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It is fundamentally important to understand the underlying mechanisms regulating prostate caner (PCa) metastasis. Despite the increased PSMA expression found in more advanced stage of PCa, little is known about the functional role of PSMA in PCa progression. With this founding from the Department of Defense Prostate Cancer Research Program, we have achieved each of these tasks during the course of this project. We have been able to (1) monitor PSMA expression in live PCa cells, (2) examine its function in cell adhesion, (3) establish its role in cell migration, (4) identify fibronetin as a specific extracellular matrix for enhanced PSMA-positive cell attachment, (5) determine the association of PSMA with integrin, a key signaling molecule known to controlling cancer progression and metastasis and (6) characterize its enzymatic activity in regulation of cell attachment and migration. Our work has contributed to new insight into the role of PSMA in PCa progression. Knowledge of PSMA in cell adhesion and migration will have a direct impact on the design of targeted treatment for patients suffering metastatic PCa.

This article is from International Journal of Oncology , volume 41 . Abstract Emergence of androgen-independent cancer cells during androgen deprivation therapy presents a significant challenge to successful treatment outcomes in prostate cancer. Elucidating the role of androgen deprivation in the transition from an androgen-dependent to an androgen-independent state may enable the development of more effective therapeutic strategies against prostate cancer. Herein, we describe an in vitro model for assessing the effects of continuous androgen-deprivation on prostate cancer cells (LNCaP) with respect to the expression of two prostate-specific markers: the androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Compared with androgen-containing normal growth medium, androgen-deprived medium apparently induced the concomitant downregulation of AR and PSMA over time. Decreased protein levels were confirmed by fluorescence imaging, western blotting and enzymatic activity studies. In contrast to the current understanding of AR and PSMA in prostate cancer progression, our data demonstrated that androgen-deprivation induced a decrease in AR and PSMA levels in androgen-sensitive LNCaP cells, which may be associated with the development of more aggressive disease-state following androgen deprivation therapy.

Prostate-Specific Membrane Antigen (PSMA) appears to be an ideal prostate cancer marker and potential therapeutic target, however there have been reports of PSMA expression in non-prostatic tissues, including brain, kidney and liver. Such expression of PSMA could weaken the potential of the gene as a prostate cancer marker or at least produce confusing and conflicting data. Prior to this project, we had demonstrated that there was another human gene, 97% identical to PSMA, which we termed the PSMA-Like gene. The first aim of this project was to characterize the differences between the non-prostatic and prostatic forms of PSMA and to determine strategies to specifically target PSMA expressed in prostate or prostate tumors. The second aim of the project was to define the minimal regulatory regions of the PSMA gene, for future utilization in gene therapy strategies, by analyzing deletion constructs of the gene regulatory regions. To date we have cloned and characterized the PSMA-Like gene, and determined ways of distinguishing the two genes at the DNA, RNA and protein levels which will aid in designing new diagnostic and therapeutic anti-prostate cancer strategies.

This protocol details the procedure for undertaking an overview of reviews. The review examines the diagnostic accuracy of 18F prostate specific membrane antigen (PSMA) PET-CT radiotracers in staging and restaging of high-risk prostate cancer patients and patients with biochemical recurrence.

This article is from Journal of Korean Medical Science , volume 27 . Abstract The present study evaluated optimal baseline prostate-specific antigen (PSA) level at different ages in order to determine the risk of developing prostate cancer (CaP). We analyzed 6,651 Korean men, aged 40-69 yr. The serum PSA levels for these men were measured at one institute from 2000 to 2004 and were determined to be between 0-4 ng/mL. Patients were divided into 4 groups of 25th-percentile intervals, based on initial PSA level. Of these, the group with an increased risk was selected, and the optimal value was determined by the maximal area under a receiver-operating characteristic curve within the selected group. The risk of CaP diagnosis was evaluated by Cox regression. The mean follow-up period was 8.3 yr. CaP was detected in 27 of the 6,651 subjects. CaP detection rate was increased according to age. The optimal PSA value to distinguish the risk of CaP was 2.0 ng/mL for 50- to 69-yr-olds. Patients with a baseline PSA level greater than the optimal value had a 27.78 fold increase in the prostate cancer risk. Baseline PSA values are useful for determining the risk of developing CaP in Korean men for 50- and 69-yr-old. We suggest that PSA testing intervals be modified based on their baseline PSA levels.

