Pathophysiology Of Prostate Cancer Research Articles

Patient-Derived Conditionally Reprogrammed Cells in Prostate Cancer Research.

Prostate cancer (PCa) remains a leading cause of mortality among American men, with metastatic and recurrent disease posing significant therapeutic challenges due to a limited comprehension of the underlying biological processes governing disease initiation, dormancy, and progression. The conventional use of PCa cell lines has proven inadequate in elucidating the intricate molecular mechanisms driving PCa carcinogenesis, hindering the development of effective treatments. To address this gap, patient-derived primary cell cultures have been developed and play a pivotal role in unraveling the pathophysiological intricacies unique to PCa in each individual, offering valuable insights for translational research. This review explores the applications of the conditional reprogramming (CR) cell culture approach, showcasing its capability to rapidly and effectively cultivate patient-derived normal and tumor cells. The CR strategy facilitates the acquisition of stem cell properties by primary cells, precisely recapitulating the human pathophysiology of PCa. This nuanced understanding enables the identification of novel therapeutics. Specifically, our discussion encompasses the utility of CR cells in elucidating PCa initiation and progression, unraveling the molecular pathogenesis of metastatic PCa, addressing health disparities, and advancing personalized medicine. Coupled with the tumor organoid approach and patient-derived xenografts (PDXs), CR cells present a promising avenue for comprehending cancer biology, exploring new treatment modalities, and advancing precision medicine in the context of PCa. These approaches have been used for two NCI initiatives (PDMR: patient-derived model repositories; HCMI: human cancer models initiatives).

Elevated periprostatic androgens, sneaky testosterone and its implications.

A subset of men with prostate cancer have elevated periprostatic androgens compared with levels in peripheral blood (termed the sneaky T phenomenon), which are associated with poor clinical outcomes after radical prostatectomy. These androgens are of testicular origin and reach the prostate, presumably through venous shunting. Varicocele physiology is accompanied by increased hydrostatic pressure within the pelvic venous system, providing a theoretical mechanistic explanation for the sneaky T phenomenon. These observations suggest a potential role for varicocele in contributing to prostate cancer pathophysiology through sneaky T, which if proved, could be a further indication for varicocele repair. Sneaky T can help to explain the differences in the natural history of benign or malignant prostatic diseases between individuals and could be a tool when deciding on the therapeutic course to take.

Natural carotenoids as a potential chemopreventive agent for prostate cancer: A literature review

Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer death among men worldwide. While the exact etiology of PCa remains unclear, various factors contribute to the onset of the disease. These factors include modifiable risk factors such as physical activity, diet, obesity, smoking, alcohol consumption, and exposure to environmental agents. In addition, unmodifiable risk factors such as age and ethnicity play a role, with men of African ancestry being more susceptible to the disease. Despite the availability of potential treatment options, prevention is of utmost importance in reducing the incidence of PCa. Researchers have turned their attention to carotenoids, which are natural compounds derived from fruit and vegetables such as citrus, tomato, and green leafy vegetables, due to their potential chemopreventive effects. Multiple phase II clinical trials have indicated a reduced incidence and progression of diagnosed PCa in patients. Laboratory studies on PCa cell lines have demonstrated that carotenoids induce apoptosis and reduce cellular accumulation and adhesion of PCa cells in a dose-dependent manner. In this literature review, we assess the chemopreventive potential of the most common carotenoids: α-carotene, β-carotene, lycopene, lutein, and β-cryptoxanthin, which are often found in a heterogeneous mixture. We also discuss their potential clinical use as well as challenges related to their safety and bioavailability. Overall, a better understanding of the etiology and pathophysiology of PCa will lead to the development of improved preventative strategies and treatments for the disease.

Cancer Stem Cells and Androgen Receptor Signaling: Partners in Disease Progression.

Cancer stem cells exhibit self-renewal, tumorigenesis, and a high differentiation potential. These cells have been detected in every type of cancer, and different signaling pathways can regulate their maintenance and proliferation. Androgen receptor signaling plays a relevant role in the pathophysiology of prostate cancer, promoting cell growth and differentiation processes. However, in the case of prostate cancer stem cells, the androgen receptor negatively regulates their maintenance and self-renewal. On the other hand, there is evidence that androgen receptor activity positively regulates the generation of cancer stem cells in other types of neoplasia, such as breast cancer or glioblastoma. Thus, the androgen receptor role in cancer stem cells depends on the cellular context. We aimed to analyze androgen receptor signaling in the maintenance and self-renewal of different types of cancer stem cells and its action on the expression of transcription factors and surface markers associated with stemness.

