Upregulation of miR-3195, miR-3687 and miR-4417 is associated with castration-resistant prostate cancer.

PURPOSE: Prostate cancer (PCa) is a leading cause of cancer-related death. Upon androgen-deprivation therapy, the disease may progress further to castration-resistant PCa (CRPC) with a poor prognosis. MicroRNAs (miRNAs) are small non-coding RNAs, which play crucial roles in gene regulation. The aim of our study is to find CRPC-associated miRNAs and to evaluate their functional role. METHODS: In this study, 23 benign prostatic hyperplasia (BPH), 76 primary PCa, and 35 CRPC specimens were included. Total RNA extracted from tissue sections was used for miRNA profiling on the Affymetrix GSC 3000 platform. Subsequently, stem-loop RT-qPCR analysis was performed to validate the expression levels of selected miRNAs. PCa cell lines were transfected with miRNA mimics or inhibitors to evaluate the effects on cell proliferation, cell migration and cell invasion. RESULTS: In our profiling study, several miRNAs were found to be deregulated in CRPC compared to primary PCa tissue, of which miR-205 (- 4.5-fold; p = 0.0009), miR-92b (- 3.1 fold; p < 0.0001) were downregulated and miR-3195 (5.6-fold; p < 0.0001), miR-3687 (8.7-fold; p = 0.0006) and miR-4417 (5.0-fold; p = 0.0005) were most upregulated. While KLK3, miR-21 and miR-141 expression levels in androgen-treated VCaP and LNCaP cells were increased, the expression levels of miR-3687 and miR-4417 were reduced. None of the miRNAs were androgen-regulated in the AR-negative PC3 cell line. Overexpression of miR-3687 reduced cell migration and cell invasion, whilst miR-3195 enhanced cell migration. CONCLUSION: We have identified several novel deregulated miRNAs in CRPC tissue, including two microRNAs that are potentially involved in tumor invasion. Our data support the hypothesized involvement of miRNAs in PCa tumorigenesis and progression to CRPC. The applicability of these miRNAs as novel biomarkers for CRPC remains to be further investigated.

[Influence of culture and religion on the treatment of cancer patients]. / Einfluss von Kultur und Religion auf die Therapie von Krebspatienten.

Religion, which is one of the most important sources of human identity, has so far hardly been taken into account in the clinic. In the largely secularized society of Germany, this has played a highly subordinate role. Currently, however, the development towards a multireligious society is emerging, which will also be reflected in everyday medical care. Disease and mortality in patients can affect different cultural-religious spheres. Although distinction between cultural and religious aspects is possible, it is not necessary for clinical practice. In the situation of oncological therapy, questions may arise which must be answered differently in the religions Christianity, Judaism and Islam and which should be taken into account when selecting therapy. The consideration of cultural-religious rules can intensify the patient's acceptance, but it can also impair it in case of disregard. Such peculiarities can be the separation into male and female spheres or the restriction of certain auxiliary substances or drugs (blood products, narcotics). Kübler-Ross's phase model is suitable for determining where cultural-religious sensitivities should be taken into account in the phases of disease and how cultural-religious offerings can benefit the course of therapy. Due to large individual, regional, cultural and confessional differences, no systematic catalogue of procedures can be provided here. However, knowledge of such differences, more sensitive interaction with patients and their families and cooperation with hospital pastors can strengthen the relationship of trust between doctor and patient and thus improve the conditions for successful oncological therapy. These aspects should not be underestimated when treating people of other faiths in Germany's secular society.

[Cold atmospheric plasma for the treatment of urological tumors]. / Kaltes atmosphärisches Plasma für die urologische Tumortherapie.

