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Special Issue "Molecular Research in Urology"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (20 April 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Jack A. Schalken (Website)

Research Director Urology, Dept. of Urology, University Hospital Nijmegen, Box 9101, Nijmegen NL-6500 HB, The Netherlands
Interests: molecular and cellbiology of oncological diseases; cadherine mediated interactions and signal transductions; molecular diagnostics; urogenital oncology; veterinary oncology

Special Issue Information

Dear Colleagues,

The unmet needs in prostate cancer diagnosis and therapy are diverse; there is an urgent need for biomarkers that can be used for the early diagnosis of patients with clinically significant prostate cancer. Significant steps forward are made and are reviewed in this issue. Once metastasized, there is still no effective treatment, let stand alone a curative therapy. A better understanding of sustained androgen receptor signaling in CRPC has now led to more effective therapies. Apart from a better insight in the molecular aspects of prostate carcinogenesis and -progression, we need to understand the tumor cell biology. Identification of cancer initiating cells and therapies targeted to eradicate these population(s) are the way forward to combat this disease.

Prof. Dr. Jack A. Schalken
Guest Editor

Submission

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF.

Keywords

  • biomarkers (diagnostic prognostic and predictive)
  • androgen receptor targeted therapy
  • novel targets for therapy
  • cancer initiating cells

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Published Papers (38 papers)

