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Special Issue "Molecular Research in Urology 2014"

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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 (15 June 2014)

Special Issue Editors

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
Guest Editor
Dr. Nees Matthias (Website)

Medical Biotechnology Knowledge Centre, VTT Technical Research Centre of Finland, Turku, Finland
Phone: +358 40 8314 839

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 have been made and are reviewed in this issue. Once metastasized, there is still no effective treatment, nor stand alone a curative therapy. However, an improved 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 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
Dr. Nees Matthias
Guest Editors

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.

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Keywords

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

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Published Papers (11 papers)

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Research

Jump to: Review, Other

Open AccessArticle Potential Therapeutic Roles of Tanshinone IIA in Human Bladder Cancer Cells
Int. J. Mol. Sci. 2014, 15(9), 15622-15637; doi:10.3390/ijms150915622
Received: 15 June 2014 / Revised: 15 August 2014 / Accepted: 19 August 2014 / Published: 4 September 2014
Cited by 7 | PDF Full-text (4128 KB) | HTML Full-text | XML Full-text
Abstract
Tanshinone IIA (Tan-IIA), one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- [...] Read more.
Tanshinone IIA (Tan-IIA), one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. Here we explored the anticancer effect of Tan-IIA in human bladder cancer cell lines. Our results showed that Tan-IIA caused bladder cancer cell death in a time- and dose-dependent manner. Tan-IIA induced apoptosis through the mitochondria-dependent pathway in these bladder cancer cells. Tan-IIA also suppressed the migration of bladder cancer cells as revealed by the wound healing and transwell assays. Finally, combination therapy of Tan-IIA with a lower dose of cisplatin successfully killed bladder cancer cells, suggesting that Tan-IIA can serve as a potential anti-cancer agent in bladder cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle Role of Serum Cholesterol and Statin Use in the Risk of Prostate Cancer Detection and Tumor Aggressiveness
Int. J. Mol. Sci. 2014, 15(8), 13615-13623; doi:10.3390/ijms150813615
Received: 6 May 2014 / Revised: 11 July 2014 / Accepted: 11 July 2014 / Published: 6 August 2014
Cited by 10 | PDF Full-text (696 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The aim of this study was to analyze the relationship between statin use along with serum cholesterol levels and prostate cancer (PCa) detection and aggressiveness. Statin users of three years or more and serum cholesterol levels (SC) were assessed in 2408 men [...] Read more.
The aim of this study was to analyze the relationship between statin use along with serum cholesterol levels and prostate cancer (PCa) detection and aggressiveness. Statin users of three years or more and serum cholesterol levels (SC) were assessed in 2408 men scheduled for prostate biopsy. SC was classified as normal (NSC: <200 mg/dL) or high (HSC: >200 mg/dL). High-grade PCa (HGPCa) was considered if the Gleason score was greater than 7. Statin users comprised 30.9% of those studied. The PCa detection rate was 31.2% of men on statins and 37% of non-statin users (p < 0.006). The PCa detection rate was 26.3% in men with NSC and 40.6% in those with HSC (p < 0.001). In the subset of NSC men, the PCa rate was 26.5% for statin users and 26.2% for non-users (p = 0.939), while in men with HSC, the PCa rate was 36.4% for statin users and 42.0% for non-statin users (p = 0.063). The HGPCa rate was 41.8% for statin users and 32.5% for non-users (p = 0.012). NSC men had a 53.8% rate of HGPCa, while the rate was only 27.6% in HSC men (p < 0.001). NSC men on statins had an HGPCa rate of 70.2%, while non-statin users had a rate of 41.2% (p < 0.001). The HGPCa rate for HSC men on statins was 18.8%, while the rate was 30.0% (p = 0.011) for non-users. Logistic regression analysis suggested that serum cholesterol levels could serve as an independent predictor of PCa risk, OR 1.87 (95% CI 1.56–2.24) and HGPCa risk, OR 0.31 (95% CI 0.23–0.44), while statin usage could not. Statin treatment may prevent PCa detection through serum cholesterol-mediated mechanisms. A disturbing increase in the HGPCa rate was observed in statin users who normalized their serum cholesterol. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle Comparative Evaluation of Urinary PCA3 and TMPRSS2: ERG Scores and Serum PHI in Predicting Prostate Cancer Aggressiveness
Int. J. Mol. Sci. 2014, 15(8), 13299-13316; doi:10.3390/ijms150813299
Received: 20 June 2014 / Revised: 15 July 2014 / Accepted: 18 July 2014 / Published: 30 July 2014
Cited by 17 | PDF Full-text (731 KB) | HTML Full-text | XML Full-text
Abstract
It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were [...] Read more.