Cold atmospheric plasma (CAP) is a highly reactive ionized physical state consisting of electrically charged particles, radicals and photons as well as electromagnetic radiation. Due to the high energy and reactivity of plasma components, physical plasmas are also referred to as the 4th aggregate state. In biological systems, CAP promotes antimicrobial, immunomodulatory, anti-inflammatory, and wound-healing effects. Moreover, CAP bears antineoplastic properties which may be applied as a potential intraoperative option in the treatment of wound and resection margins during surgery of urological tumors. Some properties such as the penetration depth in various biological tissues, the effect on physiological healthy tissue, and the molecular mode of action regarding signalling and effector pathways are the subject of further investigation. CAP treatment effectively attenuates malignant cell growth. As an intraoperative application, CAP may represent a promising option particularly for the treatment of tissue regions that are close to critical structures (e. g., nerves, adjacent organs). The present review article summarizes the current status of CAP-related studies in the field of urological oncology.

Implementation of minimally invasive percutaneous nephrolithotomy (MIP): comparison of the initial learning curve with the later on clinical routine in a tertiary centre.

OBJECTIVE: We report on the comparison of clinical results of the early phase of implementation of minimally invasive PNL (MIP) in a mentor-based approach with the later on clinical routine in a tertiary centre. PATIENTS AND METHODS: From January 2010 until January 2015 MIP was performed in 190 patients. Stone and patient characteristics were recorded in prospective manner. Perioperative complications were recorded within the Clavien-Classification. The first 120 consecutive patients undergoing MIP were evaluated and divided into three groups of 40 patients each. Mentor-based introduction of MIP was done within the first 40 patients (group A). Further patients were treated on routine clinical practice basis (group B and C). Treatment outcome was compared within the three groups. RESULTS: The groups did not significantly differ with regard to patient characteristics, operation time and decline in haemoglobin. In the mentor-based series mean stone size was 21.7 ± 12.6 vs. 15.6 ± 7.9 and 16.1 ± 8.4 mm in group B and C (p = 0.033). Primary stone-free rates were 65, 87.5 and 87.5% for the three groups (p = 0.015). Stone-free rate was higher in smaller and simple stones. Overall, complication rate was 41.7% including 36.7% Clavien grade I and II complications. CONCLUSIONS: MIP can be implemented safe and effectively with mentor-based approach. MIP has a high safety profile, which allows high safety and efficacy of MIP at the time of implementation.

Virucide properties of cold atmospheric plasma for future clinical applications.

Cold atmospheric plasma (CAP) has been repeatedly identified to bear powerful microbicidal efficacy on bacteria including multidrug resistant organisms and fungi on non-living surfaces, in biofilms as well as on contaminated and infected tissues. CAP furthermore was found to stimulate wound healing in chronic wounds and exerted anti-neoplastic effects on numerous tumor entities. Thus, CAP represents a promising medical tool for many clinical and therapeutic issues. Studies about CAP effects on virus particles recently were in arrears, but to date increasingly move into the focus of interest. Apparently, CAP treatment is followed by a promising virus inactivation and contributes to tissue regeneration. Here we review the current state of science concerning the so far investigated CAP effects on different virus species and virus-associated disorders. J. Med. Virol. 89:952-959, 2017. © 2017 Wiley Periodicals, Inc.

Jump in the fire--heat shock proteins and their impact on ovarian cancer therapy.

Ovarian cancer (OC) is a major problem in gynecological oncology. Options for diagnosis and treatment of advanced stages and thus for patient prognosis have not been improved substantially over the past decades. Heat shock proteins (HSP) are characterized as stress-induced molecular chaperones performing cell survival factor functions. In cancer cells, various crucial and clinically important cell responses are vitally influenced and modulated by HSPs, e.g., cell growth and treatment resistance. Despite the limited knowledge on HSPs in OC progression, their roles as biomarkers, prognostic factors and their drug target properties appears promising for future clinical applications and therapeutic approaches.

miRNA-145 is downregulated in atypical and anaplastic meningiomas and negatively regulates motility and proliferation of meningioma cells.

