Leptin in relation to prostate cancer and benign prostatic hyperplasia

The aim of our study was to determine whether leptin, a hormone implicated in both energy-balance and reproductive function, is involved in the etiology of prostate cancer or benign prostatic hyperplasia (BPH). We compared the serum leptin levels of 43 cases of incident prostate cancer, 41 patients with BPH, and 48 healthy controls, all recruited in Athens, Greece. Multiple logistic regression modeling was used, with adjustment for age, height, body mass index, education, estradiol, testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin and insulin like growth factor 1. Odds ratios per 4 ng/ml increment of leptin were 0.70 [95% confidence interval (CI) (0.32,1.55)] for prostate cancer and 1.06 [95% CI (0.67,1.67)] for BPH. After adjustment for body mass index, serum leptin levels were not significantly correlated with levels of any of the other hormones under study. Leptin levels are unlikely to affect the risk of either prostate cancer or BPH substantially. Int. J. Cancer 76:25–28, 1998.© 1998 Wiley-Liss, Inc.     

前列腺癌和前列腺增生组织Hepsin表达及其临床意义

目的:探讨Hepsin在前列腺癌组织中的表达,并分析其与前列腺癌临床分期及病理分级之间的关系.方法:免疫组织化学链霉菌抗生物素蛋白-过氧化物酶连结(SP)法检测68例前列腺癌、40例前列腺增生组织中Hepsin蛋白的表达,并分析其与临床分期、病理分级之间的关系.结果:Hepsin蛋白在前列腺癌组织和前列腺增生组织中阳性表达率分别为86.76% (59/68)和45.00%(18/40),差异有统计学意义,χ2=21.47,P<0.001;其阳性率在前列腺癌不同临床分期中差异有统计学意义(χ2=9.07,P=0.004),而在Gleason评分高与低分组之间差异无统计学意义,χ2=1.15,P=0.476.结论:Hepsin可作为前列腺癌的一个诊断指标,其与前列腺癌临床分期密切相关,有可能在前列腺癌的发生发展中起重要作用.     

Family history of cancer and the risk of prostate cancer and benign prostatic hyperplasia

We analysed the relation between family history of cancer in first-degree relatives and risk of prostate cancer (PC) and benign prostatic hyperplasia (BPH) using data from a multicentric case-control study conducted in Italy from 1991 to 2002 on 1,294 cases of incident, histologically confirmed PC, 1,369 cases of BPH and 1,451 men admitted to the same network of hospitals for acute, nonneoplastic conditions. Unconditional logistic regression was used to estimate odds ratios (OR) of PC and BPH, adjusted for age and other confounders. Men with a family history of PC had an OR of PC of 4.0 (95% confidence interval [CI] 2.5-6.5), and the risk was higher when the proband was younger, when 2 or more relatives were affected or when the affected relative was a brother. The risk of PC was also increased in men with a family history of cancer of the ovary (OR = 6.2, 95% CI 1.2-32), bladder (OR = 3.5, 95% CI 1.6-7.4) and kidney (OR = 3.1, 95% CI 1.1-8.5). An involvement of breast/ovarian cancer predisposition genes in a small proportion of PCs was suggested by the cluster of these cancers in female relatives of a few PC cases. The risk of BPH was increased in men with a family history of bladder cancer (OR = 2.2, 95% CI 1.0-5.0) but not PC (OR = 1.2, 95% CI 0.7-2.2). Our study adds further information on the association of family history of cancer and risk of PC and is, to our knowledge, the first comprehensive epidemiologic information on family history of cancer and risk of BPH.     

Catechol-O-methyltransferase gene polymorphisms in benign prostatic hyperplasia and sporadic prostate cancer.

