前列腺特异性抗原表达与前列腺癌组织学分级的相关性

目的　探讨血清和组织中前列腺特异性抗原 (PSA )的表达水平 ,与前列腺癌 (Pca)组织学分级的相关性。方法　采用免疫组化ABC法 ,对 70例Pca组织进行PSA检测 ,同时采用放免法测定患者血清PSA浓度。结果　PSA在Pca组织中阳性表达率为 79% ,组织PSA与前列腺癌Gleason′s分级呈显著负相关 (γ =-0 .792 ,P <0 .0 1) ,而血清PSA与组织PSA及前列腺癌Gleason′s分级无相关性。结论　组织PSA与前列腺癌组织学分级间的相关性可能协助准确判断前列腺癌分级分期及预后     

前列腺特异性膜抗原在前列腺癌患者外周血和组织中的表达及意义

目的探讨前列腺特异性膜抗原（PSMA）在前列腺癌患者（PCa）外周血和组织中的表达及其与肿瘤病理分级和临床分期之间的关系。方法采用RT-PCR方法检测前列腺特异性膜抗原（PSMA）在前列腺癌和良性增生患者外周血清中的表达;采用免疫组化法观察PSMA在前列腺不同病变组织中的表达。前列腺癌28例,前列腺上皮内瘤（PIN）7例,良性前列腺增生（BPH）30例。结果血清学检测显示PSMA mRNA在前列腺癌和良性病变组（包括PIN和BPH）患者外周血中阳性率分别为67.9%和8.1%,两者差异具有显著性（P〈0.01）。在局限性癌、局部进展性癌和远处转移癌患者外周血肿瘤细胞中,PSMA mRNA的阳性率分别为58.3%、66.7%和85.7%,随前列腺癌临床分期的进展而逐渐递增（P〈0.05）。在高分化、中分化和低分化前列腺癌中,PSMA mRNA的阳性率分别为87.5%、62.5%和50%,肿瘤分化越差,其阳性率越低（P〈0.05）。组织学检测显示PSMA在PCa、PIN、BPH三种不同前列腺病变组织中的阳性率分别为60.7%、28.6%和20.0%（P〈0.05）,在高、中、低分化前列腺癌组织中PSMA的阳性率分别为100.0%、50.0%和25.0%,与肿瘤Gleason评分之间呈负相关（P〈0.05）。在局限性癌、局部进展性癌和远处转移癌患者肿瘤组织中,PSMA的阳性率分别为58.3%（7/12）、77.8%（7/9）和42.9%（3/7）（P〉0.05）。结论PSMA在前列腺癌组织中明显高表达,并且表达量与前列腺癌临床分期和分化程度（组织学分级）密切相关;检测PSMA可能对前列腺癌诊断、治疗方案的选择及预后评估具有重要价值。     

前列腺特异性抗原人类激肽释放酶2和前列腺特异的膜抗原在前列腺癌患者外周血表达的临床意义

目的　探讨检测前列腺癌微转移的灵敏和特异性指标。方法　从 5 1例前列腺癌、33例前列腺增生 (BPH)患者及 32名正常人的外周血中分离单个核细胞 ,用巢式RT PCR方法检测其中前列腺上皮细胞前列腺特异性抗原 (PSA)、人类激肽释放酶 2 (hK2 )和前列腺特异的膜抗原 (PSMA)的表达。结果　PSA、hK2和PSMA在前列腺癌患者外周血中检出的阳性率分别为 5 2 .9%、4 3.1%和6 4 .7% ;正常人和BPH患者假阳性率分别为 6 .2 %、7.7%和 4 .6 % ,3项指标差异均有显著性 (P <0 .0 1)。各临床分期 (局限癌、侵袭性癌和转移癌 )间 ,PSA和hK2的阳性检出率差异无显著性 ;PSMA在各期前列腺癌中阳性检出率均较PSA和hK2高 ,且随临床分期进展 ,其阳性检出率亦增加 (P <0 .0 5 )。结论PSMA对前列腺癌诊断、治疗方案的选择及预后评估较PSA和hK2有更大的价值     