Meningiomas are frequent, mostly benign intracranial or spinal tumors. A small subset of meningiomas is characterized by histological features of atypia or anaplasia that are associated with more aggressive biological behavior resulting in increased morbidity and mortality. Infiltration into the adjacent brain tissue is a major factor linked to higher recurrence rates. The molecular mechanisms of progression, including brain invasion are still poorly understood. We have studied the role of micro-RNA 145 (miR-145) in meningiomas and detected significantly reduced miR-145 expression in atypical and anaplastic tumors as compared with benign meningiomas. Overexpression of miR-145 in IOMM-Lee meningioma cells resulted in reduced proliferation, increased sensitivity to apoptosis, reduced anchorage-independent growth and reduction of orthotopic tumor growth in nude mice as compared with control cells. Moreover, meningioma cells with high miR-145 levels had impaired migratory and invasive potential in vitro and in vivo. PCR-array studies of miR145-overexpressing cells suggested that collagen type V alpha (COL5A1) expression is downregulated by miR-145 overexpression. Accordingly, COL5A1 expression was significantly upregulated in atypical and anaplastic meningiomas. Collectively, our data indicate an important anti-migratory and anti-proliferative function of miR-145 in meningiomas.

[Transforming growth factor ß in prostate cancer: cellular effects and basic molecular mechanisms]. / "Transforming growth factor ß" im Prostatakarzinom : Zelluläre Wirkungen und molekulare Grundlagen.

The multifunctional cytokine transforming growth factor ß (TGFß) plays a dual role in prostate cancer (PCa), cell growth and tumorigenesis, reflected by its opposing properties of anti-oncogenic (e.g. growth inhibition and apoptosis) and pro-oncogenic effects (e.g. proliferation, cell motility and remodelling of the microenvironment). In the later stages of PCa, TGFß loses anti-proliferative and thereby tumor-suppressive functions and shifts to a tumorigenic phenotype, mainly initiated by cross-talk between TGFß signalling and other proliferation signal transduction pathways, such as mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signalling. Although TGFß plays an important role in tumor progression little is known about the underlying effects of TGFß in the molecular pathology of PCa.

Evolution and simplified terminology of natural orifice transluminal endoscopic surgery (NOTES), laparoendoscopic single-site surgery (LESS), and mini-laparoscopy (ML).

INTRODUCTION: Natural orifice transluminal endoscopic surgery (NOTES) and laparoendoscopic single-site surgery (LESS) are the next steps in the evolution of laparoscopic surgery, promising reduced morbidity and improved cosmetic result. The inconsistent terminology initially used led to confusion. Understanding the technical evolution, the current status and a unified and simplified terminology are key issues for further acceptance of both approaches. OBJECTIVE: To present LESS and NOTES in its historical context and to clarify the associated terminology. METHOD: Extensive literature search took place using the PubMed. Several hundred publications in general surgery and urology regarding LESS are present including the expert opinion of members the European Society of Uro-technology (ESUT). RESULTS: The increasing interest on NOTES and LESS is reflected by a raising number of publications during the last 4 years. The initial confusion with the terminology of single-incision surgery represented a significant issue for further evolution of the technique. Thus, consortiums of experts searched a universally acceptable name for single-incision surgery. They determined that 'laparoendoscopic single-site surgery' (LESS) was both scientifically accurate and colloquially appropriate, the term being also ratified by the NOTES working group (Endourological Society) and the ESUT. For additional use of instruments, the terms hybrid NOTES and hybrid LESS should be used. Any single use of miniaturized instruments for laparoscopy should be called mini-laparoscopy. DISCUSSION: The evolution of LESS and most likely NOTES to a new standard of minimally invasive surgery could represent an evolutionary step even greater than the one performed by the establishment of laparoscopy over open surgery.

Thulium laser enucleation of the prostate (ThuLEP): transurethral anatomical prostatectomy with laser support. Introduction of a novel technique for the treatment of benign prostatic obstruction.