This article is from Case Reports in Oncology , volume 7 . Abstract Optimal management of therapy can improve quality of life, and potentially survival, of patients with metastatic prostate cancer. Circulating tumor cell (CTC) enumeration in the peripheral blood holds promise for facilitating optimal therapy management based on high cancer specificity and prompt response to changes in disease status. We present the case of a 54-year-old male diagnosed with metastatic prostate cancer. The patient's disease status was monitored radiographically and by serial determinations of serum prostate-specific antigen concentration, performance status, and CTC enumeration. At multiple visits, the disease status was not clear due to discordance between standard assessments. The additional information provided by CTC enumeration helped clarify disease status and provided support for treatment decisions.

It is fundamentally important to understand the underlying mechanisms regulating prostate caner (PCa) metastasis. Despite the increased PSMA expression found in more advanced stage of PC a little is known about the functional role of PSMA in PCa progression. Work accomplished for the period of the report has (1) generated the fluorescently labeled anti-PSMA antibodies for monitoring PSMA expressions in live PCa cells (2) established the cell model systems with reduced PSMA expression for studying PSMA functions (3) identified fibronetin as a specific extracellular matrix for enhanced LNCaP attachment and (4) performed 2-D wound healing assays to examine the role of PSMA in PCa cell migration. Results from these studies demonstrated and further supported the idea that PSMA is involved in PCa cell adhesion and migration therefore will enhance our understanding of molecular regulatory mechanisms of PCa. Knowledge about the action of PSMA in cell adhesion and migration during PCa metastasis will have a direct impact on the improvement for design better-targeted approaches for treating patients suffering from metastatic prostate cancer.

It is fundamentally important to understand the underlying mechanisms regulating prostate caner (PCa) metastasis. Despite the increased PSMA expression found in more advanced stage of PCa, little is known about the functional role of PSMA in PCa progression. Work accomplished for the period of the report has (1) generated the fluorescently labeled anti-PSMA antibodies for monitoring PSMA expressions in live PCa cells, (2) established the cell model systems with reduced PSMA expression for studying PSMA functions, (3) identified fibronetin as a specific extracellular matrix for enhanced LNCaP attachment and (4) performed 2-D wound healing assays to examine the role of PSMA in PCa cell migration. Results from these studies demonstrated and further supported the idea that PSMA is involved in PCa cell adhesion and migration, therefore will enhance our understanding of molecular regulatory mechanisms of PCa. Knowledge about the action of PSMA in cell adhesion and migration during PCa metastasis will have a direct impact on the improvement for design better-targeted approaches for treating patients suffering from metastatic prostate cancer.

This article is from Korean Journal of Urology , volume 55 . Abstract Purpose: We are often confronted with patients in the "gray zone" (prostate-specific antigen [PSA]