Various carcinogenic metabolites, including catechol estrogens, play a role in malignant transformation. An enzyme that is capable of neutralizing the genotoxic effects of these compounds is catechol-O-methyltransferase (COMT). A variant form of this enzyme has been shown to reduce its activity by up to 4-fold; thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for benign prostatic hyperplasia (BPH) and prostate cancer. To test this hypothesis, the genetic distribution of three different COMT polymorphisms at codon 62 (C-->T), codon 72 (G-->T), and codon 158 (G-->A) were analyzed in 131 normal healthy subjects, 134 BPH, and 178 sporadic prostate cancer samples from a Japanese population. Results of these experiments show that the variant genotype at codon 62 (P = 0.060) and codon 158 (P = 0.047) are risk factors for prostate cancer but not BPH when compared with normal controls. Odds ratio (OR) and 95% confidence interval (95% CI) for cancer were 3.24 and 1.38 to 7.61, respectively, for codon 62 T/T genotype when compared with wild type. At codon 158, the A/A variant for cancer had an OR of 3.00 with a 95% CI of 1.38 to 6.54 compared with wild type. Codons 62 and 158 were in linkage disequilibrium (LD), and when compared with the C-G haplotype, other types (C-A, T-G, T-A) were observed to be associated with prostate cancer (P = 0.040) but not BPH. Codon 72 on the other hand, was not in LD with either codon 62 or 158. The homozygous variant on codon 72 was rare in this Japanese population, and the heterozygous G/T at this codon was not associated with either prostate cancer or BPH. When evaluating the risk of COMT polymorphisms with stage or grade of cancer, no associations were observed for any of the genotypes with the exception of a tendency (P = 0.096) for the variant A allele on codon 158 to be correlated with higher stages (> or = T3) of cancer. This is the first report that shows the polymorphisms of COMT to be associated with sporadic prostatic carcinogenesis. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of prostate cancer.     

Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia

Background:

An individualised risk-stratified screening for prostate cancer (PCa) would select the patients who will benefit from further investigations as well as therapy. Current detection methods suffer from low sensitivity and specificity, especially for separating PCa from benign prostatic conditions. We have investigated the use of metabolomics analyses of blood samples for separating PCa patients and controls with benign prostatic hyperplasia (BPH).

Methods:

Blood plasma and serum samples from 29 PCa patient and 21 controls with BPH were analysed by metabolomics analysis using magnetic resonance spectroscopy, mass spectrometry and gas chromatography. Differences in blood metabolic patterns were examined by multivariate and univariate statistics.

Results:

By combining results from different methodological platforms, PCa patients and controls were separated with a sensitivity and specificity of 81.5% and 75.2%, respectively.

Conclusions:

The combined analysis of serum and plasma samples by different metabolomics measurement techniques gave successful discrimination of PCa and controls, and provided metabolic markers and insight into the processes characteristic of PCa. Our results suggest changes in fatty acid (acylcarnitines), choline (glycerophospholipids) and amino acid metabolism (arginine) as markers for PCa compared with BPH.     

Proteomics-based signature for human benign prostate hyperplasia and prostate adenocarcinoma

Prostate adenocarcinoma often presents at a late stage, due to a lack of early clinical symptoms and lack of accurate objective markers. This study aimed to identify and validate proteomics-based biomarkers useful for prostate cancer diagnosis and to establish a marker-panel for prostate cancer and benign prostate hyperplasia (BPH). Global protein expression patterns in fresh tissue specimens from 8 patients with prostate carcinoma and 16 with BPH were analyzed by two-dimensional gel electrophoresis. Differentially expressed proteins were identified by MALDI-TOF mass spectrometry. We compared our results with those of published studies and defined a set of common biomarkers. We identified 22 differentially expressed proteins between BPH and prostate carcinomas. The up-regulated proteins in cancer compared to BPH included protein disulfide-isomerase, 14-3-3-protein, Enoyl CoA-hydrase, prohibitin and B-tubulin β-2. Keratin-II, desmin, HSP71, ATP-synthase-β-chain and creatine kinase-β-chain were down-regulated. Survey of the literature showed that 15 of our 22 identified proteins have been previously reported to differ in their expression levels between BPH and prostate cancer by other laboratories. The expression patterns of these biomarkers could successfully cluster BPH and adenocarcinomas as well as prostate cancer of low and high Gleason scores. This study validates protein-biomarkers that can be useful for accurate diagnosis and prognostic monitoring of prostate adenocarcinoma. Despite varied prevalence of the disease between different ethnic populations (i.e., high in Sweden, low in Saudi Arabia); the biomarkers indicate that BPH and prostate cancers are biologically 'homogeneous' in their protein expression patterns across wide geographical regions.     

