Tissue microarray analysis reveals prognostic significance of syndecan-1 expression in prostate cancer

BACKGROUND: Tissue microarrays (TMA) have recently emerged as powerful tools to rapidly analyze the clinical significance of new molecular markers in human tumors. Here, we have tested several molecular markers on a prostate TMA containing 637 different specimens. METHODS: The specimens were from 551 patients with prostate cancer and long-term follow-up information on progression (median 5.3 years), tumor-specific and overall survival (median 5.9 years). Eighty-six specimens from benign prostatic hyperplasia were included as controls. Expression of Ki67, Bcl-2, p53, CD-10 (neutral endopeptidase), and syndecan-1 (CD-138) was analyzed by immunohistochemistry. RESULTS: Gleason grade and Ki67 Labeling Index (LI) were independent predictors of early recurrence and poor survival. Bcl-2 predicted early recurrence, whereas p53 was associated with poor survival. Syndecan-1 overexpression also predicted early recurrence and was significantly associated with tumor specific survival, high Gleason grade, Ki67 LI, and Bcl-2 overexpression. Neoadjuvant hormonal therapy was associated with overexpression of Bcl-2 and inhibition of Ki67 LI and CD-10, but did not affect the expression of the remaining markers. CONCLUSIONS: The results of this TMA study confirm a dominant prognostic significance of Gleason grading and Ki67 LI in prostate cancer, as compared to a less pronounced role of Bcl-2, and p53. We identified syndecan-1 as a new prognostic factor and provide evidence for an androgen-dependent regulation of CD-10 expression.     

Tissue microarray analysis of hMSH2 expression predicts outcome in men with prostate cancer

PURPOSE: Mismatch repair genes are responsible for the coordinated correction of misincorporated nucleotides formed during DNA replication. Mismatch repair expression is altered in a subset of prostate cancers (PCs) and a recent study suggested that time to biochemical recurrence following prostatectomy correlated with the degree of hMSH2 immunohistochemical staining. We compared hMSH2 expression and survival in clinically organ confined PC. MATERIALS AND METHODS: A prostate tissue microarray was constructed using 243 specimens from patients who underwent radical prostatectomy with extended lymph node dissection for clinically organ confined PC with up to 12 years of followup. Immunohistochemistry was performed with anti-human MSH2 monoclonal antibody. Three independent observers evaluated hMSH2 expression on a scale of 0 to 4. Low expression was defined as a score of less than 2 and high expression was defined as a score of 2 or higher. Statistical analysis used the Fisher exact test, and Goodman and Kruskal gamma coefficient. RESULTS: Higher Gleason score significantly correlated with higher hMSH2 expression (p < 0.0002). Low hMSH2 expression correlated with increased overall, disease-free and biochemical disease-free survival (all p < 0.01). Analysis comparing low vs high hMSH2 expression was significant with respect to overall (p = 0.0004), disease-free (p = 0.005) and biochemical disease-free (p = 0.0177) survival. CONCLUSIONS: hMSH2 is differentially expressed in malignant prostate tissue and hMSH2 immunohistochemical staining intensity correlates with Gleason score, overall and disease-free survival. Taken together our results suggest that hMSH2 expression may be a useful prognostic biomarker for outcome in men with clinically organ confined PC.     

Exosomes as biomarker treasure chests for prostate cancer

Context

Although progress has been made with regard to types of markers (protein, DNA, RNA, and metabolites) and implementation of improved technologies (mass spectrometry, arrays, and deep sequencing), the discovery of novel biomarkers for prostate cancer (PCa) in complex fluids, such as serum and urine, remains a challenge. Meanwhile, recent studies have reported that many cancer-derived proteins and RNAs are secreted through small vesicles known as exosomes.

Objective

This narrative review describes recent progress in exosome research, focusing on the potential role of exosomes as novel biomarkers for PCa. The purpose of this review is to acquaint clinicians and researchers in the field of urology with the potential role of exosomes as biomarker treasure chests and with their clinical value.

Evidence acquisition

Medline and Embase entries between 1966 and September 2010 were searched using the keywords exosomes, microvesicles, prostasomes, biomarkers, prostate cancer, and urology. Leading publications and articles constructively contributing to exosome research were selected for this review.