This article is from BMJ : British Medical Journal , volume 346 . Abstract Objective To determine the association between concentration of prostate specific antigen (PSA) at age 40-55 and subsequent risk of prostate cancer metastasis and mortality in an unscreened population to evaluate when to start screening for prostate cancer and whether rescreening could be risk stratified.Design Case-control study with 1:3 matching nested within a highly representative population based cohort study.Setting Malmö Preventive Project, Sweden.Participants 21 277 Swedish men aged 27-52 (74% of the eligible population) who provided blood at baseline in 1974-84, and 4922 men invited to provide a second sample six years later. Rates of PSA testing remained extremely low during median follow-up of 27 years.Main outcome measures Metastasis or death from prostate cancer ascertained by review of case notes.Results Risk of death from prostate cancer was associated with baseline PSA: 44% (95% confidence interval 34% to 53%) of deaths occurred in men with a PSA concentration in the highest 10th of the distribution of concentrations at age 45-49 (≥1.6 µg/L), with a similar proportion for the highest 10th at age 51-55 (≥2.4 µg/L: 44%, 32% to 56%). Although a 25-30 year risk of prostate cancer metastasis could not be ruled out by concentrations below the median at age 45-49 (0.68 µg/L) or 51-55 (0.85 µg/L), the 15 year risk remained low at 0.09% (0.03% to 0.23%) at age 45-49 and 0.28% (0.11% to 0.66%) at age 51-55, suggesting that longer intervals between screening would be appropriate in this group.Conclusion Measurement of PSA concentration in early midlife can identify a small group of men at increased risk of prostate cancer metastasis several decades later. Careful surveillance is warranted in these men. Given existing data on the risk of death by PSA concentration at age 60, these results suggest that three lifetime PSA tests (mid to late 40s, early 50s, and 60) are probably sufficient for at least half of men.

This article is from Scandinavian Journal of Urology and Nephrology , volume 46 . Abstract Objective. Recent guidelines on serum testing of prostate-specific antigen (PSA) levels in asymptomatic men emphasize the importance of an informed decision. This study assessed the proportion of men who had received written or oral information on the possible consequences of testing of serum levels of PSA before blood draw. Material and methods. From the National Prostate Cancer Register (NPCR) in Sweden, 600 men per year were randomly selected out of all men with T1c prostate cancer who were diagnosed in the work-up of a PSA test as a part of health examination in 2006–2008. In a mailed questionnaire these men were asked whether and how they had been informed about the pros and cons of a PSA test prior to blood draw. Results. In total, 1621 out of 1800 men (90.1%) responded to the questionnaire; 39/1563 (2.5%) reported that they had received only written information before testing, 179/1563 (11.5%) had received both oral and written information, 763/1563 (48.8%) had received oral information only, 423/1563 (27.1%) had not received any information and 159/1563 (10.2%) were not aware of that a PSA test had been performed. Conclusions. The proportion of men who had received written information on the pros and cons of a PSA test before blood draw in the setting of a health examination was low. Improved routines for giving information to the patient before a PSA test are warranted.

Prostate Specific Membrane Antigen, PSMA is a type II transmembrane glycoprotein, overexpressed in prostate carcinoma (PCa) including androgen sensitive and independent disease, increased in expression with early relapse following therapy. PSMA is a carboxypeptidase with two important enzymatic functions, namely, folate hydrolase and NAALADase. We have used in vitro invasion assays to explore the possible role of PSMA in PCa cells. Androgen dependent PCa lines, which express PSMA endogenously (e.g., LNCaP, CWR22) are less invasive compared to androgen independent PSMA negative PC3 or DU145 cells. Ectopic expression of PSMA in PC3 cells reduced the invasiveness of these cells, suggesting that this reduction in the invasion capability of PSMA expressing cells is due to PSMA expression, not due to intrinsic properties of different cell lines. Expression of PSMA mutants lacking carboxypeptidase activity reduced the impact of PSMA expression on invasiveness. Thus it appears that the enzymatic activity is associated with PSMA's effect on cellular invasiveness. To test our experimental results in vivo, we have further co-expressed PSMA and luciferase reporter gene in highly invasive PC3MM2 lines. We obtained several expressors with high luciferase and PSMA expression. Tumor formation ability and metastatic potential of these lines will be tested in mice.

