Therapy For Treatment Of Prostate Cancer Research Articles

Investigating the bioactive compounds from Capsicum annum as a probable alternative therapy for prostate cancer treatment: a structure-based drug design approach

Abstract Prostate cancer remains a significant global health challenge, necessitating the exploration of novel therapeutic approaches. Androgen receptor (AR) signaling plays a critical role in prostate cancer progression and is a primary target for therapy. This study investigates the potential of phytochemicals from Capsicum annuum (Bell pepper) along with two common standand drugs (Apalutamide and Enzalutamide) as inhibitors of the human androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Utilizing computer-aided drug design techniques, molecular docking studies were conducted to evaluate the binding affinities of selected ligands against AR (PDB ID: 1XOW) and PSMA (PDB ID: 2XEI), their ADMET properties, drug-likeness, oral bioavailability, and bioactivity profiles were also examined. Coumaroylquinic acid and 5-O-caffeoylquinic acid methyl-ester emerged as top-performing ligands, demonstrating strong binding affinities of −9.4 kcal/mol and −9.2 kcal/mol, respectively, against PSMA. Additionally, molecular dynamics simulations provided insights into the stability of protein-ligand complexes, with Coumaroylquinic acid exhibiting a stable binding conformation throughout the simulation. These findings suggest the potential of C. annuum phytochemicals, particularly Coumaroylquinic acid and 5-O-caffeoylquinic acid methyl-ester, as promising inhibitors of PSMA. Moreover, other ligands (Caffeoylglucoside and 1-O-galloyl-beta-d-glucose) identified in the study demonstrate interactions with AR, highlighting a multifaceted approach to prostate cancer treatment. Overall, this study underscores the potential of C. annuum phytochemicals as a source of novel therapeutic agents for prostate cancer, laying the groundwork for further lead optimization efforts.

ROS-responsive polyprodrug micelles carrying suicide genes in combination with chemotherapy and gene therapy for prostate cancer treatment.

Prostate cancer is the most common malignant tumor in the male reproductive system, and its incidence increases with age. Chemotherapy is one of the main strategies for treating prostate cancer, but it often comes with unavoidable side effects. Nanocarriers can improve drug utilization and targeting, and cationic carriers can also carry nucleic acids for gene therapy. In this study, we prepared a cationic micelle constructed from a polyprodrug that can deliver both chemotherapeutic drugs and nucleic acids simultaneously. The typical chemotherapeutic drug hydroxycamptothecin (HCPT) was linked by reactive oxygen species (ROS)-responsive coupling agents and forms amphiphilic block polymers with low molecular weight polyethyleneimine (PEI). The resulting cationic micelles can be triggered by high levels of ROS in tumor cells and collapse to release HCPT and suicide genes to kill tumor cells. At the same time, it reduces the killing of normal cells. In prostate cancer cells, it has been confirmed that the co-delivery carriers combined with chemotherapy and a suicide gene prodrug system have shown an ideal therapeutic effect on prostate cancer.

Clinical significance of prostate volume and testosterone reduction on lower urinary tract symptoms in patients with prostate cancer undergoing androgen deprivation therapy

To investigate the effect of both prostate volume and serum testosterone changes on lower urinary tract symptoms in patients with prostate cancer undergoing androgen deprivation therapy. A total of 167 patients who received androgen deprivation therapy for prostate cancer treatment from January 2010 to August 2020 were enrolled in this retrospective study. Changes in the International Prostate Symptom Score (IPSS) in the patient groups stratified by prostate volume and the amount of testosterone reduction were assessed every 4 weeks until 12 weeks after androgen deprivation therapy initiation. Longitudinal mixed models were used to assess the adjusted effects of prostate volume and testosterone reduction on IPSS change. All mean values of IPSS-total score (IPSS-total), voiding subscore (IPSS-vs), and storage subscore (IPSS-ss) significantly decreased from baseline to week 12 in both patients with small (< 33 mL) and large (≥ 33 mL) prostates. The mean values of IPSS-total, IPSS-vs, and IPSS-ss similarly decreased in patients with large prostate with a baseline IPSS-total of ≥ 13. However, in those with small prostate, IPSS-ss specifically remained unchanged, while IPSS-total and IPSS-vs significantly decreased. In addition, only in patients with small prostate (< 33 mL), patients with lesser testosterone reduction (< Δ400 ng/dL) showed greater improvement in IPSS-ss by 7.5% compared with those with greater testosterone reduction (≥ Δ400 ng/dL). In conclusion, although androgen deprivation therapy generally improves lower urinary tract symptoms, it may worsen specifically storage symptoms in patients with relatively small prostate and greater testosterone reduction. Our finding suggests that testosterone may influence lower urinary tract symptoms in these patients.