BACKGROUND: Transurethral removal of prostatic tissue is the treatment choice for benign prostatic enlargement and benign prostatic obstruction. Urodynamic results are directly linked to the amount of removed tissue which, however, is directly associated with intra- and postoperative morbidity. Transurethral laser operations of the prostate offer the advantage of decreased bleeding complications and the possibility to treat patients with bleeding disorders or anticoagulative treatment. The aim of the article is to present a novel technique of complete transurethral removal of the transition zone (enucleation) with the support of the Thulium laser to combine complete anatomical enucleation and maximum urodynamic efficacy with minimal side-effects. MATERIALS AND METHODS: We present five distinct surgical steps for transurethral complete removal of the transition zone of the prostate (Thulium laser enucleation of the prostate, ThuLEP). Surgical steps are presented in chronological order with the help of intraoperative pictures. Laser energy of 70-90 W is only used for the incision at the verumontanum and bladder neck for removal of the middle lobe, whereas laser energy of 30 W was only used for coagulation of small vessel crossing the surgical capsule towards the transition zone and bladder neck for dissection of the lateral lobes. The lobes themselves are liberated by blunt dissection. CONCLUSIONS: ThuLEP offers complete removal of the transition zone no matter what prostatic size. The techniques combine maximum efficacy with minimal side-effects. Clinical results comparing ThuLEP with open prostatectomy or transurethral resection are awaited.

Cellular expression pattern of the protease-activated receptor 4 in the hippocampus in naïve rats and after global ischaemia.

A pronounced hippocampal expression of the Protease-activated Receptor 4 (PAR4) has recently been shown. In the current study the authors define the PAR4-associated sub-cellular structures and the influence of global ischaemia on the expression of PAR4. For that purpose the authors performed double labelling with fluorescence immunohistochemistry on tissue from naïve and post-ischaemic rats. In naïve animals - apart from the expression in granular and pyramidal neurons - there was an intensive lamellar expression of PAR4 in the CA4 region. Further analysis revealed that PAR4 was localised exclusively on mossy fibre axons in CA4 as detected by double-labelling with calbindin D-28k, but there was no overlap with markers of the neuronal cell body, interneurons, and post-synaptic, pre-synaptic and dendritic structures. Three and 14 days post ischaemia, CA1 neurons were degenerated and, consequently, there was no PAR4 signal in the CA1 band. In most other hippocampal structures no change in the PAR4 expression was detectable, with the exception of the CA3 region. Here, the fibre-associated PAR4 signal was diminished and disintegrated post ischaemia. Additionally, a redistribution from the membrane-bound neuronal localisation of PAR4 in control animals to a diffuse localisation all over the cell soma was revealed in the CA3 area 14 days post ischaemia. In conclusion, the current study proves for the first time that PAR4 is localised in mossy fibre axons. The altered expression in CA3 neurons after ischaemia indicates that PAR4 may be involved in post-ischaemic adaptive mechanisms.

[Thulium:YAG vaporesection of the prostate. First results]. / Thulium:YAG-Vaporesektion der Prostata. Erste Erfahrungen und Ergebnisse.

OBJECTIVES: Laser treatment of benign prostatic hyperplasia has been introduced. The thulium:YAG (Tm:YAG) laser combines the advantages of established laser systems. This study reports the preliminary results of vaporesection of the prostate, using this 2-microm continuous wave (cw) laser. MATERIAL AND METHODS: A total of 54 consecutive patients were treated with the Tm:YAG laser. The outcomes measured were resection time, catheter time, improvement in urinary flow rate (Q(max)), and post-voiding residual urine (PVR). International Prostate Symptom Score (IPSS) and Quality of Life Index (QoL) were recorded. RESULTS: The mean age was 61 years. Mean prostate volume was 30.3 cc. Average resection time was 52 min. Catheter time was 1.7 days. Qmax significantly improved from 4.2 to 20.9 ml on average. PVR decreased from 86 to 16 ml. IPSS and QoL score improved from 19.8 to 6.5 and 4 to 1, respectively. No patient required re-hospitalization. Transfusions were not necessary. CONCLUSIONS: These preliminary results indicate that Tm:YAG vaporesection of the prostate is safe and efficient. The 18-month follow-up data showed major improvement in voiding symptoms and QoL. Longer follow-up is needed to prove durability of these promising results.