A comparison of virtual touch tissue quantification and digital rectal examination for discrimination between prostate cancer and benign prostatic hyperplasia

Background

Virtual touch tissue quantification (VTTQ) is a new, promising technique for detecting the stiffness of tissues. The aim of this study is to compare the performance of VTTQ and digital rectal examination (DRE) in discrimination between prostate cancer and benign prostatic hyperplasia (BPH).

Patients and methods

VTTQ was performed in 209 prostate nodular lesions of 107 patients with BPH and suspected prostate cancer before the prostate histopathologic examination. The shear wave velocity (SWV) at each nodular lesion was quantified by implementing an acoustic radiation force impulse (ARFI). The performance of VTTQ and DRE in discrimination between prostate cancer and BPH was compared. The diagnostic value of VTTQ and DRE for prostate cancer was evaluated in terms of the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy.

Results

Prostate cancer was detected in 57 prostate nodular lesions by histopathologic examination. The SWV values (m/s) were significantly greater in prostate cancer and BPH than in normal prostate (2.37 ± 0.94, 1.98 ± 0.82 vs. 1.34 ± 0.47). The area under the receiver operating characteristic curve (AUC) for VTTQ (SWV>2.5m/s) to differentiate prostate nodules as benign hyperplasia or malignancy was 0.86, while it was 0.67 for DRE. The diagnostic sensitivity, specificity, PPV, NPV and accuracy were 71.93 %, 87.5 %, 68.33 %, 89.26 %, 83.25 %, respectively for VTTQ (SWV>2.5m/s), whereas they were 33.33 %, 81.57 %, 40.43 %, 76.54 %, 68.42 % respectively for DRE.

Conclusions

VTTQ can effectively detect the stiffness of prostate nodular lesions, which has a significantly higher performance than DRE in discrimination between prostate cancer and BPH.     

Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia.

Blood samples were collected from 52 incident cases of histologically confirmed prostate cancer, an equal number of cases of benign prostatic hyperplasia (BPH) and an equal number of apparently healthy control subjects. The three groups were matched for age and town of residence in the greater Athens area. Steroid hormones, sex hormone-binding globulin, and insulin-like growth factor 1 (IGF-1) were measured in duplicate by radioimmunoassay in a specialized US centre. Statistical analyses were performed using multiple logistical regression. The results for IGF-1 in relation to prostate cancer and BPH were adjusted for demographic and anthropometric factors, as well as for the other measured hormones. There was no relation between IGF-1 and BPH, but increased values of this hormone were associated with increased risk of prostate cancer; an increment of 60 ng ml(-1) corresponded to an odds ratio of 1.91 with a 95% confidence interval of 1.00-3.73. There was also some evidence for an interaction between high levels of testosterone and IGF-1 in relation to prostate cancer. This finding suggests that, in addition to testosterone, IGF-1 may increase the risk of prostate cancer in humans.     

Serum and urinary prostatic inhibin-like peptide in benign prostatic hyperplasia and carcinoma of prostate

The levels of immunoreactive prostatic inhibin-like peptide (PIP), having follicle-stimulating hormone suppressing properties, were estimated in the sera and urine samples of patients with benign prostatic hyperplasia (BPH) and prostatic carcinoma (PC) as compared to age-matched controls. Significantly elevated serum PIP levels in BPH (107.8 +/- 19 ng/ml) and PC (88.7 +/- 9 ng/ml) patients were observed as compared to those in control men (10.2 +/- 1 ng/ml). Unlike serum, in urine high levels of PIP in BPH (294 +/- 49 micrograms/24 h) and extremely low levels in PC (23.6 +/- 5 micrograms/24 h) patients were seen as compared to control values (137.6 +/- 10 micrograms/24 h). Furthermore, striking differences were observed between the urinary PIP levels of BPH and PC patients. The results of the present investigation thus indicate the possible use of urinary PIP as a biological marker for prostate cancer.     

Nedd4L expression is downregulated in prostate cancer compared to benign prostatic hyperplasia

Aims

To characterize aspects of Nedd4L in prostate cancer (PC) by assessing its expression in hyperplastic and malignant prostate tissue, and to correlate findings with PC histologic grade.