Boosting the Immune Response-Combining Local and Immune Therapy for Prostate Cancer Treatment.

Due to its slow progression and susceptibility to radical forms of treatment, low-grade PC is associated with high overall survival (OS). With the clinical progression of PC, the therapy is becoming more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by e.g., immune evasion through Treg cells, synthesis of immunosuppressive mediators, and the defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of tumors and eliminate the immunosuppressive properties of the TME. In the settings of PC treatment, this can be commonly achieved with radiation therapy (RT). In addition, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), and irreversible electroporation (IRE) were shown to boost the anti-cancer response. Nevertheless, the present guidelines restrict their application to the context of a clinical trial or a prospective cohort study. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

Alternatives to whole gland treatment for localized prostate cancer: a review of novel focal therapies.

The mainstays of the management of clinically localized prostate cancer have historically rested upon active surveillance, radiation therapy, or radical prostatectomy. Although both radiation and surgical treatment of localized prostate cancer can achieve excellent oncologic outcomes, the subsequent potential adverse effects of urinary stress incontinence and erectile dysfunction are unappealing to patients. This has led to investigational studies centered upon focal treatment of the cancerous lesion, with the aim to improve quality-of-life outcomes. In this review, we describe numerous novel modalities, including nanoparticle ablation and irreversible electroporation, which are being utilized for the focal treatment of clinically localized prostate cancer. Although many of these novel therapies are in their investigational infancy, several have revealed very promising results both in their post-treatment pathologic outcomes as well as objective quality-of-life measures. Initial data regarding novel focal therapy for prostate cancer treatment show promising short-term outcomes in regards to oncologic and quality-of-life assessments. Further investigational studies are needed to determine inclusion criteria for the selection of optimal candidates.

Castration mediated schwann cell dedifferentiation leads to slower nerve conduction, decreased neuritogenesis, and nitrergic neuron loss

ABSTRACT Introduction/Objectives Low levels of androgens due to androgen deprivation therapy for prostate cancer treatment or due to aging lead to erectile dysfunction (ED). Castration, a preclinical model of low androgens, induces ED due to damage to pelvic nerves and a loss of erectogenic nitrergic nerves. Schwann cells (SC) release neurotrophic factors to promote pelvic nerve growth and survival. It is unknown how testosterone deficiency impacts SC function. This study determines how testosterone deficiency influences SC phenotype and trophic support in neuronal regeneration. We hypothesize testosterone deficiency will decrease myelinated pelvic SC populations, delay penile nerve conduction and reduce pelvic nitrergic neurons. Methods Male Sprague Dawley rats (12 wks) were divided into control (CON) and surgical castration (CAST) groups. All experiments were performed six weeks following castration. Dorsal penile nerves (DPN; 15-16 mm) were excised, placed in a sylgard dish containing oxygenated buffer and conduction velocity of myelinated fast fibers was assessed (n=8 per group). The major pelvic ganglia (MPG) were collected and dissociated into SC or neurons. Dissociated neurons were grown on laminin coated coverslips. To determine whether SCs could provide trophic support, we co-cultured neurons on top of confluent SCs. We assessed the following co-culture groups: CON SC + CON MPG, CON SC + CAST MPG, CAST SC + CON MPG (n=4 per group, cultured in triplicate). After 72 hours, all cultures were fixed and stained with beta tubulin class III, neuronal nitric oxide synthase (nNOS), and tyrosine hydroxylase (TH) to assess neurite length and branching, nitrergic and sympathetic neuron populations, respectively. Dissociated SC were characterized via qPCR for markers of all SC (Sox10), myelinated SC (Krox20), and dedifferentiated SC (glial fibrillary acidic protein; GFAP). Results CAST slows DPN myelinated fast fiber conduction velocity. In dissociated cultured MPG neurons, castration reduces both neurite length and number of branches. Interestingly, CAST MPG neurons co-cultured with CON SC restore neurite length and branching to same level as CON MPG neurons co-cultured with CON SC; however, CAST SC do not impact CON MPG neurite length. CAST MPG neurons co-cultured with CON SC and CON MPG neurons co-cultured with CAST SC both have less nitrergic neurons than CON SC + CON MPG neurons. CAST does not impact the number of TH neurons in single or co-cultured conditions. CAST reduces gene expression of Sox10, myelinated SC, and dedifferentiated SC. Conclusions CAST markedly impairs penile nerve conduction, reduces neurite outgrowth and the proportion of pro-erectile nitrergic neurons. Healthy SC are able to rescue neuritogenesis but not the survival of nitrergic neurons. Additionally, healthy MPG neurons plated on CAST SC have a reduced number of nitrergic neurons. We believe CAST SC are undergoing a phenotypic switch from a myelinated neurotrophic form into dedifferentiated SC promoting neuritogenesis and loss of nitrergic neurons. Preserving the myelinated SC phenotype may prevent impaired nerve damage and subsequent ED in patients with testosterone deficiency. Disclosure Work supported by industry: no.