This article is from Journal for Immunotherapy of Cancer , volume 1 . Abstract None

Prostate-Specific Membrane Antigen (PSMA) is highly expressed in virtually 100% of prostate cancers and is expressed on the cell surface which makes it a useful target for both clinical and therapeutic strategies. However, there have been reports of PSMA expression in other, normal tissues, which could weaken its potential clinical use. We have shown that another gene very similar to PSMA existed, and the initial aim of this project was to clone this PSMA-Like gene. We cloned the PSMA-like gene, have shown that it is expressed in kidney and liver in humans, and that it has the same NAALADase activity that PSMA does. The gene is 97% identical to PSMA. The PSMA-like gene is not expressed in the prostate, nor is it expressed in prostate cancer or in tumor-associated neovasculature. We can now tailor anti-PSMA therapies to avoid tissues expressing the PSMA-like gene (and subsequent patient toxicity). The second aim of this project was to isolate the most active portions of the PSMA enhancer for future therapeutic (gene therapy) use. We have developed a construct which has prostate specificity, driving expression of a suicide gene, which in future could be developed for use in therapeutic approaches.

Prostate-Specific Membrane Antigen (PSMA) appears to be an ideal prostate cancer marker and potential therapeutic target, however there have been reports of PSMA expression in non-prostatic tissues, including brain, kidney and liver. Such expression of PSMA could weaken the potential of the gene as a prostate cancer marker or at least produce confusing and conflicting data. Prior to this project, we had demonstrated that there was another human gene, 97% identical to PSMA, which we termed the PSMA-Like gene. The first aim of this project was to characterize the differences between the non-prostatic and prostatic forms of PSMA and to determine strategies to specifically target PSMA expressed in prostate or prostate tumors. The second aim of the project was to define the minimal regulatory regions of the PSMA gene, for future utilization in gene therapy strategies, by analyzing deletion constructs of the gene regulatory regions. To date we have cloned and characterized the PSMA-Like gene, and determined ways of distinguishing the two genes at the DNA, RNA and protein levels which will aid in designing new diagnostic and therapeutic anti-prostate cancer strategies. In addition, we have characterized the promoter and enhancer region of PSMA, and developed gene therapy vectors that specifically kill human prostate cancer tumors growing in mice.

This article is from Cancer Cell International , volume 14 . Abstract Background: Primary and secondary brain cancers are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. Recent observations reveal that the microvascular endothelium of primary high-grade gliomas expresses prostate specific membrane antigen (PSMA). Breast cancers express PSMA and they frequently form secondary brain tumors. Hence we report here our pilot study addressing the feasibility of PSMA targeting in brain and metastatic breast tumors, by examining PSMA levels in all glioma grades (19 patients) and in breast cancer brain metastases (5 patients). Methods: Tumor specimens were acquired from archival material and normal brain tissues from autopsies. Tissue were stained and probed for PSMA, and the expression levels imaged and quantified using automated hardware and software. PSMA staining intensities of glioma subtypes, breast tumors, and breast tumor brain metastases were compared statistically versus normals. Results: Normal brain microvessels (4 autopsies) did not stain for PSMA, while a small proportion (

This article is from BMJ : British Medical Journal , volume 348 . Abstract Objective To determine the relative risks of prostate cancer incidence, metastasis, and mortality associated with screening by serum prostate specific antigen (PSA) levels at age 60.Design Population based cohort study.Setting General male population of Sweden taking part in a screening trial in Gothenburg or participating in a cardiovascular study, the Malmö Preventive Project.Participants The screened group consisted of 1756 men aged 57.5-62.5 participating in the screening arm of the Gothenburg randomized prostate cancer screening trial since 1995. The unscreened group consisted of 1162 men, born in 1921, participating in the Malmö Preventive Project, with PSA levels measured retrospectively in stored blood samples from 1981.Intervention PSA screening versus no screening.Main outcome measures Incidence rate ratios for the effect of screening on prostate cancer diagnosis, metastasis, and death by PSA levels at age 60.Results The distribution of PSA levels was similar between the two cohorts. Differences in benefits by baseline PSA levels were large. Among men with baseline levels measured, 71.7% (1646/2295) had a PSA level