前列腺特异膜抗原对前列腺疾病的临床诊断意义

目的评价血清中前列腺特异膜抗原（PSMA）浓度对前列腺疾病的辅助诊断意义。方法采用Western印迹分析检测患者血清中PSMA的浓度,前列腺特异抗原（PSA）检测采用通用的免疫化学发光法检测。分析二者在不同分组中的浓度差异及相关性。结果前列腺癌患者的血清中PSMA浓度显著高于正常人群,良性前列腺增生和前列腺炎的患者则低于正常人群,而PSA浓度无论是前列腺癌还是前列腺良性病变均高于正常人。结论前列腺特异膜抗原浓度可以作为区分前列腺癌和良性前列腺增生的辅助诊断标志物。     

前列腺特异性膜抗原在不同组织中的表达及其意义

目的：观察前列腺特异性膜抗原（PSMA）在前列腺不同病变组织及非前列腺肿瘤组织中的表达情况。从免疫化角度评价PSMA的前列腺组织器官特异性。方法：采用PSMA单克隆抗体，对111例前列腺不同病变组织和30例非前列腺肿瘤组织进行染色。结果：PSMA在绝大多数前列腺组织中存在不同程度的阳性表达，仅2例前列腺癌和4例前列腺良性增隆症呈阴性表达，而全部染色的非前列腺肿瘤组织中PSMA阴性表达。结论：PSMA仅在前列腺组织中表达，且在前列腺癌组织中呈明显高表达，是前列腺器官特异性的新型肿瘤标志物，在前列腺癌的诊断和免疫治疗方面具有良好的应用前景。     

前列腺特异性膜抗原PSMA的研究现状

近年来,前列腺特异性分子标志物——前列腺特异性膜抗原（prostrate specific membrane antigen,PSMA）倍受关注。目前研究报道多关于PSMA与前列腺癌及其相关组织的关系,部分文献报道PSMA与其他肿瘤的关系。本文主要从PSMA的一般情况、其与血管生成的关系以及在良性疾病、恶性肿瘤中的表达情况及诊断治疗进行综述。     

前列腺特异性膜抗原与前列腺癌的关系及其临床应用

前列腺特异性膜抗原(PSMA)是位于前列腺细胞膜上的Ⅱ型跨膜糖蛋白,特异地表达于上皮细胞,在前列腺癌及其转移灶中表达增高,特别是在晚期患者及对激素治疗不敏感的患者中其表达升高尤为明显.因此可作为靶蛋白,在前列腺癌的早期诊断、判断病情进展及预后,以及在前列腺癌的靶向治疗中具有重大意义.     

前列腺特异性抗原在前列腺癌诊断中的意义

前列腺特异性抗原（PSA)在前列腺癌的诊断中被广泛应用，全文就PSA生物学特性、年龄标准化PSA、PSA速度、PSA密度和游离PSA与总PSA的比值几个指标进行了介绍，并分析了它们在前列腺癌诊断中的作用。     

前列腺特异性抗原的临床应用

前列腺特异性抗原(PSA)是前列腺上皮细胞的分泌产物,可以迅速水解射精后产生的精液凝块.自1979年Wang等用免疫沉淀法提纯PSA后,PSA得到深入研究和广泛应用,成为肿瘤学和肿瘤标志物研究领域的重大进展,是前列腺癌(CAP)诊断,治疗和随访中最有价值的肿瘤标志物.本文介绍PSA在临床应用的现状.1.血清PSA的正常值瘤标的正常值是在健康人群中测定得到的.PSA是前列腺组织的特异性产物,前列腺感染疾病     

前列腺特异性膜抗原与前列腺癌的关系及其临床应用

前列腺特异性膜抗原（PSMA）是位于前列膛细胞膜上的II型跨膜糖蛋白，特异地表达于上皮细胞，在前列腺癌及其转移灶中表达增高，特别是在晚期患者及对激治疗不敏感的患者中其表达升高尤为明显，因此可作靶蛋白，在前列腺癌的早期诊断，判断病情进展及预后，以及在前列腺癌的靶向治疗中具有有重大意义。     