"In Physically Active Patients Predisposed to Bone- Muscle Attrition Receiving Androgen Deprivation Therapy for Prostate Cancer Treatment, Prospective MRI Evaluation Does Not Demonstrate Significant Muscle Alteration"

"In Physically Active Patients Predisposed to Bone- Muscle Attrition Receiving Androgen Deprivation Therapy for Prostate Cancer Treatment, Prospective MRI Evaluation Does Not Demonstrate Significant Muscle Alteration"

Dextran-Curcumin Nanosystems Inhibit Cell Growth and Migration Regulating the Epithelial to Mesenchymal Transition in Prostate Cancer Cells.

Functional nanocarriers which are able to simultaneously vectorize drugs to the site of interest and exert their own cytotoxic activity represent a significant breakthrough in the search for effective anticancer strategies with fewer side effects than conventional chemotherapeutics. Here, we propose previously developed, self-assembling dextran-curcumin nanoparticles for the treatment of prostate cancer in combination therapy with Doxorubicin (DOXO). Biological effectiveness was investigated by evaluating the cell viability in either cancer and normal cells, reactive oxygen species (ROS) production, apoptotic effect, interference with the cell cycle, and the ability to inhibit cell migration and reverse the epithelial to mesenchymal transition (EMT). The results proved a significant enhancement of curcumin efficiency upon immobilization in nanoparticles: IC50 reduced by a half, induction of apoptotic effect, and improved ROS production (from 67 to 134%) at low concentrations. Nanoparticles guaranteed a pH-dependent DOXO release, with a more efficient release in acidic environments. Finally, a synergistic effect between nanoparticles and Doxorubicin was demonstrated, with the free curcumin showing additive activity. Although in vivo studies are required to support the findings of this study, these preliminary in vitro data can be considered a proof of principle for the design of an effective therapy for prostate cancer treatment.

Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer.

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1-AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA-AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC. SIGNIFICANCE: MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.

Down-regulation of ACACA suppresses the malignant progression of Prostate Cancer through inhibiting mitochondrial potential.

Background and aim: Silencing the expression of ACACA inhibits cell proliferation and induces apoptosis in prostate cancer LNCaP cells. However, the role of ACACA in other prostate cancer cells is not fully understood. Also, the effect of knocking down ACACA gene on mitochondria remains unclear. This study aimed to discover the specific role of ACACA gene in prostate cancer (PCa) DU145 and PC3 cells as well as its effects on mitochondrial potential.Methods: The expression of ACACA gene was detected in human prostate cancer tissue microarrays and assessed in different clinical stages. Then, prostate cancer cell lines with low expression of ACACA were constructed to evaluate the changes in their cell cycle, proliferation, and metabolites. The effect of ACACA on tumor formation in vivo was analyzed. Also, mito-ATP production, mitochondrial staining, and mtDNA, nicotinamide adenine dinucleotide (NAD+/NADH), and reactive oxygen species (ROS) levels were detected.Results: ACACA was expressed more strongly in prostate cancer tissues. The expression level of ACACA was higher in patients with advanced PCa than in patients with lower grades. The proliferation ability reduced in ACACA-knockdown cells. In in vivo tests, the tumor volume and weight were lower in the experimental group than in the control group. Mito-ATP production decreased significantly after ACACA suppression, mtDNA levels and MitoTracker staining decreased in the experimental group. The ratio of NAD+/NADH and ROS levels were upregulated in the experimental group.Conclusion: Targeting ACACA gene and mitochondria might serve as a novel therapy for prostate cancer treatment.

