Cholesterol and benign prostate disease

The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH and CP/CPPS are limited, however an apparent association between BPH symptoms and cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism. Hypercholesterolemia, a major risk factor for CVD, is also a risk factor for BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol absorption from the intestine, such as the class of compounds known as polyene macrolides, can reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in the incidence of benign prostate disease and we highlight possible therapeutic approaches based on this concept.     

Intérêt du dosage de la chromogranine A sérique dans le suivi des phéochromocytomes

This study aimed at comparing the role of serum chromogranine A (CGA) over 24-h urinary total normetanephrine (NTU) and plasma concentration total normetanephrine (NTP) in the recurrence of phaeochromocytomas. A new approach focusing on the increase rate over time of CGA was studied on 24 patients with abdominal phaeochromocytoma after surgery. In the first group, 15 had a benign sporadic disease without any sign of recurrence during follow-up. In the second group, nine had recurrence from a benign or a malignant, intra- or extra-adrenal phaeochromocytoma. The evolution of CGA rates was significantly different within the two groups during follow-up (p = 0.025). A new approach of the CGA values, based on its evolution over time, showed an excellent ability to identify recurrence with an excellent accuracy. This new parameter enabled to correctly diagnose all patients with recurrence, whereas NTU and NTP failed in four patients. Finally, CGA, but above all its increase rate, may be an early marker of recurrence. CGA should be associated to NTU and NTP during follow-up as its assay is less prone to interference and easier to perform.     

Evaluation and treatment of men with biochemical prostate-specific antigen recurrence following definitive therapy for clinically localized prostate cancer

Early detection and monitoring by serum prostate-specific antigen (PSA) measurement has increased the number of men presenting with potentially curable prostate cancer. Most will choose radical prostatectomy or some form of radiation therapy for treatment, but some will have evidence of biochemical disease recurrence following therapy, shown by a rising PSA level without other clinical evidence of disease. Radical prostatectomy involves the removal of all prostate tissue, causing the serum PSA to decline to undetectable levels within four to six weeks following surgery; a subsequent rise in the serum PSA to a detectable level indicates disease recurrence. Patients should be evaluated to assess whether rising PSA levels indicate local recurrence or early metastatic disease. The advantages of salvage radiation, endocrine therapy, and other treatment modalities in local disease recurrence must be weighed against potential side effects and the resulting decrease in quality of life. Radiation therapy does not immediately eradicate all PSA-producing cells; therefore the persistence of a detectable PSA does not necessarily imply residual cancer, but rising PSA levels indicate treatment failure. Salvage surgery can be performed after radiotherapy for the purpose of removing all viable cancer cells, but should be weighed against a higher incidence of surgical complications; cryoablation offers a less invasive therapeutic modality.     

CD44 and PTGS2 Methylation are Independent Prognostic Markers for Biochemical Recurrence Among Prostate Cancer Patients with Clinically Localized Disease

Up to 30% of men with clinically localized disease who receive radical prostatectomy develop a biochemical recurrence. Gene methylation in tumor tissue may distinguish men with aggressive cancer. This study evaluated methylation of GSTP1, RARβ2, CD44 and PTGS2 with biochemical recurrence among 60 patients who underwent radical prostatectomy using logistic regression and Kaplan Meier time to event analysis. Methylation of GSTP1 and RARβ2 was not associated with recurrence, however, CD44 and PTGS2 methylation were significant predictors. In multivariate models adjusting for Gleason grade, methylation profile of CD44 and PTGS2 combined was an independent predictor of biochemical recurrence (associated with 9-fold increased risk). In addition, Kaplan Meier analysis showed CD44 and PTGS2 methylation was associated with shorter time to recurrence. CD44 and PTGS2 methylation may predict biochemical recurrence in prostate cancer patients undergoing radical prostatectomy and if validated in larger studies, may identify patients with aggressive cancer.     

Age-related changes in the innervation of the prostate gland

The adult prostate gland grows and develops under hormonal control while its physiological functions are controlled by the autonomic nervous system. The prostate gland receives sympathetic input via the hypogastric nerve and parasympathetic input via the pelvic nerve. In addition, the hypogastric and pelvic nerves also provide sensory inputs to the gland. This review provides a summary of the innervation of the adult prostate gland and describes the changes which occur with age and disease. Growth and development of the prostate gland is age dependent as is the occurrence of both benign prostate disease and prostate cancer. In parallel, the activity and influence of both the sympathetic and parasympathetic nervous system changes with age. The influence of the sympathetic nervous system on benign prostatic hyperplasia is well documented and this review considers the possibility of a link between changes in autonomic innervation and prostate cancer progression.     