It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were assessed in 154 patients who underwent radical prostatectomy for biopsy-proven prostate cancer. Univariate and multivariate analyses using logistic regression and decision curve analyses were performed. All three markers were predictors of a tumor volume ≥0.5 mL. Only PHI predicted Gleason score ≥7. T2 score and PHI were both independent predictors of extracapsular extension (≥pT3), while multifocality was only predicted by PCA3 score. Moreover, when compared to a base model (age, digital rectal examination, serum PSA, and Gleason sum at biopsy), the addition of both PCA3 score and PHI to the base model induced a significant increase (+12%) when predicting tumor volume >0.5 mL. PHI and urinary PCA3 and T2 scores can be considered as complementary predictors of cancer aggressiveness at prostatectomy. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle Potential Spermatogenesis Recovery with Bone Marrow Mesenchymal Stem Cells in an Azoospermic Rat Model
Int. J. Mol. Sci. 2014, 15(8), 13151-13165; doi:10.3390/ijms150813151
Received: 15 June 2014 / Revised: 15 July 2014 / Accepted: 16 July 2014 / Published: 24 July 2014
Cited by 5 | PDF Full-text (4712 KB) | HTML Full-text | XML Full-text
Abstract
Non-obstructive azoospermia is the most challenging type of male infertility. Stem cell based therapy provides the potential to enhance the recovery of spermatogenesis following cancer therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) possess the potential to differentiate or trans-differentiate into multi-lineage cells, [...] Read more.
Non-obstructive azoospermia is the most challenging type of male infertility. Stem cell based therapy provides the potential to enhance the recovery of spermatogenesis following cancer therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) possess the potential to differentiate or trans-differentiate into multi-lineage cells, secrete paracrine factors to recruit the resident stem cells to participate in tissue regeneration, or fuse with the local cells in the affected region. In this study, we tested whether spermatogenically-induced BMSCs can restore spermatogenesis after administration of an anticancer drug. Allogeneic BMSCs were co-cultured in conditioned media derived from cultured testicular Sertoli cells in vitro, and then induced stem cells were transplanted into the seminiferous tubules of a busulfan-induced azoospermatic rat model for 8 weeks. The in vitro induced BMSCs exhibited specific spermatogonic gene and protein markers, and after implantation the donor cells survived and located at the basement membranes of the recipient seminiferous tubules, in accordance with what are considered the unique biological characteristics of spermatogenic stem cells. Molecular markers of spermatogonial stem cells and spermatogonia (Vasa, Stella, SMAD1, Dazl, GCNF, HSP90α, integrinβ1, and c-kit) were expressed in the recipient testis tissue. No tumor mass, immune response, or inflammatory reaction developed. In conclusion, BMSCs might provide the potential to trans-differentiate into spermatogenic-like-cells, enhancing endogenous fertility recovery. The present study indicates that BMSCs might offer alternative treatment for the patients with azoospermatic infertility after cancer chemotherapy. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
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Open AccessArticle Copy Number Analysis of 24 Oncogenes: MDM4 Identified as a Putative Marker for Low Recurrence Risk in Non Muscle Invasive Bladder Cancer
Int. J. Mol. Sci. 2014, 15(7), 12458-12468; doi:10.3390/ijms150712458
Received: 25 March 2014 / Revised: 26 June 2014 / Accepted: 4 July 2014 / Published: 14 July 2014
PDF Full-text (745 KB) | HTML Full-text | XML Full-text
Abstract
Patients with non-muscle invasive bladder cancer (NMIBC) generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the [...] Read more.
Patients with non-muscle invasive bladder cancer (NMIBC) generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the copy number variations (CNVs) of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR and BRAF) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence. Formalin-fixed paraffin-embedded tissue samples from 43 patients who underwent transurethral resection of the bladder (TURB) were used; 23 patients had relapsed and 20 were disease-free after 5 years. Amplification frequencies were analyzed for all genes and MDM4 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones (0.65 vs. 0.3; Fisher’s test p = 0.023). Recurrence-free survival analysis confirmed the predictive role of MDM4 (log-rank test p = 0.041). Our preliminary results indicate a putative role for the MDM4 gene in predicting local recurrence of bladder cancer. Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle Protein Tyrosine Kinase 7 (PTK7) as a Predictor of Lymph Node Metastases and a Novel Prognostic Biomarker in Patients with Prostate Cancer
Int. J. Mol. Sci. 2014, 15(7), 11665-11677; doi:10.3390/ijms150711665
Received: 27 April 2014 / Revised: 28 May 2014 / Accepted: 12 June 2014 / Published: 1 July 2014
Cited by 5 | PDF Full-text (1041 KB) | HTML Full-text | XML Full-text
Abstract
Protein tyrosine kinase 7 (PTK7) has been studied in various tumors, but its role in prostate cancer remains unknown. This study is aimed to investigate the prognostic and predictive significance of PTK7 in patients with prostate cancer. PTK7 expression was evaluated by [...] Read more.