Dual role of reactive oxygen species in autophagy and apoptosis induced by compound PN in prostate cancer cells

Pharbitis nil (L.) Choisy (PN) is used as a traditional herb in East Asia and exhibits anti-parasitic, purgative, diuretic, anti-inflammatory, and anti-cancer activities. However, the molecular mechanisms underlying the anti-cancer activity are not well understood. This study aims to elucidate the effects of reactive oxygen species (ROS), generated after treatment with the compound PN, on the induction of apoptosis and autophagy, which are pathways that underly the mechanisms of cell death and cell survival in human prostate cancer cells. The MTT assay and western blot analysis were used to assess the effects of compound PN on cell viability and the expression of apoptosis- and autophagy-related proteins in prostate cancer PC-3 cells. The effects of PN on apoptosis (via annexin V/propidium iodide staining), autophagy (via acridine orange staining), and ROS (via DCFH-DA staining) were investigated using flow cytometry. Compound PN induced the production of intracellular and mitochondrial ROS leading to increased apoptosis and autophagy in PC-3 cells. Interestingly, pretreatment with N-acetyl-l-cysteine (NAC), an intracellular ROS scavenger, enhanced compound PN-induced apoptosis, but reduced levels of autophagy. In contrast, pretreatment with diphenyleneiodonium (DPI), an inhibitor of mitochondrial ROS, reduced compound PN-induced apoptosis and enhanced autophagy. Inhibition of autophagy led to acceleration of apoptosis in a PN-induced ROS-dependent manner. Compound PN-induced ROS production from two different sources, an intracellular source and mitochondrial source. ROS production in these differing locations had different effects on apoptosis and autophagy. They acted either by promoting cell death or cell survival through regulating autophagy to either escape or enhance apoptotic cell death. This crosstalk between ROS-activated signals in apoptosis and autophagy induction by PN provides new insights into the molecular mechanisms of this compound and suggests that PN may be a potential therapy for prostate cancer treatment.

Pre-clinical Research on Bladder Toxicity After Radiotherapy for Pelvic Cancers: State-of-the Art and Challenges.

Despite the dramatic advancements in pelvic radiotherapy, urinary toxicity remains a significant side-effect. The assessment of clinico-dosimetric predictors of radiation cystitis (RC) based on clinical data has improved substantially over the last decade; however, a thorough understanding of the physiopathogenetic mechanisms underlying the onset of RC, with its variegated acute and late urinary symptoms, is still largely lacking, and data from pre-clinical research is still limited. The aim of this review is to provide an overview of the main open issues and, ideally, to help investigators in orienting future research. First, anatomy and physiology of bladder, as well as the current knowledge of dose and dose-volume effects in humans, are briefly summarized. Subsequently, pre-clinical radiobiology aspects of RC are discussed. The findings suggest that pre-clinical research on RC in animal models is a lively field of research with growing interest in the development of new radioprotective agents. The availability of new high precision micro-irradiators and the rapid advances in small animal imaging might lead to big improvement into this field. In particular, studies focusing on the definition of dose and fractionation are warranted, especially considering the growing interest in hypo-fractionation and ablative therapies for prostate cancer treatment. Moreover, improvement in radiotherapy plans optimization by selectively reducing radiation dose to more radiosensitive substructures close to the bladder would be of paramount importance. Finally, thanks to new pre-clinical imaging platforms, reliable and reproducible methods to assess the severity of RC in animal models are expected to be developed.

Light-Induced Therapies for Prostate Cancer Treatment.

Prostate cancer (PC) is one of the most widespread tumors affecting the urinary system and the fifth-leading cause from cancer death in men worldwide. Despite PC mortality rates have been decreasing during the last years, most likely due to an intensification of early diagnosis, still more than 300,000 men die each year because of this disease. In this view, researchers in all countries are engaged in finding new ways to tackle PC, including the design and synthesis of novel molecular and macromolecular entities able to challenge different PC biological targets, while limiting the extent of unwanted side effects that significantly limit men's life quality. Among this field of research, photo-induced therapies, such as photodynamic and photothermal therapies (PDT and PTT), might represent an important advancement in PC treatment due to their extremely localized and controlled cytotoxic effect, as well as their low incidence of side effects and tumor resistance occurrence. Based on these considerations, this review aims to gather and discuss the last 5-years literature reports dealing with the synthesis and biological activity of molecular conjugates and nano-platforms for photo-induced therapies as co-adjuvant or combined therapeutic modalities for the treatment of localized PC.