Materials and methods

Radical prostatectomy (RP) specimens from 56 patients with clinically localized PC, and benign prostatic hyperplasia (BPH) transurethral resection specimens from 31 patients, were assessed for Nedd4L expression using immunohistochemistry.

Results

Nedd4L (P < 0.001) expressions were significantly decreased in PC compared to benign prostate tissue. Furthermore, downregulation of Nedd4L (P < 0.05) expression correlated with increasing Gleason score.

Conclusions

These data suggest that prostate cancer cells in vivo may need Nedd4L expression to regulate TGF-β1 signaling, and that Nedd4L expression might be involved in prostate cancer development.     

Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling.

Critical aspects of the biology and molecular basis for prostate malignancy remain poorly understood. To reveal fundamental differences between benign and malignant growth of prostate cells, we performed gene expression profiling of primary human prostate cancer and benign prostatic hyperplasia (BPH) using cDNA microarrays consisting of 6500 human genes. Frozen prostate specimens were processed to facilitate extraction of RNA from regions of tissue enriched in either benign or malignant epithelial cell growth within a given specimen. Gene expression in each of the 16 prostate cancer and nine BPH specimens was compared with a common reference to generate normalized measures for each gene across all of the samples. Using an analysis of complete pairwise comparisons of expression profiles among all of the samples, we observed clearly discernable patterns of overall gene expression that differentiated prostate cancer from BPH. Further analysis of the data identified 210 genes with statistically significant differences in expression between prostate cancer and BPH. These genes include many not recognized previously as differentially expressed in prostate cancer and BPH, including hepsin, which codes for a transmembrane serine protease. This study reveals for the first time that significant and widespread differences in gene expression patterns exist between benign and malignant growth of the prostate gland. Gene expression analysis of prostate tissues should help to disclose the molecular mechanisms underlying prostate malignant growth and identify molecular markers for diagnostic, prognostic, and therapeutic use.     

良恶性前列腺疾病肿瘤血管形成的MR灌注加权成像评价

Objective: To explore the application of MR perfusion-weighted imaging (PWI) in the benign and malignant prostate diseases, and evaluate the correlations of PWI features with vascular endothelial growth factor (VEGF) and microvessel density (MVD). Methods: Seventy-four consecutive patients who were diagnosed clinically for the prostate diseases, including forty-four cases with benign prostate hyperplasia and thirty cases with prostatic cancer proved pathologically, were examined by PWI. MVD and VEGF were stained with immunohistochemical methods. Some parameters of PWI, including the steepest slope of signal intensity-time curve (SSmax) and the change in relaxation rate (△R2* peak) at lesions, were analyzed.Correlation analysis was used to determine the relationship between the results of PWI and immunohistochemistry. Results:(1) In the benign prostate hyperplasia (BPH), SSmax and △R2* peak of perfusion curve were 34.2 2.9 and 1.49±0.11,respectively; however, in the prostatic cancer (Pca), they were 58.6±4.8 and 3.18 0.49 respectively; there were statistical differences (t = 2.16 and 2.31, P ＜ 0.05). (2) The VEGF and MVD expressions of thirty Pca patients were significantly higher than those of forty-four BPH patients (X2 = 28.64, P＜0.01; t = 21.2, P＜0.01). MVD expressions of Pca and BPH groups showed positive associations with VEGF expressions (P＜0.01). On MR perfusion-weighted imaging, SSmax and △R2* peak showed associations with MVD and VEGF expressions (P＜0.01). Conclusion: On MR perfusion-weighted imaging, SSmax and △R2* peak can reflect MVD and VEGF expression levels in the benign and malignant prostate diseases and might be implied the tumor angiogenesis so as to distinguish benign from malignant and provide the important information for the surgeon to diagnose and treat the prostatic diseases.     