Interobserver reproducibility of Gleason grading: evaluation using prostate cancer tissue microarrays.

OBJECTIVES: Due to PSA screening and increased awareness, prostate cancer (PCa) is identified earlier resulting in smaller diagnostic samples on prostate needle biopsy. Because Gleason grading plays a critical role in treatment planning, we undertook a controlled study to evaluate interobserver variability among German pathologists to grade small PCas using a series of tissue microarray (TMA) images. METHODS: We have previously demonstrated excellent agreement in Gleason grading using TMAs among expert genitourinary pathologists. In the current study, we identified 331 TMA images (95% PCa and 5% benign) to be evaluated by an expert PCa pathologist and subsequently by practicing pathologists throughout Germany. The images were presented using the Bacus Webslide Browser on a CD-ROM. Evaluations were kept anonymous and participant's scoring was compared to the expert's results. RESULTS: A total of 29 German pathologists analysed an average of 278 images. Mean percentage of TMA images which had been assigned the same Gleason score (GS) as done by the expert was 45.7%. GSs differed by no more than one point (+/-1) in 83.5% of the TMA samples evaluated. The respondents were able to correctly assign a GS into clinically relevant categories (i.e. <7, 7, >7) in 68.3% of cases. A total of 75.9% respondents under-graded the TMA images. Gleason grading agreement with the expert reviewer correlated with the number of biopsies evaluated by the pathologist per week. Years of diagnostic experience, self-description as a urologic pathologist or affiliation with a university hospital did not correlate with the pathologist's performance. CONCLUSION: The vast majority of participants under-graded the small tumors. Clinically relevant GS categories were correctly assigned in 68% of cases. This raises a potentially significant problem for pathologists, who have not had as much experience evaluating small PCas.

FlexGuard: a new laser insertion sheath: functional aspects in ureterorenoscopy (URS).

The evolution of flexible ureteroscopes led to a widespread use for the management of upper urinary tract abnormalities. The cost of purchase, maintenance and the durability of these instruments has become a major issue. This work describes a new device to avoid damages due to incorrect use of the Holmium laser during insertion of the laser fibre. A laser fibre with an optical core of 271 and 430 muicrom outside diameter was slid inside the FlexGuard laser fibre insertion sheath (LISA laser products, Germany). The outside diameter of the sheath measures 2.7 F (0.9 mm) and 2.1 F (0.7 mm) luminal diameter. The distal fibre tip was brought up to a position app. 2 mm inside the distal end of the sheath. The loaded sheath was pushed through the working channel of various ureteroscopes which were in maximum deflection. With the insertion sheath protruding about 2 mm from the distal tip of the URS the fibre was effortless forwarded out of the sheath to approach the stone. Once the laser fibre was in position, the sheath was removed, to increase the volume of irrigation fluid during laser lithotripsy. The radius of curvature (ROC) of the URS in maximum deflection and the integrity of the working channel was investigated. Using the insertion sheath the laser fibre reached the working position without any recognition of scratching or resistance. The integrity of the ureterorenoscopes was checked thoroughly be manually operated manometry. No damage of the inner surface of the working channel occurred. The ROC of the instrument did not change significantly during this procedure. After removal of the sheath the ROC remained stable. With the extended use of ureteroscopy, durability and repair costs are of concern. Damage resulting from incorrect use of laser fibres is a major issue in this respect. FlexGuard proved to avoid this damage in all flexible ureteroscopes investigated without limiting their mobility.