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Research

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Open AccessArticle MiR-205 Is Progressively Down-Regulated in Lymph Node Metastasis but Fails as a Prognostic Biomarker in High-Risk Prostate Cancer
Int. J. Mol. Sci. 2013, 14(11), 21414-21434; doi:10.3390/ijms141121414
Received: 22 July 2013 / Revised: 1 October 2013 / Accepted: 9 October 2013 / Published: 29 October 2013
Cited by 14 | PDF Full-text (1282 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the [...] Read more.
The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle PCA3 and PCA3-Based Nomograms Improve Diagnostic Accuracy in Patients Undergoing First Prostate Biopsy
Int. J. Mol. Sci. 2013, 14(9), 17767-17780; doi:10.3390/ijms140917767
Received: 21 July 2013 / Revised: 7 August 2013 / Accepted: 23 August 2013 / Published: 29 August 2013
Cited by 16 | PDF Full-text (326 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
While now recognized as an aid to predict repeat prostate biopsy outcome, the urinary PCA3 (prostate cancer gene 3) test has also been recently advocated to predict initial biopsy results. The objective is to evaluate the performance of the PCA3 test in [...] Read more.
While now recognized as an aid to predict repeat prostate biopsy outcome, the urinary PCA3 (prostate cancer gene 3) test has also been recently advocated to predict initial biopsy results. The objective is to evaluate the performance of the PCA3 test in predicting results of initial prostate biopsies and to determine whether its incorporation into specific nomograms reinforces its diagnostic value. A prospective study included 601 consecutive patients addressed for initial prostate biopsy. The PCA3 test was performed before ≥12-core initial prostate biopsy, along with standard risk factor assessment. Diagnostic performance of the PCA3 test was evaluated. The three available nomograms (Hansen’s and Chun’s nomograms, as well as the updated Prostate Cancer Prevention Trial risk calculator; PCPT) were applied to the cohort, and their predictive accuracies were assessed in terms of biopsy outcome: the presence of any prostate cancer (PCa) and high-grade prostate cancer (HGPCa). The PCA3 score provided significant predictive accuracy. While the PCPT risk calculator appeared less accurate; both Chun’s and Hansen’s nomograms provided good calibration and high net benefit on decision curve analyses. When applying nomogram-derived PCa probability thresholds ≤30%, ≤6% of HGPCa would have been missed, while avoiding up to 48% of unnecessary biopsies. The urinary PCA3 test and PCA3-incorporating nomograms can be considered as reliable tools to aid in the initial biopsy decision. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Androgen Receptor Phosphorylation at Serine 308 and Serine 791 Predicts Enhanced Survival in Castrate Resistant Prostate Cancer Patients
Int. J. Mol. Sci. 2013, 14(8), 16656-16671; doi:10.3390/ijms140816656
Received: 22 April 2013 / Revised: 22 July 2013 / Accepted: 26 July 2013 / Published: 13 August 2013
Cited by 6 | PDF Full-text (1992 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer [...] Read more.
We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR94), 308 (pAR308), 650(pAR650) and 791 (pAR791). No correlations with clinical parameters were observed for pAR94 or pAR650 in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR308 is significantly associated with a longer time to disease specific death (p = 0.011) and high pAR791 expression significantly associated with a longer time to disease recurrence (p = 0.018) in HNPC tumours and longer time to death from disease recurrence (p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p = 0.022) and low proliferating tumours (p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Lipidosterolic Extract of Serenoa Repens Modulates the Expression of Inflammation Related-Genes in Benign Prostatic Hyperplasia Epithelial and Stromal Cells
Int. J. Mol. Sci. 2013, 14(7), 14301-14320; doi:10.3390/ijms140714301
Received: 22 April 2013 / Revised: 22 May 2013 / Accepted: 18 June 2013 / Published: 10 July 2013
Cited by 12 | PDF Full-text (3459 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Despite the high prevalence of histological Benign Prostatic Hypeplasia (BPH) in elderly men, little is known regarding the molecular mechanisms and networks underlying the development and progression of the disease. Here, we explored the effects of a phytotherapeutic agent, Lipidosterolic extract of [...] Read more.
Despite the high prevalence of histological Benign Prostatic Hypeplasia (BPH) in elderly men, little is known regarding the molecular mechanisms and networks underlying the development and progression of the disease. Here, we explored the effects of a phytotherapeutic agent, Lipidosterolic extract of the dwarf palm plant Serenoa repens (LSESr), on the mRNA gene expression profiles of two representative models of BPH, BPH1 cell line and primary stromal cells derived from BPH. Treatment of these cells with LSESr significantly altered gene expression patterns as assessed by comparative gene expression profiling on gene chip arrays. The expression changes were manifested three hours following in vitro administration of LSESr, suggesting a rapid action for this compound. Among the genes most consistently affected by LSESr treatment, we found numerous genes that were categorized as part of proliferative, apoptotic, and inflammatory pathways. Validation studies using quantitative real-time PCR confirmed the deregulation of genes known to exhibit key roles in these biological processes including IL1B, IL1A, CXCL6, IL1R1, PTGS2, ALOX5, GAS1, PHLDA1, IL6, IL8, NFkBIZ, NFKB1, TFRC, JUN, CDKN1B, and ERBB3. Subsequent analyses also indicated that LSESr treatment can impede the stimulatory effects of certain proinflammatory cytokines such as IL6, IL17, and IL15 in these cells. These results suggest that LSESr may be useful to treat BPH that manifest inflammation characteristics. This also supports a role for inflammation in BPH presumably by mediating the balance between apoptosis and proliferation. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Effects of Calorie Restriction and IGF-1 Receptor Blockade on the Progression of 22Rv1 Prostate Cancer Xenografts
Int. J. Mol. Sci. 2013, 14(7), 13782-13795; doi:10.3390/ijms140713782
Received: 25 February 2013 / Revised: 22 May 2013 / Accepted: 21 June 2013 / Published: 3 July 2013
Cited by 6 | PDF Full-text (840 KB) | HTML Full-text | XML Full-text
Abstract
Calorie restriction (CR) inhibits prostate cancer progression, partially through modulation of the IGF axis. IGF-1 receptor (IGF-1R) blockade reduces prostate cancer xenograft growth. We hypothesized that combining calorie restriction with IGF-1R blockade would have an additive effect on prostate cancer growth. Severe [...] Read more.
Calorie restriction (CR) inhibits prostate cancer progression, partially through modulation of the IGF axis. IGF-1 receptor (IGF-1R) blockade reduces prostate cancer xenograft growth. We hypothesized that combining calorie restriction with IGF-1R blockade would have an additive effect on prostate cancer growth. Severe combined immunodeficient mice were subcutaneously injected with 22Rv1 cells and randomized to: (1) Ad libitum feeding/intraperitoneal saline (Ad-lib); (2) Ad-lib/20 mg/kg twice weekly, intraperitoneal ganitumab [anti-IGF-1R antibody (Ad-lib/Ab)]; (3) 40% calorie restriction/intraperitoneal saline (CR); (4) CR/ intraperitoneal ganitumab, (CR/Ab). CR and ganitumab treatment were initiated one week after tumor injection. Euthanasia occurred 19 days post treatment. Results showed that CR alone decreased final tumor weight, plasma insulin and IGF-1 levels, and increased apoptosis. Ganitumab therapy alone reduced tumor growth but had no effect on final tumor weight. The combination therapy (CR/Ab) further decreased final tumor weight and proliferation, increased apoptosis in comparison to the Ad-lib group, and lowered plasma insulin levels relative to the Ad-lib and Ad-lib/Ab groups. Tumor AKT activation directly correlated with plasma IGF-1 levels. In conclusion, whereas ganitumab therapy modestly affected 22Rv1 tumor growth, combining IGF-1R blockade with calorie restriction resulted in a significant decrease in final tumor weight and improved metabolic profile. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer
Int. J. Mol. Sci. 2013, 14(6), 12496-12519; doi:10.3390/ijms140612496