The potential value of some adipokines and cytokines as diagnostic biomarkers for prostate cancer

Abstract Background: The role of Adipokines and proinflammatory cytokines is said to be crucial in the development of prostate cancer. Vaspin, Chemerin, Omentin, Interleukins IL-1β, interleukin-8 (IL8), Colony-stimulating factor (GM-CSF) and CC chemokine ligand 18 (CCL18) have all been proven to take part in tumor growth and progression. Aim of the study: The study aimed to explore circulating novel adipocytokines, such as serum of Vaspin, Chemerin and Omentin levels in patients with prostate cancer and to determine the level of selected proinflammatory cytokines (CCL18, IL-8, IL1, and GM-CSF). Methods: Three groups were included in the current study: Group (1) :32 patients with metastatic prostate cancer who received chemotherapy, Group (2): 30 untreated patients with nonmetastatic prostate cancer, and Group (3): 30 healthy controls. ELISA technique was used to assess serum levels of Vaspin, Chemerin, Omentin, CCL18, IL-8, IL1, and GM-CSF). Results: The Prostate cancer group exhibited higher serum levels of Vaspin, Chemerin, Omentin, CCL18, IL-8, IL1, and GM-CSF compared to the control group. Chemotherapy-treated patients exhibited significantly increased levels of the pro-inflammatory cytokines (IL-8) and Adipokines (Vaspin and Omentin) and decreased levels of the pro-inflammatory cytokines (IL-1) and Adipokines (Chemerin). The correlation analysis showed a significant positive correlation of serum Chemerin with Vaspin (r = 0.957, p-value<0.0001), IL-8 (r = 0.9475, p-value < 0.0001) and IL-1β (r = 0.7771, p-value < 0.0029). Omentin and GS-CSF levels showed a non-significant positive correlation with Chemerin level (r = 0.1259; p = 0.6967).) and (r = 0.4247; p = 0.1688), respectively. While significant negative correlation was found between (Chemerin) with CCL-18 (r = –0.7916, p = 0.0022), serum Vaspin was significantly and negatively correlated with the levels of CCL-18 (r = –0.9349, p < 0.0001), whereas there was a significant positive correlation between Vaspin level with IL-8 (R=0.9995, p <0.0001); IL-1β(r = 0.561, p = 0.0057). The data demonstrated that Vaspin was positively and non-significantly correlated with the level of GS-CSF (r = 0.1437, p =0.656); serum Omentin was significantly and negatively correlated with the levels of GS-CSF (r = –0.8447, p = 0.0005), and CCL-18 (r= –0.7058, p = 0.0103), whereas there was a non-significant positive correlation between Omentin level with IL-8 (r = 0.4364, p = 0.1561). The data demonstrated that Omentin was negatively and non-significantly correlated with the level of IL-1β (r= –0.5366, p =0.0786). Conclusions: This study indicated increased levels of serum Vaspin, Chemerin, Omentin, Interleukins IL-1β, interleukin-8 (IL8), Colony-stimulating factor (GM-CSF) and CC chemokine ligand 18 (CCL18) in patients with Prostate cancer. These findings suggest that the cytokines, and adipokines, whose levels were elevated in the chemotherapy-treated patients may be involved in the pathophysiology of prostate cancer. Vaspin, Chemerin and Omentin might play an important role in Prostate cancer progression through their association with Adipokines and proinflammatory cytokines. More studies are needed to investigate the possible role of Vaspin, Chemerin and Omentin as potential markers in the development of Prostate cancer.

Investigating the Association of rs4962416 and rs6465657 with Prostate Adenocarcinoma in the Iranian Population