Oncological and functional results of open, robot-assisted and laparoscopic radical prostatectomy: does surgical approach and surgical experience matter?

The treatment of prostate cancer has undergone a fundamental change in the last decade. New surgical and nonsurgical minimal invasive methods have evolved. As the methodology of the different treatments is commonly known to urologists, this article focuses on oncological and functional outcome of open retropubic (ORP), trans- or extraperitoneal endoscopical (LRP), and robot-assisted radical prostatectomy (RALP), based on personal experience and review of the literature. A MEDLINE search was performed to review the literature on LRP and RALP between 1982 and 2007 with special emphasis on oncological and functional results, technical considerations, comparison of LRP and RALP to ORP, laparoscopic training, historical aspects, and cost-efficiency of the techniques. Based on diligent training and proctoring programs, a continuous dissemination of laparoscopic techniques takes place. There is a trend towards the extraperitoneal access in most of the minimal invasive programs at least in the European community. Mid-term outcomes of LRP and short-term outcomes of RALP achieved equivalence to open surgery with regards to complications, oncologic and functional results. Distinct advantages of LRP include less postoperative pain, lower transfusion rates, shorter convalescence, and better cosmetics. In contrast to RALP, LRP reaches cost-equivalence with open surgery in selected centers. LRP and RALP reproduce the short-term results of open surgery while providing the advantages of a minimal access. Video-assisted teaching improves the transfer of anatomical knowledge and technical knowhow, but the discussion about the longer learning curve for laparoscopy handling remains. The future will show if European centers adopt the use of robots comparable to the United States.

No improvement of functional and histological outcome after application of the metabotropic glutamate receptor 5 agonist CHPG in a model of endothelin-1-induced focal ischemia in rats.

The role of group I metabotropic glutamate receptors (mGluRs) in neurodegeneration is as yet unclear as mGluR1/5 antagonists and agonists yielded contradictory effects in different disease models. In the present study, we examined the neuroprotective potency of the selective mGluR5 agonist, (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), in endothelin-1(ET-1)-induced focal ischemia in rats. In addition to the effect of CHPG on the histologically defined infarct size, we studied its influence on sensorimotor impairments in the ladder rung walking test at late time points up to 4 weeks after the ischemic insult. Rats were treated i.c.v. with an injection of 1mM CHPG beginning 10min after the application of ET-1. Histological analyses 4 weeks after ET-1-induced ischemia demonstrated only a small, insignificant reduction in infarct size after CHPG application. In accordance with this result, there were no significant effects of the used CHPG concentration on sensorimotor impairments in the ladder rung walking test. In conclusion, our data point to the restricted value of CHPG as a neuroprotectant after transient focal ischemia and to the importance of evaluating neuroprotective effects at late post-ischemic time points.

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression.

Chronic inflammation increases the risk of cancer and many cancers, including prostate cancer, arise at sites of chronic inflammation. Inducible nitric oxide synthase (iNOS) is an enzyme dominantly expressed during inflammatory reactions. Although synthesis of high amounts of nitric oxide (NO) by iNOS has been demonstrated in pathophysiological processes, such as acute or chronic inflammation, autoimmune diseases or tumorigenesis, the role of iNOS activity in most of these diseases is poorly understood. Analysing prostate cancer biopsies by immunohistochemistry we found iNOS protein expression in tumor cells strongly paralleled by nitrotyrosine suggesting that iNOS is fully active. In vitro, NO inhibits androgen receptor-dependent promoter activity and prostate specific antigen production as well as DNA-binding activity of the androgen receptor (AR) in a concentration-dependent manner. Inhibition of the activity of androgen receptor-dependent reporter constructs is neither owing to diminished AR protein levels nor owing to an inhibition of its nuclear import. In addition, NO inhibits the proliferation of androgen receptor-positive prostate cancer cells significantly more efficiently than proliferation of androgen receptor-negative prostate cancer cells. In summary, our findings suggest that intratumoral iNOS activity favors development of prostate cancer cells that are able to proliferate androgen receptor-independently, thereby promoting prostate tumor progression.

