The isoforms differ in their affinity for the inhibitors Finasteride and Epristeride, both compounds being more effective for the low Km 5alpha-reductase isoform than the high Km 5alpha-reductase of prostatic tissue, with Finasteride displaying competitive inhibition and Epristeride uncompetitive. Finasteride and Epristeride are also inhibitors of skin 5alpha-reductase, which possesses a comparable Ki for Finasteride to that of the low Km prostatic enzyme, but Epristeride was a less potent inhibitor of the skin enzyme relative to the prostate isoform. These results suggest that the inhibitors have therapeutic potential, other than for treatment of benign prostatic hyperplasia, for treating skin disorders influenced by the action of dihydrotestosterone and warrant further investigation.     

前列腺组织中神经生长因子(NGF)表达的研究

研究前列腺组织中神经生长因子（ＮＧＦ） 的生理学意义。采用原位杂交和免疫组化法, 检测４３ 例前列腺增生组织, ８ 例腺癌组织和８ 例正常组织中β－ＮＧＦｍ ＲＮＡ及其蛋白的表达及分布。结果显示β－ＮＧＦｍ ＲＮＡ 在正常组织及增生组织中定位于间质细胞, 偶见于上皮细胞中; 而在癌组织中, 上皮细胞和间质细胞有同样强度的β－ＮＧＦｍ ＲＮＡ染色。其蛋白在良性组织中表达主要着色在间质细胞中,上皮细胞呈弱表达,而癌组织中上皮细胞见着色明显增强（Ｐ＜ ０．０５）。ＮＧＦ的自分泌异常可见是前列腺组织由良性向恶性转变的原因之一。     

Tissue kallikrein of human seminal plasma is secreted by the prostate gland

Samples of human seminal plasma were subjected to gel filtration, and the eluted fractions were analysed for their contents of tissue kallikrein-like antigen, arginine esterase activity and kininogenase activity. Two peaks of tissue kallikrein-like antigen were detected with apparent molecular masses of about 72 and 48 kDa. As judged by the criteria of molecular mass, immunoreactivity, kininogenase activity, identification of the released kinin as kallidin and inhibition studies, a genuine tissue kallikrein has been identified in the 48-kDa peak. In addition, this peak contains one or more species of immunoreactive tissue kallikrein which differ in molecular mass and enzymatic activities. The 72-kDa peak probably represents the complex of tissue kallikrein with alpha 1-proteinase inhibitor rather than a true high molecular mass tissue kallikrein. The prostate gland was identified as the site of origin of the tissue kallikrein in the seminal fluid by indirect methods and by demonstrating immunoreactive tissue kallikrein in prostatic tissue and secretion.     

The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines

We have investigated the possibility of the secretion of gonadotrophin-releasing-hormone (GnRH)-like peptides by prostatic cancer cells in culture and their presence in cytosolic preparations from human prostatic biopsy specimens. A GnRH-specific radioimmunoassay showed GnRH-like activity in concentrated cytosolic preparations and conditioned media from DU 145, an androgen-insensitive human prostatic cell line and from LNCaP, an androgen-responsive prostatic cancer cell line. GnRH immunoreactivity in culture media correlated directly with cell numbers. HPLC demonstrated that this GnRH-like material co-migrated with synthetic GnRH. This homology between synthetic GnRH and partially purified prostatic GnRH was confirmed following V8 protease and trypsin digestion which resulted in similar alterations in HPLC characteristics. The mean content of GnRH-like activity/g specimen tissue was significantly more in malignant tissue (88.5 ± 80.5 fmol) than in benign (29.6 ± 22 fmol), though more specimens of benign tissue were positive (37/54) than malignant tissue (6/22). This observation, taken with an earlier finding of GnRH-specific receptors in a hormone-sensitive cell line and human cancer specimens provides supportive evidence for the autocrine hypothesis of cell regulation.     