Serum methionine metabolites are risk factors for metastatic prostate cancer progression

Background

Clinical decision for primary treatment for prostate cancer is dictated by variables with insufficient specificity. Early detection of prostate cancer likely to develop rapid recurrence could support neo-adjuvant therapeutics and adjuvant options prior to frank biochemical recurrence. This study compared markers in serum and urine of patients with rapidly recurrent prostate cancer to recurrence-free patients after radical prostatectomy. Based on previous identification of urinary sarcosine as a metastatic marker, we tested whether methionine metabolites in urine and serum could serve as pre-surgical markers for aggressive disease.

Methodology/Principal Findings

Urine and serum samples (n = 54 and 58, respectively), collected at the time of prostatectomy were divided into subjects who developed biochemical recurrence within 2 years and those who remained recurrence-free after 5 years. Multiple methionine metabolites were measured in urine and serum by GC-MS. The role of serum metabolites and clinical variables (biopsy Gleason grade, clinical stage, serum prostate specific antigen [PSA]) on biochemical recurrence prediction were evaluated. Urinary sarcosine and cysteine levels were significantly higher (p = 0.03 and p = 0.007 respectively) in the recurrent group. However, in serum, concentrations of homocysteine (p = 0.003), cystathionine (p = 0.007) and cysteine (p<0.001) were more abundant in the recurrent population. The inclusion of serum cysteine to a model with PSA and biopsy Gleason grade improved prediction over the clinical variables alone (p<0.001).

Conclusions

Higher serum homocysteine, cystathionine, and cysteine concentrations independently predicted risk of early biochemical recurrence and aggressiveness of disease in a nested case control study. The methionine metabolites further supplemented known clinical variables to provide superior sensitivity and specificity in multivariable prediction models for rapid biochemical recurrence following prostatectomy.     

Discovery and Validation of a Prostate Cancer Genomic Classifier that Predicts Early Metastasis Following Radical Prostatectomy

Purpose

Clinicopathologic features and biochemical recurrence are sensitive, but not specific, predictors of metastatic disease and lethal prostate cancer. We hypothesize that a genomic expression signature detected in the primary tumor represents true biological potential of aggressive disease and provides improved prediction of early prostate cancer metastasis.

Methods

A nested case-control design was used to select 639 patients from the Mayo Clinic tumor registry who underwent radical prostatectomy between 1987 and 2001. A genomic classifier (GC) was developed by modeling differential RNA expression using 1.4 million feature high-density expression arrays of men enriched for rising PSA after prostatectomy, including 213 who experienced early clinical metastasis after biochemical recurrence. A training set was used to develop a random forest classifier of 22 markers to predict for cases - men with early clinical metastasis after rising PSA. Performance of GC was compared to prognostic factors such as Gleason score and previous gene expression signatures in a withheld validation set.

Results

Expression profiles were generated from 545 unique patient samples, with median follow-up of 16.9 years. GC achieved an area under the receiver operating characteristic curve of 0.75 (0.67–0.83) in validation, outperforming clinical variables and gene signatures. GC was the only significant prognostic factor in multivariable analyses. Within Gleason score groups, cases with high GC scores experienced earlier death from prostate cancer and reduced overall survival. The markers in the classifier were found to be associated with a number of key biological processes in prostate cancer metastatic disease progression.

Conclusion

A genomic classifier was developed and validated in a large patient cohort enriched with prostate cancer metastasis patients and a rising PSA that went on to experience metastatic disease. This early metastasis prediction model based on genomic expression in the primary tumor may be useful for identification of aggressive prostate cancer.     

DNA methylation profiles in African American prostate cancer patients in relation to disease progression

This study examined whether differential DNA methylation is associated with clinical features of more aggressive disease at diagnosis and prostate cancer recurrence in African American men, who are more likely to die from prostate cancer than other populations. Tumor tissues from 76 African Americans diagnosed with prostate cancer who had radical prostatectomy as their primary treatment were profiled for epigenome-wide DNA methylation levels. Long-term follow-up identified 19 patients with prostate cancer recurrence. Twenty-three CpGs were differentially methylated (FDR q ≤ 0.25, mean methylation difference ≥ 0.10) in patients with vs. without recurrence, including CpGs in GCK, CDKL2, PRDM13, and ZFR2. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence (five CpGs), regional vs. local pathological stage (two CpGs), and higher vs. lower tumor aggressiveness (one CpG). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness.     