Protein tyrosine kinase 7 (PTK7) has been studied in various tumors, but its role in prostate cancer remains unknown. This study is aimed to investigate the prognostic and predictive significance of PTK7 in patients with prostate cancer. PTK7 expression was evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis in 20 pairs of benign prostatic hyperplasia specimens and prostate cancer specimens. Then, we examined the immunohistochemical expression of PTK7 in 180 prostate cancer specimens and evaluated its clinical significances. Elevated PTK7 expression was significantly associated with lymph node metastases, seminal vesicle invasion, prostate cancer stage, the higher preoperative prostate-specific antigen, the higher Gleason score, angiolymphatic invasion, and biochemical recurrence. The results revealed that the overexpression of PTK7 in prostate cancer was an independent prognostic factor for poor overall survival and biochemical recurrence-free survival. The present data provide evidence that PTK7 predicts lymph node metastasis and poor overall survival and biochemical recurrence-free survival, highlighting its potential function as a therapeutic target for prostate cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle PSMA, EpCAM, VEGF and GRPR as Imaging Targets in Locally Recurrent Prostate Cancer after Radiotherapy
Int. J. Mol. Sci. 2014, 15(4), 6046-6061; doi:10.3390/ijms15046046
Received: 24 January 2014 / Revised: 28 March 2014 / Accepted: 28 March 2014 / Published: 10 April 2014
Cited by 9 | PDF Full-text (1557 KB) | HTML Full-text | XML Full-text
Abstract
In this retrospective pilot study, the expression of the prostate-specific membrane antigen (PSMA), the epithelial cell adhesion molecule (EpCAM), the vascular endothelial growth factor (VEGF) and the gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy [...] Read more.
In this retrospective pilot study, the expression of the prostate-specific membrane antigen (PSMA), the epithelial cell adhesion molecule (EpCAM), the vascular endothelial growth factor (VEGF) and the gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated, and their adequacy for targeted imaging was analyzed. Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Immunohistochemistry was performed. A pathologist scored the immunoreactivity in prostate cancer and stroma. Staining for PSMA was seen in 100% (17/17), EpCAM in 82.3% (14/17), VEGF in 82.3% (14/17) and GRPR in 100% (17/17) of prostate cancer specimens. Staining for PSMA, EpCAM and VEGF was seen in 0% (0/17) and for GRPR in 100% (17/17) of the specimens’ stromal compartments. In 11.8% (2/17) of cases, the GRPR staining intensity of prostate cancer was higher than stroma, while in 88.2% (15/17), the staining was equal. Based on the absence of stromal staining, PSMA, EpCAM and VEGF show high tumor distinctiveness. Therefore, PSMA, EpCAM and VEGF can be used as targets for the bioimaging of recurrent prostate cancer after EBRT to exclude metastatic disease and/or to plan local salvage therapy. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessArticle Evodiamine Induces Apoptosis and Enhances TRAIL-Induced Apoptosis in Human Bladder Cancer Cells through mTOR/S6K1-Mediated Downregulation of Mcl-1
Int. J. Mol. Sci. 2014, 15(2), 3154-3171; doi:10.3390/ijms15023154
Received: 27 December 2013 / Revised: 13 February 2014 / Accepted: 14 February 2014 / Published: 21 February 2014
Cited by 8 | PDF Full-text (1761 KB) | HTML Full-text | XML Full-text
Abstract
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anti-cancer agents, has been considered as a new strategy for anti-cancer therapy. In this study, we demonstrated that evodiamine, a quinolone alkaloid isolated from the fruit of Evodia [...] Read more.
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anti-cancer agents, has been considered as a new strategy for anti-cancer therapy. In this study, we demonstrated that evodiamine, a quinolone alkaloid isolated from the fruit of Evodia fructus, induced apoptosis and enhanced TRAIL-induced apoptosis in human bladder cancer cells. To elucidate the underlying mechanism, we found that evodiamine significantly reduced the protein levels of Mcl-1 in 253J and T24 bladder cancer cells, and overexpression of this molecule attenuated the apoptosis induced by evodiamine alone, or in combination with TRAIL. Further experiments revealed that evodiamine did not affect the mRNA level, proteasomal degradation and protein stability of Mcl-1. On the other hand, evodiamine inhibited the mTOR/S6K1 pathway, which usually regulates protein translation; moreover, knockdown of S6K1 with small interfering RNA (siRNA) effectively reduced Mcl-1 levels, indicating evodiamine downregulates c-FLIP through inhibition of mTOR/S6K1 pathway. Taken together, our results indicate that evodiamine induces apoptosis and enhances TRAIL-induced apoptosis possibly through mTOR/S6K1-mediated downregulation of Mcl-1; furthermore, these findings provide a rationale for the combined application of evodiamine with TRAIL in the treatment of bladder cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)