Bladder filling during radiation therapy for prostate cancer treatment: Assessment via bladder ultrasound scanner.

147 Background: Prostate cancer patients treated with external beam radiation therapy are instructed to present daily with a full bladder to decrease small bowel and bladder toxicity and to increase reproducibility of treatment. However, older patients may have difficulty presenting with full bladders and variation of bladder volume with treatment is unknown. The objective of this study was to assess bladder filling at the time of radiation treatment (RT) using a bladder ultrasound in patients undergoing treatment for prostate cancer. Methods: Patients with prostate cancer were prospectively enrolled prior to CT simulation from January to August 2017. Bladder volume was recorded during CT simulation and daily immediately prior to RT. Patients were instructed to drink 8-12 ounces of water 30-60 minutes prior to RT. Three bladder volume measurements were recorded daily and averaged at the time of each treatment. Average bladder volume during treatment and the number of treatments with low bladder volumes ( &lt; 50cc, &lt; 60cc, and &lt; 100cc) were reported using descriptive statistics. Results: A total of 13 patients completed a median of 42 days of RT during the study period, resulting in 550 daily bladder volumes. Ten patients were treated definitively and 3 with salvage radiation after prostatectomy. The median age of patients in the study was 72 years. Older patients were statistically more likely to present with low bladder volumes, with percentage of treatments with a bladder volume less than 50cc, 60cc, and 100cc being 29%, 42%, and 66% compared to only 4%, 7%, and 18% in patients aged &lt; 70 (P &lt; 0.01). The average bladder volume at the time of CT simulation was 176cc ± 57cc and the average volume during treatment was 140cc± 93cc, which was not statistically different (P = 0.28). The bladder volume did not significantly change over the course of treatment. Conclusions: Older patients (age 70+) with prostate cancer were more likely to present for RT with low bladder volumes in this prospective study. Our findings suggest that older patients should receive extra counseling about bladder filling and/or may require less bladder filling at the time of CT simulation to provide more accurate bowel dosimetry measurements.

MP62-17 A NEW INSIGHT OF CELL-CELL INTERACTIONS IN TUMOR STROMA OF PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2016MP62-17 A NEW INSIGHT OF CELL-CELL INTERACTIONS IN TUMOR STROMA OF PROSTATE CANCER Kenichiro Ishii, Takeshi Sasaki, Manabu Miki, Manabu Kato, Hideki Kanda, Kiminobu Arima, Taizo Shiraishi, and Yoshiki Sugimura Kenichiro IshiiKenichiro Ishii More articles by this author , Takeshi SasakiTakeshi Sasaki More articles by this author , Manabu MikiManabu Miki More articles by this author , Manabu KatoManabu Kato More articles by this author , Hideki KandaHideki Kanda More articles by this author , Kiminobu ArimaKiminobu Arima More articles by this author , Taizo ShiraishiTaizo Shiraishi More articles by this author , and Yoshiki SugimuraYoshiki Sugimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.925AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Activation of tumor-stroma interactions plays a critical role in the promotion of tumorigenesis. During primary cancer progression, cancer cells generate the carcinoma-associated fibroblasts (CAFs) in adjacent normal fibroblasts, and then CAFs support the proliferation and invasion of adjacent cancer cells in a paracrine fashion. In the tumor microenvironment, CAFs communicate not only with cancer cells but also surrounding stromal cells. The tumor stroma consists not only of CAFs but also normal fibroblasts, myofibroblasts, or smooth muscle cells. Unfortunately, we know very little about cell-cell interactions in the tumor stroma. To investigate stromal cell-cell interactions, we performed in vitro co-culture experiments using primary cultured human prostate cancer (PCa) CAFs PCaSC-8 cells, and commercialized normal human prostate stromal cells PrSC and PrSMC. METHODS PCaSC-8 cells were isolated from needle biopsy samples of a PCa patient. PrSC and PrSMC were purchased from Lonza Group Ltd. Co-culture experiments were performed using cell culture inserts. RESULTS Cell growth of PrSC and PrSMC was significantly increased by co-culturing with PCaSC-8 cells, while that of PCaSC-8 cells was not affected by co-culturing neither with PrSC or PrSMC. In the condition of co-cultures with PCaSC-8 cells, mRNA expression of TNC, ACTA2 and FGF2 was significantly increased in PrSC. In contrast, expression of EGF, FGF7, HGF, and IGF1 mRNA was significantly increased in PrSMC. In PCaSC-8 cells, mRNA expression of ACTA2, HGF, and IGF1 was significantly increased by co-culturing with PrSC. In both PrSC and PrSMC, protein production of IL-6 was significantly increased by co-culturing with PCaSC-8 cells. In addition, VEGF in PrSC was significantly increased by co-culturing with PCaSC-8 cells. In PCaSC-8 cells, IL-6 and VEGF were significantly increased by co-culturing with PrSC. CONCLUSIONS We previously reported that PCa cells induced CAF-like differentiation in normal fibroblasts, i.e. PCa cells generate the CAFs. Here our results have demonstrated that normal fibroblasts co-cultured with CAFs become activated and exhibit the biochemical characteristics consistent with CAFs, i.e. CAFs also induce CAF-like differentiation in normal fibroblasts. Of interest, normal fibroblasts boost the biochemical characteristics of CAFs. Those cell-cell interactions in the tumor stroma suggest that CAFs may spread autonomously. In this cell competition, CAFs must be winner in the tumor stroma. Identifying mechanisms underlying the cell competition in the tumor stroma is an initial step toward designing CAF-targeted therapy for treatment of PCa. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e819 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kenichiro Ishii More articles by this author Takeshi Sasaki More articles by this author Manabu Miki More articles by this author Manabu Kato More articles by this author Hideki Kanda More articles by this author Kiminobu Arima More articles by this author Taizo Shiraishi More articles by this author Yoshiki Sugimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Local radiotherapy increases the level of autoantibodies to ribosomal P0 protein but not to heat shock proteins, extracellular matrix molecules and EGFR/ErbB2 receptors in prostate cancer patients