Transurethral microwave thermotherapy for the treatment of BPH: still a challenger?

Minimally invasive therapies for treatment of benign prostatic hyperplasia (BPH) compete with the gold standard transurethral resection of the prostate (TURP). Comparisons of efficacy and safety have broadened the knowledge of different treatment modalities. Concerns of quality of life such as unaltered sexual function as well as cost considerations drive the market to develop techniques of lower level invasiveness. Among the competitors the office based transurethral microwave thermotherapy (TUMT) provides the broadest scale of scientific data. Numerous manufacturers sell various modifications of this technology. According to different clinical studies TUMT proved to be an effective, safe, and durable therapy for the treatment of lower urinary tract symptoms (LUTS) secondary to BPH. However, TURP still holds the steadier long-term results and is more effective to reduce obstruction as well as other LUTS.

Effects of WNT/beta-catenin pathway activation on signaling through T-cell factor and androgen receptor in prostate cancer cell lines.

Dysregulation of the WNT/beta-catenin pathway is thought to contribute to prostate cancer progression. Mutations of beta-catenin occurring in 5-7% of advanced prostate cancers may act by stimulating TCF-dependent and/or androgen receptor (AR)-dependent transcription. Using a reporter gene approach we found overexpressed mutated beta-catenin to enhance AR-regulated probasin-promoter activity in the AR-positive prostate cancer cell line 22Rv1, particularly at low androgen levels. In 22Rv1 cells mutated beta-catenin was able to stimulate TCF-dependent transcription but was unable to do so in LNCaP cells where it activates the AR. Since beta-catenin mutations are rare in vivo, we studied further possible routes of WNT-pathway modulation. Higher concentrations of LiCl, a GSK3beta-inhibitor, were required to activate TCF-dependent rather than AR-dependent reporter constructs. In 22Rv1 overexpression of E-cadherin repressed androgen-dependent transcription, but did not inhibit transcription of TCF-dependent reporter genes as in bladder cancer cell lines. Interestingly, Wnt-3a stimulated proliferation selectively in the AR-positive prostate cancer cell lines 22Rv1 and LNCaP, even though TCF-dependent reporter gene transcription was not induced in LNCaP cells. In summary, the data from our study support the idea that activation of WNT/beta-catenin signaling in AR-positive prostate cancer cells may predominantly act through AR-dependent mechanisms rather than classical TCF-dependent mechanisms.

The androgen receptor in hormone-refractory prostate cancer: relevance of different mechanisms of androgen receptor signaling (Review).

The last decade has brought increased awareness to prostate cancer as a significant health problem. Prostate cancer is very heterogeneous in its etiology and progression, but androgen signaling appears to be a common key element in its development and progression. Blocking of androgen signaling results in a decrease in tumor volume as well as a decline in serum PSA in the majority of patients with prostate cancer. Today, endocrine therapy involves androgen depletion by orchiectomy or by treatment with LHRH-analoga as well as blockade of the androgen receptor (AR) with anti-androgens. However, during these treatments almost all tumors relapse to a hormone-insensitive state. The mechanisms that lead from initially androgen-sensitive to androgen-unresponsive tumor cell growth have been partly elucidated by new insights into the molecular mechanisms of androgen receptor signaling over the past several years. In addition to androgen receptor mutations that broaden the ligand-specificity of the AR, androgen-independent transactivation of the AR by peptide growth factors such as epidermal growth factor and insulin-like growth factor-I has been discovered. Furthermore, analysis of proteins that interact with the AR led to the isolation of coactivator proteins that mediate transcriptional activation by the AR. The following review will discuss the elements involved in androgen receptor signaling and summarize the present knowledge of their biological and clinical relevance in advanced prostate cancer.