Received: 3 May 2013 / Revised: 29 May 2013 / Accepted: 3 June 2013 / Published: 14 June 2013
Cited by 14 | PDF Full-text (1712 KB) | HTML Full-text | XML Full-text
Abstract
Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, [...] Read more.
Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Expression and Role of GPR87 in Urothelial Carcinoma of the Bladder
Int. J. Mol. Sci. 2013, 14(6), 12367-12379; doi:10.3390/ijms140612367
Received: 22 April 2013 / Revised: 1 June 2013 / Accepted: 3 June 2013 / Published: 10 June 2013
Cited by 3 | PDF Full-text (498 KB) | HTML Full-text | XML Full-text
Abstract
The orphan GPR87 has recently been matched with its ligand LPA, which is a lipid mediator with multiple physiological functions, including cancer cell proliferation. This study aimed to clarify the role of GPR87 in urothelial carcinoma of the bladder. GPR87 expression was [...] Read more.
The orphan GPR87 has recently been matched with its ligand LPA, which is a lipid mediator with multiple physiological functions, including cancer cell proliferation. This study aimed to clarify the role of GPR87 in urothelial carcinoma of the bladder. GPR87 expression was assessed in seven human bladder cancer cell lines. A replication-deficient recombinant adenoviral vector expressing shRNA targeting GPR87 (Ad-shGPR87), was constructed. Gene silencing was carried out using Ad-shGPR87. Immunohistochemical analysis was performed for transurethral resection of bladder tumor samples from 71 patients with non-muscle-invasive bladder cancer. We observed GPR87 expression in five of the seven cell lines, and silencing GPR87 gene expression significantly reduced cell viability. GPR87 expression was positive in 38 (54%) of 71 tumors. Ki-67 index was associated with positive GPR87 staining status (p < 0.0001). Patients with GPR87-positive tumors had shorter intravesical recurrence-free survival than those with GPR87-negative tumors (p = 0.010). Multivariate analysis revealed that GPR87 staining status was an independent prognostic parameter for intravesical recurrence (p = 0.041). Progression from non-muscle-invasive to muscle-invasive tumor was more frequently observed in patients with GPR87-positive tumors, although this trend did not reach statistical significance (p = 0.056). These results warrant further prospective studies to clarify the role of GPR87 expression in intravesical recurrence and progression in bladder cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Enhanced Inhibition of Bladder Cancer Cell Growth by Simultaneous Knockdown of Antiapoptotic Bcl-xL and Survivin in Combination with Chemotherapy
Int. J. Mol. Sci. 2013, 14(6), 12297-12312; doi:10.3390/ijms140612297
Received: 22 April 2013 / Revised: 27 May 2013 / Accepted: 5 June 2013 / Published: 7 June 2013
Cited by 3 | PDF Full-text (423 KB) | HTML Full-text | XML Full-text
Abstract
The overexpression of antiapoptotic genes, such as Bcl-xL and survivin, contributes to the increased survival of tumor cells and to the development of treatment resistances. In the bladder cancer cell lines EJ28 and J82, the siRNA-mediated knockdown of survivin reduces cell proliferation [...] Read more.
The overexpression of antiapoptotic genes, such as Bcl-xL and survivin, contributes to the increased survival of tumor cells and to the development of treatment resistances. In the bladder cancer cell lines EJ28 and J82, the siRNA-mediated knockdown of survivin reduces cell proliferation and the inhibition of Bcl-xL sensitizes these cells towards subsequent chemotherapy with mitomycin C and cisplatin. Therefore, the aim of this study was to analyze if the simultaneous knockdown of Bcl-xL and survivin might represent a more powerful treatment option for bladder cancer than the single inhibition of one of these target genes. At 96 h after transfection, reduction in cell viability was stronger after simultaneous inhibition of Bcl-xL and survivin (decrease of 40%–48%) in comparison to the single target treatments (decrease of 29% at best). Furthermore, simultaneous knockdown of Bcl-xL and survivin considerably increased the efficacy of subsequent chemotherapy. For example, cellular viability of EJ28 cells decreased to 6% in consequence of Bcl-xL and survivin inhibition plus cisplatin treatment whereas single target siRNA plus chemotherapy treatments mediated reductions down to 15%–36% only. In conclusion, the combination of simultaneous siRNA-mediated knockdown of antiapoptotic Bcl-xL and survivin—a multitarget molecular-based therapy—and conventional chemotherapy shows great potential for improving bladder cancer treatment. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
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Open AccessArticle Role of EZH2 in the Growth of Prostate Cancer Stem Cells Isolated from LNCaP Cells
Int. J. Mol. Sci. 2013, 14(6), 11981-11993; doi:10.3390/ijms140611981
Received: 2 February 2013 / Revised: 22 May 2013 / Accepted: 29 May 2013 / Published: 5 June 2013
Cited by 16 | PDF Full-text (1465 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Enhancer of zeste homolog 2 (EZH2) plays a crucial role in embryonic and somatic stem cells for their proliferation and differentiation. However, the roles and underlying mechanisms of EZH2 in prostate cancer stem cells (PCSCs) remain unknown. This study aimed to investigate [...] Read more.
Enhancer of zeste homolog 2 (EZH2) plays a crucial role in embryonic and somatic stem cells for their proliferation and differentiation. However, the roles and underlying mechanisms of EZH2 in prostate cancer stem cells (PCSCs) remain unknown. This study aimed to investigate the effects of EZH2 on PCSCs. PCSCs were isolated from the human prostate cancer cell line LNcap by fluorescence activated cell sorting (FACS). EZH2 expression was compared between PCSCs and non-PCSCs. The association between EZH2 function and PCSC growth was investigated using siRNA-mediated knock-down of EZH2. Cell growth was investigated by MTT, cell cycle and apoptosis of PCSCs were explored by flow cytometric analysis. Finally, the upstream pathway miRNA level was determined via a luciferase reporter assay, and the downstream pathway cycle regulators were examined via reverse transcriptase-polymerase chain reaction. The results showed that LNcap cell line comprised a greater proportion of CD44+/CD133+ cells by comparison to the PC-3 cell line. EZH2 was up-regulated in PCSCs compared with non-PCSCs. Silence of EZH2 inhibited cell growth and the cell cycle and promoted the progression of apoptosis. Furthermore, EZH2 was a direct target of miR-101 in PCSCs and EZH2’s mRNA levels were inversely correlated with miR-101 expression and cyclin E2 (a cell-cycle regulator) was suppressed by siEZH2. In conclusion, EZH2 is essential for PCSC growth, partly through a negative regulation by miR-101 and positively regulating cyclin E2. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Enhanced Inhibition of Prostate Tumor Growth by Dual Targeting the Androgen Receptor and the Regulatory Subunit Type Iα of Protein Kinase A in Vivo
Int. J. Mol. Sci. 2013, 14(6), 11942-11962; doi:10.3390/ijms140611942
Received: 18 April 2013 / Revised: 29 May 2013 / Accepted: 29 May 2013 / Published: 4 June 2013
Cited by 2 | PDF Full-text (899 KB) | HTML Full-text | XML Full-text
Abstract
Progression to castration resistance is a major problem in the treatment of advanced prostate cancer and is likely to be driven by activation of several molecular pathways, including androgen receptor (AR) and cyclic AMP-dependent protein kinase A (PKA). In this study, we [...] Read more.
Progression to castration resistance is a major problem in the treatment of advanced prostate cancer and is likely to be driven by activation of several molecular pathways, including androgen receptor (AR) and cyclic AMP-dependent protein kinase A (PKA). In this study, we examined the therapeutic efficacy of a combined inhibition of the AR and the regulatory subunit type Iα (RIα) of protein kinase A with second generation antisense oligonucleotides (ODNs) in androgen-sensitive LNCaP and castration-resistant LNCaPabl tumors in vivo. We found that targeting the AR alone inhibited LNCaP, as well as LNCaPabl tumors. Combined inhibition resulted in an improved response over single targeting and even a complete tumor remission in LNCaPabl. Western blot analysis revealed that both ODNs were effective in reducing their target proteins when administered alone or in combination. In addition, treatment with the ODNs was associated with an induction of apoptosis. Our data suggest that dual targeting of the AR and PKARIα is more effective in inhibiting LNCaP and LNCaPabl tumor growth than single treatment and may give a treatment benefit, especially in castration-resistant prostate cancers. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Genome-Wide Investigation of Multifocal and Unifocal Prostate Cancer — Are They Genetically Different?