Prostate cancer is a common cancer among men in developed countries. Although hormonotherapy and radiotherapy (RT) represent valid therapies for prostate cancer treatment, novel immunological approaches have been explored. The development of clinical trials employing cancer vaccines has indicated that immune response to tumor antigens can be boosted and that vaccine administration can improve patient survival. Immune response to tumor antigens could also be enhanced after standard therapies. In the present study, we determined the occurrence of antibodies to extracellular matrix (ECM) molecules, heat shock protein (HSP), ribosomal P0 protein, EGFR, ErbB2 and prostate-specific antigen (PSA) in 35 prostate cancer patients prior to and following local RT and hormonotherapy. We demonstrated that immunity to P0, ECM molecules [collagens (C) CI, CIII, CV, fibronectin (FN) and laminin (LM)] and to HSP90 was associated with malignancy in untreated patients. None of the patient sera showed antibodies to EGFR, while 2 and 1patients showed reactivity to ErbB2 and PSA, respectively. We also demonstrated that 8months after therapy the IgG serum levels to CI, CIII, FN and HSP90 significantly decreased. Conversely, the level of P0 autoantibodies increased after therapy in 10patients. Five of the 10patients with increased levels of P0 autoantibodies were treated with RT plus hormonotherapy. Treatment of patients did not change the levels of antibodies against EGFR, ErbB2 and PSA. Our results indicated that the modification of antibody level to self molecules after standard treatment of prostate cancer patients is influenced by the type of antigen. Ribosomal P0 protein appears to be a high immunogenic antigen and its immunogenicity increases following RT. In addition, 10patients with increased levels of autoantibodies to P0 showed PSA mean levels lower than the remaining 25patients at 18months. This study may contribute to a better understanding of the immunobiological behavior of prostate cancer patients following standard treatment.

788 ABERRANT ACTIVATION OF PARACRINE LOOP BETWEEN PROSTATE CANCER CELLS AND CARCINOMA-ASSOCIATED FIBROBLASTS BY OVEREXPRESSION OF STROMAL INTERLEUKIN-6