Effect of exogenous testosterone replacement on prostate-specific antigen and prostate-specific membrane antigen levels in hypogonadal men

Previous studies have suggested that serum prostate-specific antigen (PSA) levels are under androgenic influence, especially in patients with adenocarcinoma of the prostate. PSMA (prostate-specific membrane antigen) is thought to reflect hormonal or clonal resistance or an independence with respect to testosterone regulation. The influence of testosterone on serum PSA expression in normal men is not clear. We studied the effect of exogenous testosterone administration on the serum levels of PSA and PSMA in hypogonadal men. Serial serum PSA, serum PSMA by Western blot, and serum total testosterone levels were obtained at intervals of every 2–4 weeks in 10 hypogonadal men undergoing treatment with exogenous testosterone, delivered as testosterone enanthate injection or by testosterone patch. Linear and quadratic orthogonal polynomial scores were calculated for PSMA, PSA, and testosterone. A 2-tailed, paired t-test failed to demonstrate a significant correlation between serum PSA (linear P = 0.432, quadratic P = 0.290) or PSMA (linear P = 0.162, quadratic P = 0.973) and serum testosterone levels. This study suggests that in hypogonadal men, neither PSMA nor PSA expression is testosterone-dependent.     

RM2 antigen (beta1,4-GalNAc-disialyl-Lc4) as a new marker for prostate cancer

Although prostate-specific antigen (PSA) has been widely used for early detection of prostate cancer, PSA has problems with specificity and prediction of pathological stage. Therefore, a new marker for prostate cancer is urgently required. We examined expression of a novel carbohydrate antigen, beta1,4-GalNAc-disialyl-Lc(4), defined by the monoclonal antibody RM2, in prostate cancer using 75 cases of radical prostatectomy specimens. RM2 immunoreactivity was negative to weak in all benign glands, and weak to moderate in high-grade prostatic intraepithelial neoplasia. In prostatic adenocarcinoma, RM2 immunoreactivity was negative to weak (lower expression) in 20 cases, and moderate to strong (higher expression) in 55 cases. A clear difference of RM2 expression level was observed between Gleason patterns 3 and >/=4. Higher expression of RM2 antigen was significantly associated with primary Gleason pattern >/=4, high Gleason score (>/=8), larger tumor volume and advanced tumor stage. Furthermore, 5-year PSA failure-free survival was significantly lower in the higher expression group. However, no significant relationship was observed between RM2 expression level and preoperative serum PSA. Western blot analysis in prostate cancer cell lines PC3 and LNCap revealed that major 49-kDa and minor 39-kDa glycoproteins were common to both cells, but there was an increase of 59- and 125-kDa glycoproteins unique to LNCap and an increase of 88- and 98-kDa glycoproteins unique to PC3. RM2 antigen is a new histological marker for prostate cancer that may reflect the Gleason grading system. Identification of the glycoproteins carrying the RM2 antigen will provide new insights into the properties of prostate cancer.     

Expression analysis of delta-catenin and prostate-specific membrane antigen: their potential as diagnostic markers for prostate cancer

The current approach to prostate cancer diagnosis has major limitations including the inability of prostate-specific antigen (PSA) assays to accurately differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the imprecision of transrectal ultrasound (TRUS) biopsy sampling. We have employed cDNA microarray screening to compare gene expression patterns in BPH and tumour samples to identify expression markers that may be useful in discriminating between these conditions. Screening of 3 individual cDNA arrays identified 8 genes with expression 3-fold greater in 6 tumour tissues than in 1 nontumour sample and 1 BPH sample. Real-time PCR was used to confirm the overexpression of these 8 genes and 12 genes selected from the literature against a panel of 17 tumours and 11 BPH samples. Two genes, delta-catenin (delta-catenin; CTNND2) and prostate-specific membrane antigen (PSMA; FOLH1), were significantly overexpressed in prostate cancer compared to BPH. Prostate epithelial cells stained positively for delta-catenin and PSMA in our prostate cancer tissues, whereas the majority of our BPH tissues were negative for both markers. Thus we have identified delta-catenin (not previously associated with prostatic adenocarcinoma) and confirmed the potential of PSMA as potential candidates for the diagnosis and management of prostate cancer.     