Int. J. Mol. Sci. 2013, 14(6), 11816-11829; doi:10.3390/ijms140611816
Received: 22 April 2013 / Revised: 20 May 2013 / Accepted: 27 May 2013 / Published: 3 June 2013
Cited by 10 | PDF Full-text (909 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Prostate cancer is widely observed to be biologically heterogeneous. Its heterogeneity is manifested histologically as multifocal prostate cancer, which is observed more frequently than unifocal prostate cancer. The clinical and prognostic significance of either focal cancer type is not fully established. To [...] Read more.
Prostate cancer is widely observed to be biologically heterogeneous. Its heterogeneity is manifested histologically as multifocal prostate cancer, which is observed more frequently than unifocal prostate cancer. The clinical and prognostic significance of either focal cancer type is not fully established. To investigate prostate cancer heterogeneity, the genetic profiles of multifocal and unifocal prostate cancers were compared. Here, we report observations deduced from tumor-tumor comparison of copy number alteration data of both focal categories. Forty-one fresh frozen prostate cancer foci from 14 multifocal prostate cancers and eight unifocal prostate cancers were subjected to copy number variation analysis with the Affymetrix SNP 6.0 microarray tool. With the investigated cases, tumors obtained from a single prostate exhibited different genetic profiles of variable degrees. Further comparison identified no distinct genetic pattern or signatures specific to multifocal or unifocal prostate cancer. Our findings suggest that samples obtained from multiple sites of a single unifocal prostate cancer show as much genetic heterogeneity and variability as separate tumors obtained from a single multifocal prostate cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Value of PCA3 to Predict Biopsy Outcome and Its Potential Role in Selecting Patients for Multiparametric MRI
Int. J. Mol. Sci. 2013, 14(6), 11347-11355; doi:10.3390/ijms140611347
Received: 1 April 2013 / Revised: 21 May 2013 / Accepted: 23 May 2013 / Published: 28 May 2013
Cited by 11 | PDF Full-text (309 KB) | HTML Full-text | XML Full-text
Abstract
PCA3 (prostate cancer gene 3) and multiparametric 3 tesla MRI are new promising diagnostic tools in the detection of PCa. Our aim was to study the clinical value of the Progensa PCA3-test: its predictive value for biopsy outcome, Gleason score and MRI [...] Read more.
PCA3 (prostate cancer gene 3) and multiparametric 3 tesla MRI are new promising diagnostic tools in the detection of PCa. Our aim was to study the clinical value of the Progensa PCA3-test: its predictive value for biopsy outcome, Gleason score and MRI outcome. We evaluated, retrospectively, 591 patients who underwent a Progensa PCA3-test at the Radboud University Nijmegen Medical Centre between May 2006 and December 2009. Prostate biopsies were performed in 290 patients; a multiparametric 3 tesla MRI of the prostate was performed in 163/591 patients. The PCA3-score was correlated to biopsy results and MRI outcome. The results show that PCA3 was highly predictive for biopsy outcome (p < 0.001); there was no correlation with the Gleason score upon biopsy (p = 0.194). The PCA3-score of patients with a suspicious region for PCa on MRI was significantly higher (p < 0.001) than in patients with no suspicious region on MRI (52 vs. 21). In conclusion, PCA3 is a valuable diagnostic biomarker for PCa; it did not correlate with the Gleason score. Furthermore, multiparametric MRI outcome was significantly correlated with the PCA3-score. Thus, PCA3 could be used to select patients that require MRI. However, in patients with a negative PCA3 and high clinical suspicion of PCa, a multiparametric MRI should also be done. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Impact of an Altered Wnt1/β-Catenin Expression on Clinicopathology and Prognosis in Clear Cell Renal Cell Carcinoma
Int. J. Mol. Sci. 2013, 14(6), 10944-10957; doi:10.3390/ijms140610944
Received: 14 March 2013 / Revised: 12 April 2013 / Accepted: 10 May 2013 / Published: 24 May 2013
Cited by 10 | PDF Full-text (551 KB) | HTML Full-text | XML Full-text
Abstract
In renal cell carcinoma (RCC), single members of the Wnt/β-catenin signaling cascade were recently identified to contribute to cancer progression. However, the role of Wnt1, one of the key ligands in β-catenin regulation, is currently unknown in RCC. Therefore, alterations of the [...] Read more.
In renal cell carcinoma (RCC), single members of the Wnt/β-catenin signaling cascade were recently identified to contribute to cancer progression. However, the role of Wnt1, one of the key ligands in β-catenin regulation, is currently unknown in RCC. Therefore, alterations of the Wnt1/β-catenin axis in clear cell RCC (ccRCC) were examined with regard to clinicopathology, overall survival (OS) and cancer specific survival (CSS). Corresponding ccRCCs and benign renal tissue were analyzed in 278 patients for Wnt1 and β-catenin expression by immunohistochemistry in tissue microarrays. Expression scores, including intensity and percentage of stained cells, were compared between normal kidney and ccRCCs. Data was categorized according to mean expression scores and correlated to tumor and patients’ characteristics. Survival was analyzed according to the Kaplan-Meier and log-rank test. Univariable and multivariable Cox proportional hazard regression models were used to explore the independent prognostic value of Wnt1 and β-catenin. In ccRCCs, high Wnt1 was associated with increased tumor diameter, stage and vascular invasion (p ≤ 0.02). High membranous β-catenin was associated with advanced stage, vascular invasion and tumor necrosis (p ≤ 0.01). Higher diameter, stage, node involvement, grade, vascular invasion and sarcomatoid differentiation (p ≤ 0.01) were found in patients with high cytoplasmic β-catenin. Patients with a high cytoplasmic β-catenin had a significantly reduced OS (hazard ratio (HR) 1.75) and CSS (HR 2.26), which was not independently associated with OS and CSS after adjustment in the multivariable model. Increased ccRCC aggressiveness was reflected by an altered Wnt1/β-catenin signaling. Cytoplasmic β-catenin was identified as the most promising candidate associated with unfavorable clinicopathology and impaired survival. Nevertheless, the shift of membranous β-catenin to the cytoplasm with a subsequently increased nuclear expression, as shown for other malignancies, could not be demonstrated to be present in ccRCC. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Inhibition of CCL2 Signaling in Combination with Docetaxel Treatment Has Profound Inhibitory Effects on Prostate Cancer Growth in Bone
Int. J. Mol. Sci. 2013, 14(5), 10483-10496; doi:10.3390/ijms140510483
Received: 16 February 2013 / Revised: 14 March 2013 / Accepted: 6 May 2013 / Published: 21 May 2013
Cited by 7 | PDF Full-text (951 KB) | HTML Full-text | XML Full-text
Abstract
The C-C chemokine ligand 2 (CCL2) stimulates migration, proliferation, and invasion of prostate cancer (PCa) cells, and its signaling also plays a role in the activation of osteoclasts. Therefore targeting CCL2 signaling in regulation of tumor progression in bone metastases is an [...] Read more.
The C-C chemokine ligand 2 (CCL2) stimulates migration, proliferation, and invasion of prostate cancer (PCa) cells, and its signaling also plays a role in the activation of osteoclasts. Therefore targeting CCL2 signaling in regulation of tumor progression in bone metastases is an area of intense research. The objective of our study was to investigate the efficacy of CCL2 blockade by neutralizing antibodies to inhibit the growth of PCa in bone. We used a preclinical model of cancer growth in the bone in which PCa C4-2B cells were injected directly into murine tibiae. Animals were treated for ten weeks with neutralizing anti-CCL2 antibodies, docetaxel, or a combination of both, and then followed an additional nine weeks. CCL2 blockade inhibited the growth of PCa in bone, with even more pronounced inhibition in combination with docetaxel. CCL2 blockade also resulted in increases in bone mineral density. Furthermore, our results showed that the tumor inhibition lasted even after discontinuation of the treatment. Our data provide compelling evidence that CCL2 blockade slows PCa growth in bone, both alone and in combination with docetaxel. These results support the continued investigations of CCL2 blockade as a treatment for advanced metastatic PCa. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle D-pinitol Inhibits Prostate Cancer Metastasis through Inhibition of αVβ3 Integrin by Modulating FAK, c-Src and NF-κB Pathways