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2012788 ABERRANT ACTIVATION OF PARACRINE LOOP BETWEEN PROSTATE CANCER CELLS AND CARCINOMA-ASSOCIATED FIBROBLASTS BY OVEREXPRESSION OF STROMAL INTERLEUKIN-6 Kenichiro Ishii, Yoichi Iwamoto, Manabu Kato, Kazuhiro Iguchi, Atsushi Mizokami, Kiminobu Arima, Taizo Shiraishi, and Yoshiki Sugimura Kenichiro IshiiKenichiro Ishii Tsu, Japan More articles by this author , Yoichi IwamotoYoichi Iwamoto Tsu, Japan More articles by this author , Manabu KatoManabu Kato Tsu, Japan More articles by this author , Kazuhiro IguchiKazuhiro Iguchi Gifu, Japan More articles by this author , Atsushi MizokamiAtsushi Mizokami Ishikawa, Japan More articles by this author , Kiminobu ArimaKiminobu Arima Tsu, Japan More articles by this author , Taizo ShiraishiTaizo Shiraishi Tsu, Japan More articles by this author , and Yoshiki SugimuraYoshiki Sugimura Tsu, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.876AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In the tumor microenvironment, activation of tumor-stromal interactions is considered to play a critical role in the promotion of tumorigenesis. During primary cancer progression, cancer cells generate the carcinoma-associated fibroblasts (CAFs) in adjacent normal fibroblasts, and then CAFs support the proliferation and invasion of adjacent cancer cells in a paracrine fashion. The serum level of interleukin-6 (IL-6) is a significant prognostic factor for prostate cancer (PCa) patients with disseminated diseases, suggesting positive roles of IL-6 in the aberrant activation of paracrine loop between PCa cells and CAFs. In this study, we investigated the relationship between responsiveness of PCa cells to stromal IL-6 and cellular AR signaling. METHODS The androgen-low-sensitive E9 cells were obtained from androgen-sensitive LNCaP cell population by limiting dilution method in regular culture condition. In contrast, the androgen-insensitive AIDL cells were established from LNCaP cells by continuous passaging in hormone-depleted condition. PCaSC-8 and PCaSC-9 cells were primary cultured from different human PCa specimens. RESULTS IL-6 and VEGF protein levels in both PCaSC-8 and PCaSC-9 cells were generally higher than normal human prostate stromal cells PrSC. In contrast to stromal cells, no IL-6 secretion from LNCaP, E9, and AIDL was detected. IL-6 treatment (10 ng/mL) suppressed cell proliferation of LNCaP and E9 accompanied with changes of cell morphology, i.e. induction of neuroendocrine-like differentiation. Induction of PSA secretion was observed only in IL-6-treated LNCaP. VEGF secretion was significantly increased in both IL-6-treated LNCaP and AIDL. A selective alpha1-adrenoceptor antagonist naftopidil (10 μM) but not tamsulosin suppressed IL-6-induced VEGF secretion in AIDL. CONCLUSIONS In this study, we have shown the evidence that secretions of IL-6 and VEGF from primary cultured CAFs derived PCa patients are generally higher than normal fibroblasts. Our results suggest that overexpression of stromal IL-6 might increase VEGF secretion from adjacent PCa cells in a paracrine fashion. Using LNCaP sublines, E9 and AIDL, differing in androgen-sensitivity, we demonstrated here that IL-6-induced VEGF secretion from PCa cells might be through cellular AR signaling-independent pathway. Identifying mechanisms underlying the aberrant activation of paracrine loop between PCa cells and CAFs is an initial step toward designing CAF-targeted therapy for treatment of PCa. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e322-e323 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenichiro Ishii Tsu, Japan More articles by this author Yoichi Iwamoto Tsu, Japan More articles by this author Manabu Kato Tsu, Japan More articles by this author Kazuhiro Iguchi Gifu, Japan More articles by this author Atsushi Mizokami Ishikawa, Japan More articles by this author Kiminobu Arima Tsu, Japan More articles by this author Taizo Shiraishi Tsu, Japan More articles by this author Yoshiki Sugimura Tsu, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Contemporary outcomes of focal therapy in prostate cancer: what do we know so far…

Despite the enthusiasm for an organ preserving approach to prostate cancer treatment, studies that support the supposition that this approach will offer patients the "Trifecta" of prostate cancer therapy are lacking. Review of published peer review literature using a combination of the terms "Focal", "Prostate Cancer", "Therapy", "Cryoablation", "HIFU", and "Clinical Trial". To date only three prospective clinical trials of subtotal prostate cryoablation and one of subtotal high-intensity focused ultrasound (HIFU) have been reported along with one retrospective review of patients treated in a subtotal manner with cryotherapy. In total, these reports present only 166 patients. All current strategies for focally ablative therapy for prostate cancer treatment have varied in their eligibility criteria and in the amount of tissue targeted for destruction and/or preservation. Very little is published on either the oncologic outcomes or quality-of-life outcomes following subtotal prostate ablation to justify its growing popularity with both patients and physicians. Significant research and clinical trials that examine patient selection, biopsy strategies, and ablative energies, along with oncologic efficacy and quality-of-life outcomes are needed. This article will review the current state of knowledge regarding subtotal prostate ablative strategies.