Detection and characterization of the prostate-specific membrane antigen (PSMA) in tissue extracts and body fluids

The prostate-specific membrane antigen (PSMA) glycoprotein is recognized by the monoclonal antibody (MAb) 7EII -C5.3 as a predominant 100 kDa and minor 180 kDa component in LNCaP cell line extracts and its expression has been shown by immunohistochemistry to be highly restricted to prostate epithelium. The aim of the present study was to utilize Western blot analysis to determine if PSMA could be detected in human tissue extracts and body fluids and if so, which molecular forms were present. PSMA was detected as 120 and 200 kDa bands in normal, benign and malignant prostate tissues and seminal plasma. Further analysis demonstrated that the larger molecular form of PSMA may be a dimer of the lower m.w. species. The PSMA glycoprotein was not detected in the majority of non- prostate tissue extracts examined except for a low yet significant amount in normal salivary gland, brain and small intestine, suggesting that PSMA may not be as prostate-specific as originally thought. Since the prostate-specific antigen (PSA) has been shown to be maximally shed into the serum in high-grade and metastatic prostate carcinomas, it was surprising that PSMA could not be detected in serum by Western blot analysis even in patients with actively progressive metastatic disease. Second generation antibodies generated against different epitopes may be required to determine if PSMA is shed into serum. Our results support the hypothesis that PSMA is a novel prostate biomarker. © 1995 Wiley-Liss, Inc.     

Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer.

PURPOSE: The restricted expression of the surface glycoprotein prostrate-specific membrane antigen (PSMA) to normal prostate tissue, primary and metastatic prostate cancer (PCa), and the neovasculature of various nonprostatic epithelial malignancies has enabled targeting strategies for PCa treatment using anti-PSMA antibodies. EXPERIMENTAL DESIGN: Using prostatectomy specimens, immunohistochemical staining for PSMA (7E11 antibody) was performed on formalin-fixed paraffin-embedded sections of 136 cases of PCa. Cytoplasmic immunoreactivity was scored for intensity and distribution, and results were correlated with tumor grade, pathological stage, DNA ploidy status (Feulgen spectroscopy), and disease recurrence. PSMA mRNA expression in selected primary tumors and metastatic lesions was also detected using in situ hybridization and autoradiography. RESULTS: Generally, PCa cells expressed relatively increased levels of PSMA as compared with benign elements. Among the PCa cases, increased (high) PSMA expression correlated with tumor grade (P = 0.030), pathological stage (P = 0.029), aneuploidy (P = 0.010), and biochemical recurrence (P = 0.001). The mean serum prostate-specific antigen level of 18.28 ng/ml at the time of diagnosis for the PSMA-overexpressing tumors was significantly greater than the mean serum prostate-specific antigen of 9.10 ng/ml for the non-PMSA-overexpressing group (P = 0.006). On multivariate analysis, pathological stage (P = 0.018) and PSMA expression (P = 0.002) were independent predictors of biochemical recurrence. PSMA protein overexpression in high-grade primary PCa tumors and metastatic lesions also correlated with increased PSMA mRNA expression levels using in situ hybridization and autoradiography. CONCLUSIONS: This study demonstrates for the first time that overexpression of PSMA in primary PCa correlates with other adverse traditional prognostic factors and independently predicts disease outcome.     

Increased prostate-specific membrane antigen expression in LNCaP cells following treatment with bispecific antisense oligonucleotides directed against bcl-2 and EGFR