Int. J. Mol. Sci. 2013, 14(5), 9790-9802; doi:10.3390/ijms14059790
Received: 29 March 2013 / Revised: 26 April 2013 / Accepted: 2 May 2013 / Published: 8 May 2013
Cited by 13 | PDF Full-text (1118 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. D-pinitol, a 3-methoxy analogue of d-chiro-inositol, was identified as an active principle in soy foods and legumes, and it has been proven to [...] Read more.
Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. D-pinitol, a 3-methoxy analogue of d-chiro-inositol, was identified as an active principle in soy foods and legumes, and it has been proven to induce tumor apoptosis and metastasis of cancer cells. In this study, we investigated the anti-metastasis effects of D-pinitol in human prostate cancer cells. We found that D-pinitol reduced the migration and the invasion of prostate cancer cells (PC3 and DU145) at noncytotoxic concentrations. Integrins are the major adhesive molecules in mammalian cells and have been associated with the metastasis of cancer cells. Treatment of prostate cancer cells with D-pinitol reduced mRNA and cell surface expression of αvβ3 integrin. In addition, D-pinitol exerted its inhibitory effects by reducing focal adhesion kinase (FAK) phosphorylation, c-Src kinase activity and NF-kB activation. Thus, D-pinitol may be a novel anti-metastasis agent for the treatment of prostate cancer metastasis. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle LILRA3 Is Associated with Benign Prostatic Hyperplasia Risk in a Chinese Population
Int. J. Mol. Sci. 2013, 14(5), 8832-8840; doi:10.3390/ijms14058832
Received: 21 February 2013 / Revised: 21 March 2013 / Accepted: 8 April 2013 / Published: 24 April 2013
Cited by 2 | PDF Full-text (200 KB) | HTML Full-text | XML Full-text
Abstract
A recent prostate cancer (PCa) genome-wide association study (GWAS) identified rs103294, a single nucleotide polymorphism (SNP) located on LILRA3, a key component in the regulation of inflammatory inhibition, to be significantly associated with PCa risk in a Chinese population. Because inflammation [...] Read more.
A recent prostate cancer (PCa) genome-wide association study (GWAS) identified rs103294, a single nucleotide polymorphism (SNP) located on LILRA3, a key component in the regulation of inflammatory inhibition, to be significantly associated with PCa risk in a Chinese population. Because inflammation may be a common etiological risk factor between PCa and benign prostatic hyperplasia (BPH), the current study was conducted to investigate the association of rs103294 with BPH risk. rs103294 was genotyped in a Chinese population of 426 BPH cases and 1,008 controls from Xinhua Hospital in Shanghai, China. Association between rs103294, BPH risk and clinicopathological traits were tested with adjustment for age. rs103294 was significantly associated with BPH risk with a p-value of 0.0067. Individuals with risk allele “C” had increased risk for BPH (OR = 1.34, 95% CI: 1.09–1.66). Stratified analysis revealed a stronger association risk for younger patients who are below 72 years old (OR = 1.51, 95% CI: 1.06–2.16). Our study represents the first effort to demonstrate that LILRA3 gene is significantly associated with BPH risk in a Chinese population. Our results support a common role of inflammation in the development of PCa and BPH. Additional studies are needed to further evaluate our results. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Plasma miRNAs as Biomarkers to Identify Patients with Castration-Resistant Metastatic Prostate Cancer
Int. J. Mol. Sci. 2013, 14(4), 7757-7770; doi:10.3390/ijms14047757
Received: 16 February 2013 / Revised: 20 March 2013 / Accepted: 22 March 2013 / Published: 10 April 2013
Cited by 27 | PDF Full-text (681 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs (miRNAs) have emerged as key regulators of numerous biological processes, and increasing evidence suggests that circulating miRNAs may be useful biomarkers of clinical disease. In this study, we sought to identify plasma miRNAs that differentiate patients with metastatic castration resistant prostate [...] Read more.
MicroRNAs (miRNAs) have emerged as key regulators of numerous biological processes, and increasing evidence suggests that circulating miRNAs may be useful biomarkers of clinical disease. In this study, we sought to identify plasma miRNAs that differentiate patients with metastatic castration resistant prostate cancer (mCRPC) from those with localized prostate cancer (PCa). Pooled plasma samples from patients with localized PCa or mCRPC (25 per group) were assayed using the Exiqon miRNA qPCR panel, and the differential expression of selected candidates was validated using qRT-PCR. We identified 63 miRNAs upregulated in mCRPC versus localized PCa, while only four were downregulated. Pearson’s correlation analysis revealed two highly correlated groups: one consisting of miR-141, miR375 and miR-200c and the other including miR151-3p, miR423-3p, miR-126, miR152 and miR-21. A third group, containing miR-16 and miR-205, showed less correlation. One miRNA from each group (miR-141, miR151-3p and miR-16) was used for logistic regression analysis and proved to increase the sensitivity of the prostate-specific antigen (PSA) test alone. While no miRNA alone differentiated localized PCa and mCRPC, combinations had greater sensitivity and specificity. The expression of these 10 candidates was assayed for association with clinical parameters of disease progression through the cBio portal. Our results demonstrate that plasma levels of selected miRNAs are potential biomarkers to differentiate localized PCa and mCRPC. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessArticle Alteration of Podocyte Protein Expression and Localization in the Early Stage of Various Hemodynamic Conditions
Int. J. Mol. Sci. 2013, 14(3), 5998-6011; doi:10.3390/ijms14035998
Received: 18 January 2013 / Revised: 3 March 2013 / Accepted: 5 March 2013 / Published: 15 March 2013
Cited by 4 | PDF Full-text (4329 KB) | HTML Full-text | XML Full-text
Abstract
Given that podocalyxin (PCX) and nestin play important roles in podocyte morphogenesis and the maintenance of structural integrity, we examined whether the expression and localization of these two podocyte proteins were influenced in the early stage of various hemodynamic conditions. Mice kidney [...] Read more.
Given that podocalyxin (PCX) and nestin play important roles in podocyte morphogenesis and the maintenance of structural integrity, we examined whether the expression and localization of these two podocyte proteins were influenced in the early stage of various hemodynamic conditions. Mice kidney tissues were prepared by in vivo cryotechnique (IVCT). The distribution of glomeruli and podocyte proteins was visualized with DAB staining, confocal laser scanning microscopy and immunoelectron microscopy. The mRNA levels were examined by real-time quantitative PCR. The results showed the following: Under the normal condition, PCX stained intensely along glomerular epithelial cells, whereas nestin was clearly staining in the endothelial cells and appeared only weakly in the podocytes. Under the acute hypertensive and cardiac arrest conditions, PCX and nestin staining was not clear, with a disarranged distribution, but the colocalization of PCX and nestin was apparent under this condition. In addition, under the acute hypertensive and cardiac arrest conditions, the mRNA levels of PCX and nestin were significantly decreased. Collectively, the abnormal redistribution and decreased mRNA expressions of PCX and nestin are important molecular events at the early stage of podocyte injury during hemodynamic disorders. IVCT may have more advantages for morphological analysis when researching renal diseases. Full article
(This article belongs to the Special Issue Molecular Research in Urology)