Evidence That Selenium Binding Protein 1 Is a Tumor Suppressor in Prostate Cancer

Selenium-Binding Protein 1 (SBP1, SELENBP1, hSP56) is a selenium-associated protein shown to be at lower levels in tumors, and its lower levels are frequently predictive of a poor clinical outcome. Distinguishing indolent from aggressive prostate cancer is a major challenge in disease management. Associations between SBP1 levels, tumor grade, and disease recurrence following prostatectomy were investigated by duplex immunofluorescence imaging using a tissue microarray containing tissue from 202 prostate cancer patients who experienced biochemical (PSA) recurrence after prostatectomy and 202 matched control patients whose cancer did not recur. Samples were matched by age, ethnicity, pathological stage and Gleason grade, and images were quantified using the Vectra multispectral imaging system. Fluorescent labels were targeted for SBP1 and cytokeratins 8/18 to restrict scoring to tumor cells, and cell-by-cell quantification of SBP1 in the nucleus and cytoplasm was performed. Nuclear SBP1 levels and the nuclear to cytoplasm ratio were inversely associated with tumor grade using linear regression analysis. Following classification of samples into quartiles based on the SBP1 levels among controls, tumors in the lowest quartile were more than twice as likely to recur compared to those in any other quartile. Inducible ectopic SBP1 expression reduced the ability of HCT-116 human tumor cells to grow in soft agar, a measure of transformation, without affecting proliferation. Cells expressing SBP1 also demonstrated a robust induction in the phosphorylation of the p53 tumor suppressor at serine 15. These data indicate that loss of SBP1 may play an independent contributing role in prostate cancer progression and its levels might be useful in distinguishing indolent from aggressive disease.     

Selenium level in benign and cancerous prostate

The dietary microelement selenium (Se) has been proposed as a potential chemopreventive agent for prostate cancer. This element is present in various amounts in all tissues. Little information is available on Se level in patients with prostate gland disorders. The levels of Se in prostatic gland of patients with prostate cancer, benign prostate hyperplasia, and healthy controls were examined. The Se level for benign prostate hyperplasia (156±30.6 ng/g) was the same as in the control group (157±26.0 ng/g), but in the gland of prostate cancer patients (182±34.1 ng/g wet weight), the Se level was significantly (p<0.01) higher than in both healthy controls and benign prostate hyperplasia. Thus, the Se level in human healthy controls is lower than in kidney and liver but higher compared with other tissues.     

Adiponectin as a potential marker of prostate cancer progression: studies in organ-confined and locally advanced prostate cancer

Serum levels of adiponectin were measured in patients with benign prostatic hyperplasia and prostate cancer of pT2 and pT3 stage. Adiponectin ELISA assay, immunohistochemistry, and selected metabolic and biochemical parameters measurement was performed in 25 patients with benign prostatic hyperplasia and 43 with prostate cancer (17 patients with organ-confined and 26 patients with locally advanced disease). Serum adiponectin levels did not differ between prostate benign hyperplasia and cancer clinical stage T2, but was significantly higher in pT3 relative to pT2 group (14.51+/-4.92 vs. 21.41+/-8.12, P = 0.003). Tissue immunohistochemistry showed enhanced staining in neoplastic prostate glands and intraepithelial neoplasia relative to benign prostatic hyperplasia without distinction between disease grade and stage. Serum adiponectin levels are higher in locally advanced relative to organ-confined prostate cancer and may thus serve as an auxiliary marker providing further improvement for discrimination between pT2 and pT3 stages.     

RhoA as a mediator of clinically relevant androgen action in prostate cancer cells

Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa.     

TGF-β regulates DNA methyltransferase expression in prostate cancer, correlates with aggressive capabilities, and predicts disease recurrence

Background

DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP). The specific mechanisms of DNMT''s role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.

Methodology/Principal Findings

We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.

Conclusions and Significance

Our findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.     

MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer

The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p<0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p<0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer.     

Metabolic profile in patients with benign prostate hyperplasia or prostate cancer and normal glucose tolerance.

Familial predisposition together with several environmental factors may be involved in the pathogenesis of common prostate disease such as benign hypertrophy or prostate neoplasm. A higher incidence of both these conditions has been described in some insulin-resistant states such as obesity, but not much information is available on the effect of metabolic profile on gland morphology. The aim of this study was to evaluate the relation between glucose and lipid pattern and prostate diameters in two groups of non-diabetic individuals with benign prostate hypertrophy or cancer. 109 patients were recruited; plasma glucose, lipids and hormonal profile as well as an ultrasonographic evaluation of the gland volume and diameters were determined. Patients with prostate cancer had significantly higher levels of insulin and were more insulin resistant; in contrast, in subjects with prostate hypertrophy, fasting plasma glucose and--to a lesser extent--serum triglycerides emerged as the main determinants of gland volume. These observations may indicate that an improvement of insulin sensitivity and strategies to maintain a strict glucose and lipid control even in non-diabetic subjects are useful objectives in the prevention of prostate diseases.     