Evidence synthesis

Exosomes are small vesicles (50–100 nm) secreted by almost all tissues; they represent their tissue origin. Purification of prostate- and PCa-derived exosomes will allow us to profile exosomes, providing a promising source of protein and RNA biomarkers for PCa. This profiling will contribute to the discovery of novel markers for the early diagnosis and reliable prognosis of PCa.

Conclusions

Although the initial results are promising, further investigations are required to assess the clinical value of these exosomes in PCa.     

Potential biomarker for early risk assessment of prostate cancer

BACKGROUND: Catechol estrogen quinones (CEQ) derived from 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2) react with DNA to form depurinating--N7Gua and--N3Ade adducts. This damage leads to mutations that can initiate breast and prostate cancer. To determine whether this damage occurs in humans, urine samples from men with prostate cancer and benign urological conditions, and healthy controls were analyzed. The objective was determining whether any of the cancer patients had formed the depurinating 4-OHE1(E2)-1-N3Ade adducts. METHODS: The adducts were extracted from samples by using affinity columns equipped with a monoclonal antibody developed for detecting 4-OHE1(E2)-1-N3Ade adducts. Eluted extracts were separated by capillary electrophoresis with field-amplified sample stacking and/or ultraperformance liquid chromatography. Absorption/luminescence spectroscopies and mass spectrometry were used to identify the adducts. RESULTS: 4-OHE1-1-N3Ade was detected at higher levels in samples from subjects with prostate cancer (n = 7) and benign urological conditions (n = 4) compared to healthy males (n = 5). CONCLUSION: This is the first demonstration that CEQ-derived DNA adducts are present in urine samples from subjects with prostate cancer.     

Caveolin-1:一种前列腺癌的标志物

前列腺癌严重威胁男性健康,早期诊断缺乏特异性生物标志物。caveolin-1(Cav-1)是一种功能基因,也是胞膜窖的重要外壳结构蛋白,与分子运输,细胞粘附和信号转导等多种细胞功能密切相关,在前列腺癌的发生发展中发挥重要作用。Cav-1可作为生物活性分子在前列腺癌微环境中促进肿瘤增殖和肿瘤血管生成。此外,Cav-1在前列腺癌原发灶及转移灶中均过度表达,尤其是转移灶。目前,Cav-1可在外周血被检测到,其表达水平对提高前列腺癌的诊断有提示意义,与预后相关。本文就Cav-1的结构、生物学特性以及与前列腺癌的相关性进行综述。     

Pan-cadherin as a high level phenotypic biomarker for prostate cancer

PURPOSE: High level phenotypic biomarkers such as cadherins are needed to identify individuals at risk for biologically active prostate cancer and determine which individuals with elevated prostate specific antigen or a prostate nodule are candidates for re-biopsy. Cadherins are a high level phenotypic biomarker associated with decreased cell adhesion, which is a cardinal event in carcinogenesis. Recently we reported that G-actin and tissue transglutaminase type II are potential biomarkers for prostate cancer. In this study we present cadherins as a potential third component of the biomarker profile. MATERIALS AND METHODS: Prostate tissues from 38 patients with cancer and 33 controls with a 10-year prostate cancer-free followup were labeled for pan-cadherin by immunohistochemical testing. Immunoreactivity was quantified using a Pathology Workstation (Autocyte Inc., Elon College, North Carolina). RESULTS: Visually benign glands from controls generally expressed cadherins, whereas regions of adenocarcinoma were generally negative. On quantitative immunohistochemistry 36 of 38 prostate cancer cases expressed a lower mean percent area positive for cadherin than the 19 benign prostatic hyperplasia and 14 prostatitis cases (odds ratio 978, 95% confidence interval 45 to 21,140, relative risk 18, 95% confidence interval 5 to 67, p <0.0001). Receiver operating characteristics analysis of immunohistochemical testing data showed that an optimal threshold of 7 produced 95% sensitivity and 100% specificity. CONCLUSIONS: Quantitative down-regulation of cadherin expression in prostate cancer tissue sections is a strong biomarker for prostate cancer. Analysis of cadherin and other high level phenotypic biomarker expression in the premalignant field may provide additional diagnostic information to decide which patients need re-biopsy, more intensive monitoring or chemoprevention.     