Review

Jump to: Research, Other

Open AccessReview Prognostic DNA Methylation Markers for Prostate Cancer
Int. J. Mol. Sci. 2014, 15(9), 16544-16576; doi:10.3390/ijms150916544
Received: 8 August 2014 / Revised: 5 September 2014 / Accepted: 11 September 2014 / Published: 18 September 2014
Cited by 21 | PDF Full-text (799 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer (PC) is the most commonly diagnosed neoplasm and the third most common cause of cancer-related death amongst men in the Western world. PC is a clinically highly heterogeneous disease, and distinction between aggressive and indolent disease is a major challenge [...] Read more.
Prostate cancer (PC) is the most commonly diagnosed neoplasm and the third most common cause of cancer-related death amongst men in the Western world. PC is a clinically highly heterogeneous disease, and distinction between aggressive and indolent disease is a major challenge for the management of PC. Currently, no biomarkers or prognostic tools are able to accurately predict tumor progression at the time of diagnosis. Thus, improved biomarkers for PC prognosis are urgently needed. This review focuses on the prognostic potential of DNA methylation biomarkers for PC. Epigenetic changes are hallmarks of PC and associated with malignant initiation as well as tumor progression. Moreover, DNA methylation is the most frequently studied epigenetic alteration in PC, and the prognostic potential of DNA methylation markers for PC has been demonstrated in multiple studies. The most promising methylation marker candidates identified so far include PITX2, C1orf114 (CCDC181) and the GABRE~miR-452~miR-224 locus, in addition to the three-gene signature AOX1/C1orf114/HAPLN3. Several other biomarker candidates have also been investigated, but with less stringent clinical validation and/or conflicting evidence regarding their possible prognostic value available at this time. Here, we review the current evidence for the prognostic potential of DNA methylation markers in PC. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
Open AccessReview Possible Prognostic and Therapeutic Significance of c-Kit Expression, Mast Cell Count and Microvessel Density in Renal Cell Carcinoma
Int. J. Mol. Sci. 2014, 15(7), 13060-13076; doi:10.3390/ijms150713060
Received: 28 May 2014 / Revised: 17 July 2014 / Accepted: 17 July 2014 / Published: 23 July 2014
Cited by 6 | PDF Full-text (897 KB) | HTML Full-text | XML Full-text
Abstract
Renal cell carcinoma (RCC) is the most frequent renal tumor and its incidence is increasing worldwide. Tumor angiogenesis is known to play a crucial role in the etiopathogenesis of RCC and over the last few years an even deeper knowledge of its [...] Read more.
Renal cell carcinoma (RCC) is the most frequent renal tumor and its incidence is increasing worldwide. Tumor angiogenesis is known to play a crucial role in the etiopathogenesis of RCC and over the last few years an even deeper knowledge of its contribution in metastatic RCC development has led to the development of numerous molecular targeting agents (such as sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and dovitinib). The above agents are principally directed against vascular endothelial growth factor receptor (VEGFR) members and also against c-Kit receptor (c-KitR). The role of c-kitR inhibition on clear cell RCC (ccRCC), the main RCC subtype, is less well established. Whether c-kitR activation through its ligand, stem cell factor (SCF) contributes significantly to the effects of tyrosine kinase inhibitors (TKIs) treatment remains to be established. It is important to underscore that the c-KitR is expressed on mast cells (MCs) and cancer cells. After an examination of the c-KitR/SCF pathway, we review here the principal studies that have evaluated c-Kit expression in RCC. Moreover, we summarize some investigations that have observed the distribution of MCs in primary renal cancer and in adjacent normal tissue with appropriate histological immunohistochemical techniques. We also focus on few studies that have evaluated the correlation between RCC proliferation, MC count and microvessel density (MVD), as hallmarks of tumor angiogenesis. Thus, the aim of this review of the literature is to clarify if c-KitR expression, MC count and MVD could have prognostic significance and the possible predictive therapeutic implications in RCC. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)

Other

Jump to: Research, Review

Open AccessLetter Molecular Research in Urology 2014: Update on PET/MR Imaging of the Prostate
Int. J. Mol. Sci. 2014, 15(8), 13401-13405; doi:10.3390/ijms150813401
Received: 15 June 2014 / Revised: 23 July 2014 / Accepted: 28 July 2014 / Published: 31 July 2014
Cited by 1 | PDF Full-text (1728 KB) | HTML Full-text | XML Full-text
Abstract This article gives an overview of recent publications and potential indications of Positron emission tomography/ Magnetic resonance (PET/MR) imaging of prostate cancer. Full article
(This article belongs to the Special Issue Molecular Research in Urology 2014)
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