Review

Jump to: Research

Open AccessReview Molecular Research in Penile Cancer—Lessons Learned from the Past and Bright Horizons of the Future?
Int. J. Mol. Sci. 2013, 14(10), 19494-19505; doi:10.3390/ijms141019494
Received: 19 July 2013 / Revised: 11 September 2013 / Accepted: 12 September 2013 / Published: 26 September 2013
Cited by 2 | PDF Full-text (293 KB) | HTML Full-text | XML Full-text
Abstract
Penile cancer is a rare tumor. There is a limited understanding of the biological mediators of prognostic and therapeutic importance in penile cancer. However, there exists some fundamental understanding of the major pathways involved in the development of penile pre-neoplastic lesions and [...] Read more.
Penile cancer is a rare tumor. There is a limited understanding of the biological mediators of prognostic and therapeutic importance in penile cancer. However, there exists some fundamental understanding of the major pathways involved in the development of penile pre-neoplastic lesions and neoplasms. The aim of the present review is to highlight our current state of molecular knowledge in penile cancer to foster the necessary tools for researchers to pave major advancements in our current treatment paradigms and cancer specific outcomes. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Molecular Signatures in Urologic Tumors
Int. J. Mol. Sci. 2013, 14(9), 18421-18436; doi:10.3390/ijms140918421
Received: 1 July 2013 / Revised: 5 August 2013 / Accepted: 15 August 2013 / Published: 6 September 2013
Cited by 1 | PDF Full-text (390 KB) | HTML Full-text | XML Full-text
Abstract
Urologic tumors continue to represent a huge fraction of cancer cases in the United States, with over 376,310 estimated new diagnoses in 2013. As with many types of tumors, urologic tumors vary greatly in their phenotype, ranging from minimally invasive to malignancies [...] Read more.
Urologic tumors continue to represent a huge fraction of cancer cases in the United States, with over 376,310 estimated new diagnoses in 2013. As with many types of tumors, urologic tumors vary greatly in their phenotype, ranging from minimally invasive to malignancies possessing great metastatic potential. The increasing need for more efficient and less invasive methods of cancer detection, as well as the ability to predict severity of the disease phenotype is readily evident—yet reliable methods remain elusive in a clinical setting today. Comprehensive panels of gene clusters are being developed toward the generation of molecular signatures in order to better diagnose urologic malignancies, and identify effective treatment strategies in the emerging era of personalized medicine. In this review, we discuss the current literature on the credibility and biomarker value of such molecular signatures in the context of clinical significance relating to the pathological aggressiveness of urologic tumors (prostate, bladder and renal cancer)—also exploiting their predictive potential in the response to treatment. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Experimental Evidence of Persistent Androgen-Receptor-Dependency in Castration-Resistant Prostate Cancer
Int. J. Mol. Sci. 2013, 14(8), 15615-15635; doi:10.3390/ijms140815615
Received: 4 July 2013 / Revised: 14 July 2013 / Accepted: 15 July 2013 / Published: 26 July 2013
Cited by 4 | PDF Full-text (352 KB) | HTML Full-text | XML Full-text
Abstract
In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under [...] Read more.
In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent sublines derived from originally androgen-dependent LNCaP prostate cancer cells overexpress the AR and PSA, for which silencing the AR gene suppresses cellular proliferation. The overexpression of the AR confers androgen-independent growth ability on androgen-dependent prostate cancer cells. Some patient-derived prostate cancer xenograft lines also acquire castration-resistant growth ability secreting PSA. More recent publications have shown that the AR activated in CRPC cells regulates distinct gene sets from that in androgen-dependent status. This concept provides very important insights in the development of novel anti-prostate cancer drugs such as new generation anti-androgens and CYP17 inhibitors. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Genetic and Molecular Differences in Prostate Carcinogenesis between African American and Caucasian American Men
Int. J. Mol. Sci. 2013, 14(8), 15510-15531; doi:10.3390/ijms140815510
Received: 20 June 2013 / Revised: 8 July 2013 / Accepted: 10 July 2013 / Published: 25 July 2013
Cited by 16 | PDF Full-text (674 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. Prostate cancer incidence and associated mortality are highest in African American men in comparison to other races. The observed differences [...] Read more.
Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. Prostate cancer incidence and associated mortality are highest in African American men in comparison to other races. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different pathways of prostate carcinogenesis between African American and Caucasian men. This review focuses on some of the recent molecular biology discoveries, which have been investigated in prostate carcinogenesis and their likely contribution to the known discrepancies across race and ethnicity. Key discussion points include the androgen receptor gene structure and function, genome-wide association studies and epigenetics. The new observations of the ethnic differences of the ERG oncogene, the most common prostate cancer gene, are providing new insights into ERG based stratification of prostate cancers in the context of ethnically diverse patient populations. This rapidly advancing knowledge has the likely potential to benefit clinical practice. Current and future work will improve the ability to sub-type prostate cancers by molecular alterations and lead to targeted therapy against this common malignancy. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Extracellular MicroRNAs in Urologic Malignancies: Chances and Challenges
Int. J. Mol. Sci. 2013, 14(7), 14785-14799; doi:10.3390/ijms140714785
Received: 4 June 2013 / Revised: 27 June 2013 / Accepted: 1 July 2013 / Published: 16 July 2013
Cited by 30 | PDF Full-text (199 KB) | HTML Full-text | XML Full-text
Abstract
Small noncoding RNAs that are 19-23 nucleotides long, known as microRNAs (miRNAs), are involved in almost all biological mechanisms during carcinogenesis. Recent studies show that miRNAs released from live cells are detectable in body fluids and may be taken up by other [...] Read more.
Small noncoding RNAs that are 19-23 nucleotides long, known as microRNAs (miRNAs), are involved in almost all biological mechanisms during carcinogenesis. Recent studies show that miRNAs released from live cells are detectable in body fluids and may be taken up by other cells to confer cell-cell communication. These released miRNAs (here referred to as extracellular miRNAs) are often protected by RNA-binding proteins or embedded inside circulating microvesicles. Due to their relative stability, extracellular miRNAs are believed to be promising candidates as biomarkers for diagnosis and prognosis of disease, or even as therapeutic agents for targeted treatment. In this review, we first describe biogenesis and characteristics of these miRNAs. We then summarize recent publications involving extracellular miRNA profiling studies in three representative urologic cancers, including: prostate cancer, bladder cancer, and renal cell carcinoma. We focus on the diagnostic, prognostic, and therapeutic potential of these miRNAs in biological fluids, such as serum, plasma, and urine. Finally, we discuss advantages and challenges of these miRNAs in clinical applications. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer
Int. J. Mol. Sci. 2013, 14(7), 14800-14832; doi:10.3390/ijms140714800
Received: 8 May 2013 / Revised: 27 June 2013 / Accepted: 27 June 2013 / Published: 16 July 2013
Cited by 9 | PDF Full-text (289 KB) | HTML Full-text | XML Full-text
Abstract
As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies [...] Read more.
As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Posttranslational Modification of the Androgen Receptor in Prostate Cancer
Int. J. Mol. Sci. 2013, 14(7), 14833-14859; doi:10.3390/ijms140714833
Received: 5 June 2013 / Revised: 1 July 2013 / Accepted: 3 July 2013 / Published: 16 July 2013
Cited by 24 | PDF Full-text (388 KB) | HTML Full-text | XML Full-text
Abstract
The androgen receptor (AR) is important in the development of the prostate by regulating transcription, cellular proliferation, and apoptosis. AR undergoes posttranslational modifications that alter its transcription activity, translocation to the nucleus and stability. The posttranslational modifications that regulate these events are [...] Read more.
The androgen receptor (AR) is important in the development of the prostate by regulating transcription, cellular proliferation, and apoptosis. AR undergoes posttranslational modifications that alter its transcription activity, translocation to the nucleus and stability. The posttranslational modifications that regulate these events are of utmost importance to understand the functional role of AR and its activity. The majority of these modifications occur in the activation function-1 (AF1) region of the AR, which contains the transcriptional activation unit 1 (TAU1) and 5 (TAU5). Identification of the modifications that occur to these regions may increase our understanding of AR activation in prostate cancer and the role of AR in the progression from androgen-dependent to castration-resistant prostate cancer (CRPC). Most of the posttranslational modifications identified to date have been determined using the full-length AR in androgen dependent cells. Further investigations into the role of posttranslational modifications in androgen-independent activation of full-length AR and constitutively active splicing variants are warranted, findings from which may provide new therapeutic options for CRPC. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview The Potential Role of Lycopene for the Prevention and Therapy of Prostate Cancer: From Molecular Mechanisms to Clinical Evidence
Int. J. Mol. Sci. 2013, 14(7), 14620-14646; doi:10.3390/ijms140714620
Received: 17 May 2013 / Revised: 29 May 2013 / Accepted: 20 June 2013 / Published: 12 July 2013
Cited by 32 | PDF Full-text (493 KB) | HTML Full-text | XML Full-text
Abstract
Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red, lipophilic and naturally occurring in many fruits and vegetables, with tomatoes and tomato-based products containing the highest concentrations of bioavailable lycopene. Several epidemiological studies have [...] Read more.
Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red, lipophilic and naturally occurring in many fruits and vegetables, with tomatoes and tomato-based products containing the highest concentrations of bioavailable lycopene. Several epidemiological studies have linked increased lycopene consumption with decreased prostate cancer risk. These findings are supported by in vitro and in vivo experiments showing that lycopene not only enhances the antioxidant response of prostate cells, but that it is even able to inhibit proliferation, induce apoptosis and decrease the metastatic capacity of prostate cancer cells. However, there is still no clearly proven clinical evidence supporting the use of lycopene in the prevention or treatment of prostate cancer, due to the only limited number of published randomized clinical trials and the varying quality of existing studies. The scope of this article is to discuss the potential impact of lycopene on prostate cancer by giving an overview about its molecular mechanisms and clinical effects. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Sarcosine as a Potential Prostate Cancer Biomarker—A Review
Int. J. Mol. Sci. 2013, 14(7), 13893-13908; doi:10.3390/ijms140713893
Received: 22 May 2013 / Revised: 20 June 2013 / Accepted: 22 June 2013 / Published: 4 July 2013
Cited by 20 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer (CaP) is the most common type of tumour disease in men. Early diagnosis of cancer of the prostate is very important, because the sooner the cancer is detected, the better it is treated. According to that fact, there is great [...] Read more.
Prostate cancer (CaP) is the most common type of tumour disease in men. Early diagnosis of cancer of the prostate is very important, because the sooner the cancer is detected, the better it is treated. According to that fact, there is great interest in the finding of new markers including amino acids, proteins or nucleic acids. Prostate specific antigen (PSA) is commonly used and is the most important biomarker of CaP. This marker can only be detected in blood and its sensitivity is approximately 80%. Moreover, early stages cannot be diagnosed using this protein. Currently, there does not exist a test for diagnosis of early stages of prostate cancer. This fact motivates us to find markers sensitive to the early stages of CaP, which are easily detected in body fluids including urine. A potential is therefore attributed to the non-protein amino acid sarcosine, which is generated by glycine-N-methyltransferase in its biochemical cycle. In this review, we summarize analytical methods for quantification of sarcosine as a CaP marker. Moreover, pathways of the connection of synthesis of sarcosine and CaP development are discussed. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Recent Progress in Pharmaceutical Therapies for Castration-Resistant Prostate Cancer
Int. J. Mol. Sci. 2013, 14(7), 13958-13978; doi:10.3390/ijms140713958
Received: 13 May 2013 / Revised: 19 June 2013 / Accepted: 20 June 2013 / Published: 4 July 2013
Cited by 23 | PDF Full-text (280 KB) | HTML Full-text | XML Full-text
Abstract
Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. [...] Read more.
Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Hedgehog Signaling in Prostate Cancer and Its Therapeutic Implication
Int. J. Mol. Sci. 2013, 14(7), 13979-14007; doi:10.3390/ijms140713979
Received: 17 May 2013 / Revised: 28 June 2013 / Accepted: 1 July 2013 / Published: 4 July 2013
Cited by 23 | PDF Full-text (1518 KB) | HTML Full-text | XML Full-text
Abstract
Activation of Hedgehog (Hh) signaling is implicated in the development and progression of several tumor types, including prostate cancer, which is still the most common non-skin malignancy and the third leading cause of cancer-related mortality in men in industrialized countries worldwide. Several [...] Read more.
Activation of Hedgehog (Hh) signaling is implicated in the development and progression of several tumor types, including prostate cancer, which is still the most common non-skin malignancy and the third leading cause of cancer-related mortality in men in industrialized countries worldwide. Several studies have indicated that the Hh pathway plays a crucial role in the development as well as in the progression of this disease to more aggressive and even therapy-resistant disease states. Moreover, preclinical data have shown that inhibition of Hh signaling has the potential to reduce prostate cancer invasiveness and metastatic potential. Clinical trials investigating the benefit of Hh inhibitors in patients with prostate cancer have recently been initiated. However, acquired drug resistance has already been observed in other tumor types after long-term Hh inhibition. Therefore, combining Hh inhibitors with ionizing radiation, chemotherapy or other molecular targeted agents could represent an alternative therapeutic strategy. In this review, we will highlight the role of Hh signaling in the development and progression of prostate cancer and summarize the different therapeutic applications of Hedgehog inhibition. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Molecular and Functional Imaging for Detection of Lymph Node Metastases in Prostate Cancer
Int. J. Mol. Sci. 2013, 14(7), 13842-13857; doi:10.3390/ijms140713842
Received: 20 May 2013 / Revised: 21 June 2013 / Accepted: 21 June 2013 / Published: 3 July 2013
Cited by 8 | PDF Full-text (1416 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Knowledge on lymph node metastases is crucial for the prognosis and treatment of prostate cancer patients. Conventional anatomic imaging often fails to differentiate benign from metastatic lymph nodes. Pelvic lymph node dissection is an invasive technique and underestimates the extent of lymph [...] Read more.
Knowledge on lymph node metastases is crucial for the prognosis and treatment of prostate cancer patients. Conventional anatomic imaging often fails to differentiate benign from metastatic lymph nodes. Pelvic lymph node dissection is an invasive technique and underestimates the extent of lymph node metastases. Therefore, there is a need for more accurate non-invasive diagnostic techniques. Molecular and functional imaging has been subject of research for the last decades, in this respect. Therefore, in this article the value of imaging techniques to detect lymph node metastases is reviewed. These techniques include scintigraphy, sentinel node imaging, positron emission tomography/computed tomography (PET/CT), diffusion weighted magnetic resonance imaging (DWI MRI) and magnetic resonance lymphography (MRL). Knowledge on pathway and size of lymph node metastases has increased with molecular and functional imaging. Furthermore, improved detection and localization of lymph node metastases will enable (focal) treatment of the positive nodes only. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview The Present and Future of Prostate Cancer Urine Biomarkers
Int. J. Mol. Sci. 2013, 14(6), 12620-12649; doi:10.3390/ijms140612620
Received: 23 April 2013 / Revised: 27 May 2013 / Accepted: 3 June 2013 / Published: 17 June 2013
Cited by 6 | PDF Full-text (2055 KB) | HTML Full-text | XML Full-text
Abstract
In order to successfully cure patients with prostate cancer (PCa), it is important to detect the disease at an early stage. The existing clinical biomarkers for PCa are not ideal, since they cannot specifically differentiate between those patients who should be treated [...] Read more.
In order to successfully cure patients with prostate cancer (PCa), it is important to detect the disease at an early stage. The existing clinical biomarkers for PCa are not ideal, since they cannot specifically differentiate between those patients who should be treated immediately and those who should avoid over-treatment. Current screening techniques lack specificity, and a decisive diagnosis of PCa is based on prostate biopsy. Although PCa screening is widely utilized nowadays, two thirds of the biopsies performed are still unnecessary. Thus the discovery of non-invasive PCa biomarkers remains urgent. In recent years, the utilization of urine has emerged as an attractive option for the non-invasive detection of PCa. Moreover, a great improvement in high-throughput “omic” techniques has presented considerable opportunities for the identification of new biomarkers. Herein, we will review the most significant urine biomarkers described in recent years, as well as some future prospects in that field. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Urinary Bladder Cancer Susceptibility Markers. What Do We Know about Functional Mechanisms?
Int. J. Mol. Sci. 2013, 14(6), 12346-12366; doi:10.3390/ijms140612346
Received: 6 May 2013 / Revised: 23 May 2013 / Accepted: 30 May 2013 / Published: 10 June 2013
Cited by 13 | PDF Full-text (376 KB) | HTML Full-text | XML Full-text
Abstract
Genome-wide association studies (GWAS) have been successful in the identification of the several urinary bladder cancer (UBC) susceptibility loci, pointing towards novel genes involved in tumor development. Despite that, functional characterization of the identified variants remains challenging, as they mostly map to [...] Read more.
Genome-wide association studies (GWAS) have been successful in the identification of the several urinary bladder cancer (UBC) susceptibility loci, pointing towards novel genes involved in tumor development. Despite that, functional characterization of the identified variants remains challenging, as they mostly map to poorly understood, non-coding regions. Recently, two of the UBC risk variants (PSCA and UGT1A) were confirmed to have functional consequences. They were shown to modify bladder cancer risk by influencing gene expression in an allele-specific manner. Although the role of the other UBC risk variants is unknown, it can be hypothesized—based on studies from different cancer types—that they influence cancer susceptibility by alterations in regulatory networks. The insight into UBC heritability gained through GWAS and further functional studies can impact on cancer prevention and screening, as well as on the development of new biomarkers and future personalized therapies. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Thrombospondin-1 in Urological Cancer: Pathological Role, Clinical Significance, and Therapeutic Prospects