Possible relations between oxidative damage and apoptosis in benign prostate hyperplasia and prostate cancer patients

Cancer has been described as the twentieth century plague, and is a very common health problem. It has been reported that ROS and ROS products play a key role in cancer and that oxidative damage is effective in apoptosis initiation. In this study we aimed to evaluate the relationship between MDA (malondialdehyde), DNA damage (8-hydroxyguanine, 8-OH-dG), and caspase-3 in BHP and prostate cancer patients. Twenty male patients with prostate cancer and 20 male patients with benign prostate hyperplasia were included into this study. The MDA (nanomole), DNA damage (nanograms per millilitre), and caspase-3 (nanograms per millilitre) levels were measured in prostate cancer and benign prostate hyperplasia using Elisa kits (Millipore Corporation, Billerica, MA, USA). In the prostate cancer group, serum MDA (30.96?±?9.25) and DNA damage (4.42?±?0.36) levels were significantly raised (p?<?0.05) when compared to the benign prostate hyperplasia group (24.05?±?8.06, 3.99?±?0.54). However, in the prostate cancer group, serum caspase-3 (2.36?±?0.82) levels were statistically significantly lowered (p?<?0.05) compared with the benign prostate hyperplasia group (3.15?±?1.04). We observed that altered prooxidant, DNA damage levels may lead to an increase in oxidative damage and may consequently play an important role in prostate carcinogenesis. These findings indicate that, although the triggering of these changes is unknown, changes in the levels of MDA, DNA damage, and caspase-3 in the blood are related to prostatic carcinoma development. In addition, it would be appropriate to conduct new studies with a large number of patients at different stages.     

Gene expression profile in the peripheral blood of patients with prostate cancer and benign prostatic hyperplasia

Background: Prostate cancer consists of multifactorial and multifocal events, generating differential gene expression in tumor cells. Methods: The molecular profile of 14 gene expression was analyzed through cDNA array in blood samples of patients with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). Results: Messenger RNA from patient's blood showed significant differences between PCa and BPH groups only for the NOS3 gene, with an occurrence chance for PCa 5.8-fold higher than BPH disease. Conclusion: The NOS3 gene expression in the patient's blood may be used as a putative biomarker for prostate cancer.     

DWI单、双指数模型对中央腺体前列腺癌及良性前列腺增生的鉴别诊断价值

背景与目的：鉴别中央腺体前列腺癌（central gland prostate cancer, CGPCa）与良性前列腺增生（benign prostatic hyperplasia, BPH）一直是临床工作的难点之一,传统的检查方法不能很好地区分两者。弥散加权成像（diffusion weighted imaging,DWI）单、双指数模型可以定量反映组织弥散及血流灌注信息。探究DWI单、双指数模型定量参数（单指数：ADC _total ,双指数：ADC _slow 、ADC _fast 及f值）对CGPCa与BPH的鉴别诊断价值。方法：回顾性分析在海军军医大学（第二军医大学）长海医院经前列腺穿刺病理学检查证实的36例CGPCa、48例BPH［25例基质型增生（stromal hyperplasia,SH）和23例腺体型增生（glandular hyperplasia,GH）］患者的MRI检查及临床资料。MRI检查包含多b值（0、50、100、150、200、500、800、1 000、1 500、2 000 s/mm ² ）DWI扫描。在DWI图像上画取感兴趣区（region of interest,ROI）,获得CGPCa、SH及GH患者ADC _total 、ADC _slow 、ADC _fast 及f值。采用方差分析、LSD-t检验比较各参数差异性,受试者工作特征（receiver operating characteristic,ROC）曲线分析各参数鉴别CGPCa与BPH的效能,并比较ROC曲线的曲线下面积的差异。结果：3组病理类型两两之间ADC _total 和ADC _slow 差异均有统计学意义（P＜0.000 1）。CGPCa与SH之间f值差异有统计学意义（P=0.002）;CGPCa与GH、GH与SH之间f值差异无统计学意义（P=0.053、P=0.201）。3组病理类型ADC fast 差异无统计学意义（P=0.685）。在CGPCa与BPH鉴别诊断中,ADC _total 、ADC _slow ROC曲线的曲线下面积均为0.998,诊断效能均较高。f值ROC曲线的曲线下面积为0.674,显著小于ADC _total 、ADC _slow （P＜0.000 1）,诊断效能较低。结论：DWI单指数模型参数ADC _total 、双指数模型参数ADC _slow 均可以反映组织内细胞结构附近的水分子弥散情况,对鉴别CGPCa与BPH具有较大价值。