WE‐D‐201C‐02: MRI‐Guided Transurethral Diagnosis and Treatment of Localized Prostate Cancer

Minimally‐invasive, image‐guided treatments for localized prostate cancer that provide local control with a low side‐effect profile would have a major impact in improving disease management. Accurate localization of disease with imaging coupled with technologies capable of precise treatment could enable evolution of prostate cancer treatment from a whole gland to a more targeted approach. MRI‐guided transurethral ultrasound therapy is such a technology in which high‐intensity ultrasound energy is delivered to the prostate from a device inserted into the urethra. The goal of the treatment is to generate a prescribed spatial pattern of thermal coagulation in the gland. The treatment is performed in a closed‐bore MR imager to obtain quantitative temperature maps during ultrasound heating of the prostate. This temperature information is used by the treatment delivery system to adapt the exposure conditions dynamically during treatment to compensate for changes in blood flow, tissue absorption and thermal conduction. Previous numerical, phantom, and canine studies have demonstrated that this approach offers a high degree of spatial treatment accuracy (±1–2 mm). Recent clinical evaluation of the technology has confirmed the feasibility of performing this treatment in humans. The desire to deliver more targeted treatments in the prostate for reduced morbidity requires accurate localization of disease, ideally with medical imaging. A unique opportunity that exists in transurethral ultrasound therapy is to generate shear waves in the adjacent prostate gland through vibration of the device. These shear waves can be imaged with MRI and quantitative stiffness maps can be calculated for localization of disease, or evaluation of the pattern of thermal coagulation in the gland. Initial experiments have been performed in phantoms and canines to explore the feasibility of this concept. This presentation will introduce the concept of transurethral ultrasound therapy and will review the results obtained with this technology. In addition the potential to combine this therapy with diagnostic approaches such as MR elastography will be discussed.Learning Objectives:1. Describe the role of high‐intensity ultrasound therapy for prostate cancer treatment.2. Describe the technology for transurethral ultrasound therapy3. Explain the potential role of prostate MR elastography for prostate imaging/diagnosis using transurethral devices4. Describe the potential of quantitative MR temperature feedback in achieving closed‐loop heating in vivo, and challenges in its implementation

SU‐FF‐J‐56: Integrating Real‐Time Tracking Into Image Guided Radiation Therapy for Prostate Cancer Treatment

Purpose: To investigate how a real‐time tracking technique, based on implanted transponders, could be effectively integrated into the current process for image‐guided radiation treatment of prostate cancer. Method and Materials: Current prostate IGRT process includes MR‐imaging for prostate delineation, CT simulation for treatment planning, and daily on‐board kV‐ and CBCT‐imaging for target alignment. The real‐time tracking technique uses implanted radiofrequency transponders and an external detector array (Calypso4D) to monitor prostate motion. This study assess (1) magnetic field induced displacement of transponders during MR imaging, (2) image artifacts introduced by transponders in CT and MR images, (3) image artifacts caused by the transponder detector antenna array in in‐room kV and CBCT images. A tissue‐equivalent phantom mimicking prostate tissue stiffness was constructed and implanted with 3 operational transponders prior to phantom solidification. CT scans were performed before and immediately after 1.5T and 3.0T MR imaging of the phantom, which used prostate‐typical pulse sequences. Transponder positions were independently localized by the Calypso system and by CT/CT image registration and evaluated for MR induced displacement. Image artifacts by modality were assessed in phantom and patient cases. Results: MR‐induced position displacements are minimal (&lt;1.0mm) for both 1.5T and 3T scanners. The temperature variation due to MRI RF heating is &lt;0.1°C. MR image artifacts are most significant with the gradient echo sequence, and have radii ∼1.5cm and length∼4.0cm. The detector array caused significant deterioration in the CBCT image quality. The visibility of transponders and bony anatomy was not affected on the kV images. Major changes of the IGRT protocol: (a) MR and CT imaging back‐to‐back for treatment planning is changed to MR prior‐ and CT post‐implant; (b) Daily CBCT prior‐ is changed to post‐treatment and with detector array removed. Conclusion: There are tradeoffs in the clinical IGRT flow to accommodate and minimize the substantial imaging artifacts.