Int. J. Mol. Sci. 2013, 14(6), 12249-12272; doi:10.3390/ijms140612249
Received: 25 April 2013 / Revised: 3 June 2013 / Accepted: 3 June 2013 / Published: 7 June 2013
Cited by 12 | PDF Full-text (370 KB) | HTML Full-text | XML Full-text
Abstract
Angiogenesis is an important process for tumor growth and progression of various solid tumors including urological cancers. Thrombospondins (TSPs), especially TSP-1, are representative “anti”-angiogenic molecules and many studies have clarified their pathological role and clinical significance in vivo and in vitro. [...] Read more.
Angiogenesis is an important process for tumor growth and progression of various solid tumors including urological cancers. Thrombospondins (TSPs), especially TSP-1, are representative “anti”-angiogenic molecules and many studies have clarified their pathological role and clinical significance in vivo and in vitro. In fact, TSP-1 expression is associated with clinicopathological features and prognosis in many types of cancers. However, TSP-1 is a multi-functional protein and its biological activities vary according to the specific tumor environments. Consequently, there is no general agreement on its cancer-related function in urological cancers, and detailed information regarding regulative mechanisms is essential for a better understanding of its therapeutic effects and prognostic values. Various “suppressor genes” and “oncogenes” are known to be regulators and TSP-1-related factors under physiological and pathological conditions. In addition, various types of fragments derived from TSP-1 exist in a given tissue microenvironment and TSP-1 derived-peptides have specific activities. However, a detailed pathological function in human cancer tissues is not still understood. This review will focus on the pathological roles and clinical significance of TSP-1 in urological cancers, including prostate cancer, renal cell carcinoma, and urothelial cancer. In addition, special attention is paid to TSP-1-derived peptide and TSP-1-based therapy for malignancies. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Autophagy in Prostate Cancer and Androgen Suppression Therapy
Int. J. Mol. Sci. 2013, 14(6), 12090-12106; doi:10.3390/ijms140612090
Received: 17 April 2013 / Revised: 27 May 2013 / Accepted: 31 May 2013 / Published: 6 June 2013
Cited by 5 | PDF Full-text (757 KB) | HTML Full-text | XML Full-text
Abstract
The role of autophagy is known to be highly complex and context-dependent, leading to both cancer suppression and progression in several tumors including melanoma, breast and prostate cancer. In the present review, recent advances in an understanding of the involvement of autophagy [...] Read more.
The role of autophagy is known to be highly complex and context-dependent, leading to both cancer suppression and progression in several tumors including melanoma, breast and prostate cancer. In the present review, recent advances in an understanding of the involvement of autophagy in prostate cancer treatment are described. The regulatory effects of androgens on prostate cancer cell autophagy are particularly discussed in order to highlight the effects of autophagy modulation during androgen deprivation. A critical evaluation of the studies examined in the present review suggests the attractive possibility of autophagy inhibition combined with hormonal therapy as a promising approach for prostate cancer treatment. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Application of Monoclonal Antibody G250 Recognizing Carbonic Anhydrase IX in Renal Cell Carcinoma
Int. J. Mol. Sci. 2013, 14(6), 11402-11423; doi:10.3390/ijms140611402
Received: 28 April 2013 / Revised: 14 May 2013 / Accepted: 15 May 2013 / Published: 29 May 2013
Cited by 18 | PDF Full-text (963 KB) | HTML Full-text | XML Full-text
Abstract
Monoclonal antibody G250 (mAbG250) recognizes a determinant on carbonic anhydrase IX (CAIX). CAIX is expressed by virtually all renal cell carcinomas of the clear cell type (ccRCC), but expression in normal tissues is restricted. The homogeneous CAIX expression in ccRCC and excellent [...] Read more.
Monoclonal antibody G250 (mAbG250) recognizes a determinant on carbonic anhydrase IX (CAIX). CAIX is expressed by virtually all renal cell carcinomas of the clear cell type (ccRCC), but expression in normal tissues is restricted. The homogeneous CAIX expression in ccRCC and excellent targeting capability of mAbG250 in animal models led to the initiation of the clinical evaluation of mAbG250 in (metastatic) RCC (mRCC) patients. Clinical studies confirmed the outstanding targeting ability of mAbG250 and cG250 PET imaging, as diagnostic modality holds great promise for the future, both in detecting localized and advanced disease. Confirmation of the results obtained in the non-randomized clinical trials with unmodified cG250 is needed to substantiate the value of cG250 treatment in mRCC. cG250-Based radio immuno-therapy (RIT) holds promise for treatment of patients with small-volume disease, and adjuvant treatment with unmodified cG250 may be of value in selected cases. In the upcoming years, ongoing clinical trials should provide evidence for these assumptions. Lastly, whether cG250-based RIT can be combined with tyrosine kinase inhibitors, which constitutes the current standard treatment for mRCC, needs to be established. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview The Genomic Landscape of Prostate Cancer
Int. J. Mol. Sci. 2013, 14(6), 10822-10851; doi:10.3390/ijms140610822
Received: 7 April 2013 / Revised: 6 May 2013 / Accepted: 9 May 2013 / Published: 24 May 2013
Cited by 9 | PDF Full-text (604 KB) | HTML Full-text | XML Full-text
Abstract
By the age of 80, approximately 80% of men will manifest some cancerous cells within their prostate, indicating that prostate cancer constitutes a major health burden. While this disease is clinically insignificant in most men, it can become lethal in others. The [...] Read more.
By the age of 80, approximately 80% of men will manifest some cancerous cells within their prostate, indicating that prostate cancer constitutes a major health burden. While this disease is clinically insignificant in most men, it can become lethal in others. The most challenging task for clinicians is developing a patient-tailored treatment in the knowledge that this disease is highly heterogeneous and that relatively little adequate prognostic tools are available to distinguish aggressive from indolent disease. Next-generation sequencing allows a description of the cancer at an unprecedented level of detail and at different levels, going from whole genome or exome sequencing to transcriptome analysis and methylation-specific immunoprecipitation, followed by sequencing. Integration of all these data is leading to a better understanding of the initiation, progression and metastatic processes of prostate cancer. Ultimately, these insights will result in a better and more personalized treatment of patients suffering from prostate cancer. The present review summarizes current knowledge on copy number changes, gene fusions, single nucleotide mutations and polymorphisms, methylation, microRNAs and long non-coding RNAs obtained from high-throughput studies. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Current Status of Biomarkers for Prostate Cancer
Int. J. Mol. Sci. 2013, 14(6), 11034-11060; doi:10.3390/ijms140611034
Received: 19 April 2013 / Revised: 13 May 2013 / Accepted: 14 May 2013 / Published: 24 May 2013
Cited by 39 | PDF Full-text (390 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer (PCa) is a leading cause of cancer-related death of men globally. Since its introduction, there has been intense debate as to the effectiveness of the prostate specific antigen (PSA) test as a screening tool for PCa. It is now evident [...] Read more.
Prostate cancer (PCa) is a leading cause of cancer-related death of men globally. Since its introduction, there has been intense debate as to the effectiveness of the prostate specific antigen (PSA) test as a screening tool for PCa. It is now evident that the PSA test produces unacceptably high rates of false positive results and is not prognostic. Here we review the current status of molecular biomarkers that promise to be prognostic and that might inform individual patient management. It highlights current efforts to identify biomarkers obtained by minimally invasive methods and discusses current knowledge with regard to gene fusions, mRNA and microRNAs, immunology, and cancer-associated microparticles. Full article
(This article belongs to the Special Issue Molecular Research in Urology)
Open AccessReview Human Prostatic Acid Phosphatase: Structure, Function and Regulation
Int. J. Mol. Sci. 2013, 14(5), 10438-10464; doi:10.3390/ijms140510438
Received: 15 April 2013 / Revised: 8 May 2013 / Accepted: 8 May 2013 / Published: 21 May 2013
Cited by 15 | PDF Full-text (582 KB) | HTML Full-text | XML Full-text
Abstract
Human prostatic acid phosphatase (PAcP) is a 100 kDa glycoprotein composed of two subunits. Recent advances demonstrate that cellular PAcP (cPAcP) functions as a protein tyrosine phosphatase by dephosphorylating ErbB-2/Neu/HER-2 at the phosphotyrosine residues in prostate cancer (PCa) cells, which results in [...] Read more.
Human prostatic acid phosphatase (PAcP) is a 100 kDa glycoprotein composed of two subunits. Recent advances demonstrate that cellular PAcP (cPAcP) functions as a protein tyrosine phosphatase by dephosphorylating ErbB-2/Neu/HER-2 at the phosphotyrosine residues in prostate cancer (PCa) cells, which results in reduced tumorigenicity. Further, the interaction of cPAcP and ErbB-2 regulates androgen sensitivity of PCa cells. Knockdown of cPAcP expression allows androgen-sensitive PCa cells to develop the castration-resistant phenotype, where cells proliferate under an androgen-reduced condition. Thus, cPAcP has a significant influence on PCa cell growth. Interestingly, promoter analysis suggests that PAcP expression can be regulated by NF-κB, via a novel binding sequence in an androgen-independent manner. Further understanding of PAcP function and regulation of expression will have a significant impact on understanding PCa progression and therapy. Full article
(This article belongs to the Special Issue Molecular Research in Urology)

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