Detection of aggressive prostate cancer associated glycoproteins in urine using glycoproteomics and mass spectrometry

Clinical management of prostate cancer remains a significant challenge due to the lack of available tests for guiding treatment decisions. The blood prostate‐specific antigen test has facilitated early detection and intervention of prostate cancer. However, blood prostate‐specific antigen levels are less effective in distinguishing aggressive from indolent prostate cancers and other benign prostatic diseases. Thus, the development of novel approaches specific for prostate cancer that can differentiate aggressive from indolent disease remains an urgent medical need. In the current study, we evaluated urine specimens from prostate cancer patients using LC‐MS/MS, with the aim of identifying effective urinary prostate cancer biomarkers. Glycoproteins from urine samples of prostate cancer patients with different Gleason scores were characterized via solid phase extraction of N‐linked glycosite‐containing peptides and LC‐MS/MS. A total of 2923 unique glycosite‐containing peptides were identified. Glycoproteomic comparison on urine and tissues from aggressive and non‐aggressive prostate cancers as well as sera from prostate cancer patients revealed that the majority of AG prostate cancer associated glycoproteins were more readily detected in patient's urine than serum samples. Our data collectively indicate that urine provides a potential source for biomarker testing in patients with AG prostate cancer.     

Analysis of morphology of adrenal pheochromocytoma as regards their potential malignancy

BACKGROUND: Adrenal pheochromocytoma are diagnosed the most often in patients with arterial hypertension or with thyroid medullar cancer and suspicion of MEN II syndromes. The aim of the study is to analyse the morphology of pheochromocytomas on the basis of Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) in order to estimate their potential malignancy. MATERIAL AND METHODS: Forty tumours were subjected to analysis. Mean patients age was 45.2+/-13.4 years. The diagnosis of pheochromocytoma was establish before surgery in 87.5%. 12.5% of patients were referred to surgery on the basis of tumour diameter (range 70 to 102 mm). In 20.0% of patients MEN II syndromes were diagnosed. RESULTS: In pathological examination benign pheochromo-cytoma was diagnosed in 39 presented patients. In 1 cases malignant form of pheochromocytoma was diagnosed on the basis of lymph nodes metastases. Number of points in PASS was >or=4 in 9 of 40 tumours (22.5%). Among 35 patients operated on more than 12 months ago 2 patients died: 1 patient with malignant pheochromocytoma (PASS=8 points) and 1 patient with MEN IIA syndrome (due to disseminated thyroid medullar cancer). In remaining 7 observed patients with PASS>or=4 points neither recurrence nor metastases were diagnosed within the period of observation (13-90 months). In 1 out of patients with PASS<4 points a local recurrence was surgically removed 82 months after primary operation. CONCLUSION: Analysis of pheochromocytoma in PASS is only of rough character and does not allow for clear-cut histological diagnosis of benign and malignant tumours. The only unquestionable criterion of pheochromocytoma's malignancy remain metastases.     

Current Clinical Applications of the In-capromab Pendetide Scan (ProstaScint(R) Scan, Cyt-356)

Prostate-specific antigen (PSA) has been extremely helpful in the detection of new or recurrent prostate cancer. However, localization of the recurrent tumor has been challenging with currently available radiographic modalities. The (111)In-capromab pendetide scan was developed to diagnose accurately and, more importantly, localize and stage a new or recurrent prostate cancer. Studies suggest that the (111)In-capromab pendetide scan can provide more accurate staging of clinically localized prostate cancer prior to staging lymphadenectomy or definitive therapy. It can also provide valuable information when local adjuvant radiation therapy is considered in men with biochemical cancer recurrence following radical prostatectomy.     

Alteration of G1/S transition regulators influences recurrences in head and neck squamous carcinomas

Head-Neck Squamous Cell Carcinoma (HN-SCC) is a clinically challenging disease associated with a high mortality rate. The chemo-radiotherapy treatments that aim to preserve the organ represent the current gold standard therapy for advanced laryngeal disease, reserving surgery only for non-responsive or relapsed cases. Despite these aggressive approaches, local persistent or recurrent disease remains the primary cause of treatment failure but we still do not have known factors and/or markers able to predict the outcome of the disease and in particular the risk of local relapse. Here we address this point on a series of 54 cases of HN-SCC for whom the presence of local relapse was known. Using immunohistochemistry (IHC) analysis to evaluate protein expression and localization in the recurrence free and recurrence positive samples, we studied the expression of key cell cycle regulators including p53, p16, p27, pRB, Cyclin D1, Cyclin D3, and Stathmin. Overall by analyzing seven different cell cycle regulators we can hypothesize that the alteration of G1/S regulation represents a fundamental event in the onset/progression of HN-SCC cancers and that the associate use of Cyclin D1/p16 expression should be considered as a possible biomarker toward the identification of those patients that will probably develop a recurrent disease and thus should benefit of a more aggressive treatment.