Elasticity as a biomarker for prostate cancer: a systematic review

• To systematically review the range of methods available for assessing elasticity in the prostate and to examine its use as a biomarker for prostate cancer.

• A systematic review of the electronic database PubMed was performed up to December 2012.
• All relevant studies assessing the use of elasticity as a biomarker for prostate cancer were included except those not studying human prostates or reporting a sensitivity, specificity or quantitative elasticity value.

• There has been much interest in the use of elasticity in the detection of prostate cancer and there have been many publications using various methods of detection. The most common method of assessment is an imaging method, called sonoelastography. Further imaging methods include ultrasound (US), three‐dimensional US and magnetic resonance elastography. These methods are reviewed for sensitivity and specificity.
• The other method of assessment is the mechanical method. These use quantitative elasticity values to differentiate benign from malignant areas of the prostate. This method of assessment has shown that the elasticity changes for differing Gleason grades and T stages of disease within the prostate. Quantitative elasticity values offer the potential of using ‘threshold’ elasticity values under which the prostate is benign.

• Tissue elasticity has great potential as a diagnostic and prognostic biomarker for prostate cancer and can be assessed using various methods. Currently transrectal sonoelastography has the most evidence supporting its use in clinical practice.

     

Transforming growth factor beta as a clinical biomarker for prostate cancer

ObjectivesTumor biomarkers to detect prostate cancer earlier may reduce prostate cancer deaths. Transforming growth factor-beta1 and -beta2 (TGF-beta1 and -beta2) become overexpressed in prostate cancer and might be useful tumor markers of prostate cancer.MethodsPlasma and urinary TGF-beta1 and plasma TGF-beta2 levels were studied preoperatively in 74 consecutive patients who had prostate cancer and underwent radical prostatectomy and were compared with those of 29 similarly aged male control patients who had no clinical evidence of prostate cancer.ResultsPlasma TGF-beta1 levels were similar in both prostate cancer and control groups and did not correlate with serum prostate-specific antigen (PSA), clinical and pathologic stages, or Gleason grade. Urinary TGF-beta 1 levels, however, increased 3.5-fold in patients with prostate cancer relative to controls and tended to be higher with advancing clinical and pathologic stages. Plasma TGF-beta2 levels, like plasma TGF-beta1 levels, were similar for both the study and control groups, but when stratified by pathologic stage or Gleason grade, patients with prostate cancer with pathologic Stage T2a and Gleason grade of 3 or less had significantly increased plasma TGF-beta2 levels as compared with either control patients or patients with prostate cancer with pathologic Stages T2b/T2c and T3/T4 or Gleason grade of 4 or more, suggesting that early prostate cancer may contribute to plasma TGF-beta2 levels.ConclusionsUnlike plasma TGF-beta1 levels, urinary TGF-beta1 and plasma TGF-beta2 levels were higher in patients with prostate cancer and may be useful biomarkers of prostate cancer. Copyright 1997 by Elsevier Science Inc. UROLOGY 49: 151-155, 1997.     

Clinical proteomics: Applications for prostate cancer biomarker discovery and detection

The science of proteomics comprises much more than simply generating lists of proteins that change in expression as a cause of or consequence of pathophysiology. The goal of proteomics should be to characterize the information flow through the intercellular protein circuitry that communicates with the extracellular microenvironment and then ultimately to the serum/plasma macroenvironment. Serum proteomic pattern diagnostics is a new type of proteomic concept in which patterns of ion signatures generated from high dimensional mass spectrometry data are used as diagnostic classifiers. This recent approach has exciting potential for clinical utility of diagnostic patterns because low molecular weight metabolites, peptides, and protein fragments may have higher accuracy than traditional biomarkers of cancer detection. Intriguingly, we now have discovered that this diagnostic information exists in a bound state, complexed with circulating highly abundant carrier proteins. These diagnostic fragments may one day be harvested by circulating nanoparticles, designed to absorb, enrich, and amplify the repertoire of diagnostic biomarkers generated-even at the critical, initial stages of carcinogenesis.     