Antisense oligonucleotides have been employed against in vivo and in vitro prostate cancer models. While most oligos consist of a single mRNA binding site, targeting a single gene product or others sharing sequence homology, our laboratory has developed bispecific oligos directed toward even unrelated proteins. This study evaluates the inhibition of in vitro propagating LNCaP cells employing mono- and bispecific oligos directed against bcl-2 [the second bispecific binding site was directed against the epidermal growth factor receptor (EGFR)]. Employing RT-PCR, the expression of non-targeted proteins encoded by mRNA for prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were subsequently evaluated. When LNCaP prostate tumor cells were incubated with bispecific oligos (directed against bcl-2 and EGFR) and compared to lipofectin-containing controls significant growth inhibition resulted. In subsequent experiments, the levels of mRNA encoding PSMA were unexpectedly found to be elevated following treatment with the bispecific oligos but not with the monospecific directed solely against bcl-2. No differences were detected in mRNA levels encoding PSA following treatment with either mono- or bispecific oligos. Previously, we suggested that cell growth inhibition produced by some bispecifics could be attributed to complementary double-stranded regions formed by intra-strand base pairs. Double-stranded nucleic acids are known inducers of interferon, which promote expression of cell surface HLA type antigens. If induced, perhaps this cytokine also enhances PSMA expression, making prostate tumor cells a more recognizable target for cytotoxic T cells.     

Prostate cancer progression in the presence of undetectable or low serum prostate-specific antigen level

BACKGROUND: The serum prostate-specific antigen (PSA) level after definitive treatment for prostate cancer (PC) is a powerful predictor of outcome. Occasionally, PC progression can occur despite low or undetectable PSA levels. The authors report on the clinical and pathologic characteristics of patients who experienced PC progression with undetectable or low PSA levels. METHODS: From an electronic database of all patients with PC who were treated at The University of Texas M. D. Anderson Cancer Center between 1999 and 2004, a group of 46 patients was identified who had progression to metastatic PC detected with concomitant PSA levels from 0.1 ng/mL to 2 ng/mL. Patient charts were reviewed for tumor stage, Gleason score, pretreatment PSA level, and the presence of atypical histologic variants (ie, ductal, sarcomatoid, or small cell cancers). The nadir PSA level after treatment and the PSA level at the time metastatic PC was detected were determined. The patients were followed semiannually, and imaging studies were obtained at the discretion of treating physicians. The sites of metastasis and histologic confirmation were reported when available. RESULTS: Twenty-three of 46 patients underwent radical prostatectomy, 11 patients received radiation therapy, and 12 received hormone treatment as their initial form of therapy. Progression to metastatic disease with concomitant, undetectable PSA levels occurred in 10 patients, including 3 patients who had not received treatment with hormones. The sites of metastasis included bone (n = 35 patients), liver (n = 7 patients), retroperitoneal lymph nodes (n = 5 patients), lungs (n = 4 patients), and brain (n = 1 patient). Aggressive and locally advanced PC were common features in these patients: Eighty-five percent had Gleason scores >or=7, 63% had clinical T3 or T4 tumors, and 41% had pretreatment PSA levels >10 ng/mL. Atypical histologic variants were observed in 21 patients (46%) and in 8 of 10 patients who progressed with undetectable PSA levels. In 10 patients (22%), metastasis were detected in the presence of an undetectable PSA level. Eight of those patients had small cell carcinoma. In 19 patients (41%), progression to metastasis occurred without any increase in their PSA from the nadir level. Thirty-one patients (67%) were asymptomatic at the time metastasis was detected, and the detection of metastasis in these patients occurred only because of routine imaging studies. CONCLUSIONS: Progression of PC may occur despite undetectable or low PSA levels. Complete physical evaluation and imaging studies may be indicated in the surveillance of patients with high-grade, locally advanced tumors, especially when atypical histologic variants are present.     

Relationship between prostate volume, prostate-specific antigen nadir, and biochemical control