Expression of luteinizing hormone and follicle-stimulating hormone receptor in the dog prostate

A possible role for gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the prostate physiology has been suggested in humans and rats. This study aimed at investigating the presence of receptors for LH and FSH (LHR and FSHR) in the canine prostate. Prostates were collected at post mortem from 6 clinically healthy, sexually intact beagles free from any prostatic disorder. Tissue was sampled from dorsal, middle and ventral regions of each prostate. Immunohistochemical localization was performed on wax-embedded sections using polyclonal antibodies for LHR or FSHR. The pattern and intensity of staining in the parenchyma (glandular epithelium) and stroma were determined using a semiquantitative histologic assessment. Receptors for LH and FSH were consistently present in both the glandular epithelium and the stroma in all tissue samples examined. Expression for both receptors was higher in the glandular epithelium than the stroma of all prostatic regions (P < 0.001). In the glandular epithelium, LHR (P < 0.01) and FSHR (P < 0.05) expression was lower in the lateral than the other regions, and there was no difference between dorsal and ventral regions. However, variations in the expression for LHR and FSHR among prostatic regions were not found in the stroma. These findings have demonstrated that LHR and FSHR are expressed in the dog prostate, and the variation observed in their levels of expression among its regions and tissue layers suggests a potential role of gonadotrophins LH and FSH in the regulation of the prostate physiology, particularly the glandular epithelium.     

CYR61, a cellular proliferation marker in dogs with prostatic disease

The life expectancy of dogs is increasing and is associated with a greater frequency of age-related disease, including that of the prostate gland. A marker of cell proliferation, CYR61, may be detected in a number of conditions in humans, including hyperplasia and neoplasia. The objective of the present study was to investigate the degree of CYR61 expression in a number of different prostate diseases in dogs in order to understand the potential of this marker for diagnosis of prostatic disease. Immunohistochemistry with a CYR61 antibody was performed on prostatic tissue from 22 dogs with different diseases. Intense stromal staining was observed in cases of prostatic dysplasia and benign prostate hyperplasia. In contrast, CYR61 staining was very intense in alveolar epithelial cells in cases of epithelial benign prostate hyperplasia and one case of adenocarcinoma. An obvious CYR61 staining pattern was absent in cases of prostatitis. In conclusion, CYR61 may be a useful marker of cell proliferation in a number of prostatic pathologies, although further studies of normal tissue are warranted.     

经直肠实时组织超声弹性成像诊断前列腺良恶性病灶的价值

目的:探索经直肠实时组织超声弹性成像技术在前列腺良恶性病灶诊断中的应用价值。方法:选取2013年12月至2014年5月我科疑似前列腺癌(PCa)并拟行穿刺活检的患者49例,以病例活检结果作为金标准,对比经直肠实时组织超声弹性成像技术、经直肠超声(TRUS)及直肠指诊(DRE)在疑似PCa患者中的诊出结果,并对直肠超声进行弹性图像评分及应变指数分析。结果:弹性图像评分≥4分时,其对PCa的敏感性、特异性及准确性分别为92.3%、91.3%和93.9%;良性病灶的应变指数为2.84±4.72,恶性病灶的应变指数为32.12±15.05,差异有统计学意义(P0.05)。结论:经直肠实时组织超声弹性成像技术可提高PCa的诊出率,在前列腺良恶性病灶的鉴别及指导治疗与预后方面有重要价值。     

Soft tissue tumors of the prostate: a review

Prostate cancer is a leading cause of cancer-related death in adult men. Some prostates that are suspected to be involved by prostatic adenocarcinoma or nodular prostatic hyperplasia through clinical examination and imaging studies proves on histologic examination to be a soft tissue tumor. This paper outlines the most common soft tissue tumors of the prostate and categorizes them into benign, malignant or miscellaneous. Pathologists must be aware that most, if not all, soft tissue tumors of the body may also be found in the prostate. Diagnostic immunohistochemistry is an important adjunct to histopathology for proper diagnosis and tumor subclassification.     