Changing the operative strategy for thyroid cancer by node sampling

One hundred fifty patients underwent thyroid surgery from 1979 to 1981, of whom 48 showed cancer for a 32 percent rate. In eight patients (16 percent), obvious clinical nodal disease was treated with modified neck dissection. Of the remaining 40 patients, internal jugular node sampling was carried out in 33, and revealed microscopic metastatic cancer in 12 patients who then underwent appropriate neck dissection. Node sampling increased our yield of nodal metastases from 16 to 42 percent, permitted one-hospitalization treatment, and afforded our patients the possibility of complete cancer control and prevention of the emergence of future recurrent disease. It is recommended that node sampling be incorporated into the operative strategy for thyroid cancer to permit intelligent selection of patients for modified neck dissection.     

Urinary nerve growth factor as an oncologic biomarker for prostate cancer aggressiveness

ObjectivesWe investigated urinary nerve growth factor (NGF) as a novel urinary biomarker for high-grade prostate cancer (PCa).Methods and materialsAfter institutional review board approval for a prospective pilot study, we enrolled men at the preoperative visit before robotic-assisted radical prostatectomy. Demographics, urinary flow parameters, and urine samples were collected. Urinary NGF and urinary creatinine were obtained in the translational science laboratory. Pathologic and postoperative demographics were collected after surgery. NGF is the primary outcome variable (dependent variable). The pathologic Gleason score (ordinal variable≤6, 7, and ≤8) served as an independent grouping variable. Multivariate analysis using a general linear model was conducted to investigate associations between independent variables and NGF (dependent variable) after adjusting for urinary concentration and volume.ResultsWe enrolled and analyzed urine samples and pathologic data from 115 subjects. Patient pathology included 24% (n = 28) Gleason score 6 or less, 68% (n = 78) Gleason score 7, and 8% (n = 9) Gleason score 8 or greater. Perineural invasion was more prevalent in higher-grade disease (P<0.001). The median NGF level was 24.1 pg/ml (range: 0.16–270.5 pg/ml) and was transformed to the log base 10 scale. Total bladder volume, urinary creatinine level, prostate-specific antigen level, and diabetes were correlated with the Log NGF. In a general linear model, adjusting for bladder volume and urinary creatinine, increasing Log₁₀ NGF was associated with higher Gleason score (Gleason category≤6, 7, and≥8; P = 0.003).ConclusionsUrinary NGF may be a biomarker for higher-grade PCa. Our pilot study suggests further investigation is warranted to determine whether urinary NGF could provide unique additional information in patients with PCa.     

Laparoscopic lymph-node sampling in locally advanced prostate cancer

OBJECTIVE: To assess the role of laparoscopic lymph node sampling in patients with locally advanced prostate cancer before radical radiotherapy, and to show that the procedure is safe when carried out by urologists with the appropriate training. PATIENTS AND METHODS: Patients were selected prospectively using a combination of prostate-specific antigen (PSA) level, clinical stage and Gleason grade, which predicted a > 20% risk of lymph node metastases. Between October 1998 and March 2001, 50 patients (mean age 65 years, range 54-78) underwent laparoscopic pelvic lymphadenectomy. Age, presenting PSA level, Gleason grade, clinical stage, operative time, length of stay, and any adverse events were recorded. The histology reports were reviewed for the presence of nodal metastases. The selection criteria were compared between the groups with and with no nodal metastases. RESULTS: The mean (range) PSA level of the men was 36.8 (4.4-184) ng/mL and the Gleason grade 6.8 (4-9); 58% had stage T3 disease and 12 patients (24%) had lymph node metastases. There were no statistically significant differences in PSA, Gleason grade or clinical stage between those with positive or negative nodes. The mean operative duration was 110 min, although this decreased from 133 min for the first 10 cases; one case was converted to an open procedure. The median (range) postoperative stay was 1 (1-12) days. There were two major (5%) and seven (17%) minor complications. CONCLUSIONS: This study confirms that laparoscopic lymph nodes can be sampled safely by urologists with experience in laparoscopic surgery. Patients with a significant risk of metastases can be selected preoperatively using a combination of PSA, clinical stage and Gleason grade. Lymph node sampling in this group is necessary, as there is no other method of reliably identifying the subgroup of patients with metastatic disease in which radical conformal radiotherapy cannot be justified.