PURPOSE: In patients treated with definitive three-dimensional conformal radiotherapy (3D-CRT) for localized prostatic adenocarcinoma, we sought to evaluate the relationship between pretreatment prostate gland volume and posttreatment prostate-specific antigen (PSA) nadir, as well as the relationship of prostate volume and PSA nadir with biochemical control (bNED). Two subgroups were studied: favorable (PSA <10 ng/mL, Gleason score 2-6, and T1-T2A) and unfavorable (one or more: PSA >/=10 ng/mL, Gleason score 7-10, T2B-T3). MATERIALS AND METHODS: A total of 655 men (n = 271 favorable and 384 unfavorable) were treated with 3D-CRT alone between May 1989 and November 1997. All patients had information on prostate volume and a minimum follow-up of 24 months (median 56, range 24-126). Of the 655 men, 481 (n = 230 favorable and 251 unfavorable) remained bNED at time of analysis, with biochemical failure defined in accordance with the American Society for Therapeutic Radiology and Oncology consensus definition. Factors analyzed for predictors of bNED included pretreatment prostate volume, posttreatment PSA nadir, pretreatment PSA, palpation T stage, Gleason score, center of the prostate dose, and perineural invasion (PNI). We also analyzed pretreatment prostate volume and its correlation to prognostic factors. For bNED patients, the relationship between PSA nadir and prostate volume was evaluated. RESULTS: On multivariate analysis, prostate volume (p = 0.04) and palpation T stage (p = 0.02) were the only predictors of biochemical failure in the favorable group. On multivariate analysis of the unfavorable group, pretreatment PSA (p <0.0001), Gleason score (p = 0.02), palpation T stage (p = 0.009), and radiation dose (p <0.0001) correlated with biochemical failure, and prostate volume and PNI did not. For all 481 bNED patients, a positive correlation between pretreatment volume and PSA nadir was demonstrated (p <0.0001). Subgroup analysis of the favorable and unfavorable patients also demonstrated a positive correlation between prostate volume and PSA nadir (p = 0.003 and p = 0.0002, respectively). Using multiple regression analysis, the following were found to be predictive of PSA nadir in all bNED patients: prostate volume (p <0.0001), pretreatment PSA (p <0.0001), palpation T stage (p = 0.0002), and radiation dose (p = 0.0034). Gleason score and PNI were not predictive. For the favorable group, palpation T stage (p = 0.0006), pretreatment PSA (p = 0.0083), prostate volume (p = 0.0186), and Gleason score (p = 0.0592) were predictive of PSA nadir, and PNI and radiation dose were not predictive. In the unfavorable group, prostate volume (p = 0.0024), radiation dose (p = 0.0039), pretreatment PSA (p = 0.0182), and palpation T stage (p = 0.0296) were predictive of PSA nadir, and Gleason score and PNI were not predictive. CONCLUSION: This report is the first demonstration that prostate volume is predictive of PSA nadir for patients who are bNED in both favorable and unfavorable subgroups. PSA nadir did not correlate with bNED status in the favorable patients, but it was strongly predictive in the unfavorable patients. Prostate gland volume was also predictive of bNED failure in the favorable but not the unfavorable group.     

Tumor angiogenesis is associated with MUC1 overexpression and loss of prostate-specific antigen expression in prostate cancer.

The biological potential of prostate cancer is highly variable and cannot be satisfactorily predicted by histopathological criteria alone. Therefore, additional and more precise information is desirable. Although angiogenesis has been suggested as being of prognostic importance in many human cancers, and MUC1, also known as episialin, was thought to be responsible for the development of metastasis, the role of these parameters in prostate cancer remains unclear. The aim of this study was to investigate whether angiogenesis, assessed as microvessel density (MVD), was correlated with the expression of prostate tumor MUC1 and prostate-specific antigen (PSA) or with histopathological grade at diagnosis, and to determine whether any of these factors might provide additional information with regard to prostate tumor biology. Paraffin-embedded material from 60 patients with prostate carcinoma was examined immunohistochemically, using the monoclonal antibody CD31 to determine MVD, and the monoclonal antibodies CCE831 and ER-PR8 to assess MUC1 and PSA expression, respectively. The tumors were categorized according to the Gleason grading system. MUC1 overexpression was significantly related to a high intratumoral angiogenesis (P = 0.02). By contrast, a high PSA expression by prostate cancer cells was associated with low MVD (P = 0.03). No correlation was found between MUC1 and PSA expression. Usually, high-grade tumors were not PSA-expressive and tended to display increased angiogenesis. These differences, however, were not of statistical significance. Similarly, there was no statistically significant association between histological grade and MUC1 expression or angiogenesis. It is suggested that PSA may have a direct suppressive effect on new blood vessel formation in prostate cancer, whereas the expression of MUC1 in this tumor may be connected with an angiogenic phenotype. Additional studies are obviously needed to clarify the precise role of these proteins in prostate cancer.