Con A conjugated to Europium(III) cryptate as a new histological tool for prostate cancer investigation using confocal microscopy

Lectins are carbohydrate recognition proteins that can be used as probes to reveal the glycosylation state of cells. They frequently have been used for diagnostic and prognostic cancer studies. For fluorescence based analysis, lectins commonly are conjugated to fluorescein isothiocyanate (Con A-FITC); however, this molecule loses its fluorescence quickly. We conjugated Europium cryptate to Con A (Con A-cryp-Eu) for use as a histochemical luminescent probe to recognize glucose/mannose residues in benign prostatic hyperplasia and prostatic carcinoma tissues, and used confocal microscopy instead of commercial Con A-FITC. Tissues were treated with Evans blue to suppress intrinsic tissue fluorescence before incubation with Con A-cryp-Eu or Con A-FITC. Con A-cryp-Eu exhibited hemagglutinating activity. Con A-cryp-Eu showed the same binding pattern as Con A-FITC in prostate stroma and gland cells. Staining was strong in benign prostate hyperplasia and prostate carcinoma tissues. Con A-cryp-Eu probe stained glucose/mannose residues in prostatic carcinoma more intensely than Con A-FITC. Furthermore, staining with Con A-cryp-Eu showed greater fluorescence intensity than Con A-FITC and the emission of Con A-cryp-Eu was more stable than the Con A-FITC for seven days under the same storage conditions. Maintenance of the luminescent properties and the binding pattern of Con A-cryp-Eu favor its use as an auxiliary histochemistry probe for prostatic tissue studies.     

Insulin Receptor Isoforms A and B as well as Insulin Receptor Substrates-1 and -2 Are Differentially Expressed in Prostate Cancer

Aims/Hypothesis

In different cancers types, insulin receptor isoform composition or insulin receptor substrate (IRS) isoforms are different to healthy tissue. This may be a molecular link to increased cancer risk in diabetes and obesity. Since this is yet unclear for prostate cancer, we investigated IR isoform composition and IRS balance in prostate cancer compared to benign and tumor adjacent benign prostate tissue and brought this into relation to cell proliferation.

Methods

We studied 23 benign prostate samples from radical cystectomy or benign prostatic hyperplasia surgery, 30 samples from benign tissue directly adjacent to prostate cancer foci and 35 cancer samples from different patients. RNA expression levels for insulin receptor isoforms A and B, IRS-1, IRS-2, and IGF-1 receptor were assessed by quantitative real-time RT-PCR. In addition, RNA- and protein expression of the cell cycle regulator p27^Kip1 was quantified by real-time RT-PCR and immunohistochemistry.

Results

Insulin receptor isoform A to B ratio was significantly higher in cancer as well as in tumor adjacent benign prostate tissue compared to purely benign prostates (p<0.05). IRS-1 to IRS-2 ratios were lower in malignant than in benign prostatic tissue (p<0.05). These altered ratios both in cancer and adjacent tissue were significantly associated with reduced p27^Kip1 content (p<0.02). Interestingly, IGF-1 receptor levels were significantly lower in patients with type 2 diabetes (p = 0.0019).

Conclusions/Interpretation

We found significant differences in the insulin signaling cascade between benign prostate tissue and prostate cancer. Histological benign tissue adjacent to cancer showed expression patterns similar to the malignancies. Our findings suggest a role of the insulin signaling pathway in prostate cancer and surrounding tissue and can hence be relevant for both novel diagnostic and therapeutic approaches in this malignancy.     

Lactate dehydrogenase isoenzymes in benign and malignant prostatic tissues

84 prostatic tissue specimens consisted of 62 benign hyperplasias and 22 carcinomas have been studied regarding Lactate dehydrogenase isoenzymes pattern. A consistent and definite shift of the LDH5 : LDH1 ratio has been found in carcinomas respect to benign hyperplasias.