Background: Prostate cancer is one of the most commonly diagnosed malignancies in the developed world. Despite other risk factors like age, diet, environment and the pathogenesis of prostate cancer, recent advances in molecular genetics suggest that genetic inheritance plays an important role in prostate cancer. Objective: We attempted to analyze the association of SNPs rs4962416 and rs6465657 in the development of prostate cancer. A better understanding of the association of SNPs in prostate cancer susceptibility may improve risk prediction, improve precision mapping, and provide new insights into the underlying pathophysiology of prostate cancer. To date, no one has investigated these two SNPs in the Iranian populations, and according to the heterogeneity that exists, SNPs in communities should be examined separately. Methods: This case-control study includes 82 people with prostate adenocarcinoma as cases and 96 people with benign prostatic hyperplasia (BPH) as controls. Genotyping of each participant was done by TETRA ARMS-PCR method and for statistical analysis chi-squared, Fisher’s exact logistic regression was used to find the SNPs associated with prostate cancer. Result: The frequency of the polymorphisms rs4962416 and rs6465657 in the prostate adenocarcinoma group was evaluated compared to the BPH control group (p-value < 0.05%) to choose the meaningful SNP. For rs4962416, we didn’t find any meaningful association with prostatic cancer (p=0.402) but for rs6465657 there was a significant difference between genotype frequency (p=0.001). Conclusion: rs6465657 polymorphism which is associated with prostate cancer, can be chosen as a biomarker for this cancer and there should be more investigation on this SNP as these results need to be confirmed in a larger population.

Targeting the Androgen Signaling Axis in Prostate Cancer.

Activation of the androgen receptor (AR) and AR-driven transcriptional programs is central to the pathophysiology of prostate cancer. Despite successful translational efforts in targeting AR, therapeutic resistance often occurs as a result of molecular alterations in the androgen signaling axis. The efficacy of next-generation AR-directed therapies for castration-resistant prostate cancer has provided crucial clinical validation for the continued dependence on AR signaling and introduced a range of new treatment options for men with both castration-resistant and castration-sensitive disease. Despite this, however, metastatic prostate cancer largely remains an incurable disease, highlighting the need to better understand the diverse mechanisms by which tumors thwart AR-directed therapies, which may inform new therapeutic avenues. In this review, we revisit concepts in AR signaling and current understandings of AR signaling-dependent resistance mechanisms as well as the next frontier of AR targeting in prostate cancer.

Preclinical and Clinical Research Models of Prostate Cancer: A Brief Overview.

The incidence and mortality from prostate cancer (PCa) are on the rise which poses a major public health concern worldwide. In this narrative review, we have summarized the characteristics of major in vitro and in vivo PCa models including their utility in developing treatment strategies. Androgens, particularly, testosterone and dihydrotestosterone (DHT) activate the androgen receptor (AR) signaling pathway that facilitates the development and progression of castration resistant PCa. Several enzymes namely, CYP17A1, HSD17B, and SRD5A are essential to furnishing DHT from dehydroepiandrosterone in the classical pathway while DHT is formed from androstanediol in the backdoor pathway. The advancement in delineating the molecular heterogeneity of PCa has been possible through the development of several in vitro and in vivo research models. Generally, tissue culture models are advantageous to understand PCa biology and investigate the efficacy and toxicity of novel agents; nevertheless, animal models are indispensable to studying the PCa etiology and treatment since they can simulate the tumor microenvironment that plays a central role in initiation and progression of the disease. Moreover, the availability of several genetically engineered mouse models has made it possible to study the metastasis process. However, the conventional models are not devoid of limitations. For example, the lack of heterogeneity in tissue culture models and the variation of metastatic characteristics in xenograft models are obviously challenging. Additionally, due to the racial and ethnic disparities in PCa pathophysiology, a new model that can represent PCa encompassing different ethnicities is urgently needed. New models should continue to evolve to address the genetic and molecular complexities as well as to further elucidate the finer details of the steroidogenic pathway associated with PCa.

Androgen-Responsive Oncogenic lncRNA RP11-1023L17.1 Enhances c-Myc Protein Stability in Prostate Cancer

Long noncoding RNAs (lncRNAs) have been found as novel participants in the pathophysiology of prostate cancer (PCa), which is predominantly regulated by androgen and its receptor. The biological function of androgen-responsive lncRNAs remains poorly understood. Here, we identified that lncRNA RP11-1023L17.1, which is highly expressed in PCa. RP11-1023L17.1 expression, can be directly repressed by the androgen receptor in PCa cells. RP11-1023L17.1 depletion inhibited the proliferation, migration, and cell cycle progression, and promoted the apoptosis of PCa cells, indicating that RP11-1023L17.1 acts as an oncogene in PCa cells. Microarray results revealed that RP11-1023L17.1 depletion downregulated the c-Myc transcription signature in PCa cells. RP11-1023L17.1 depletion-induced cellular phenotypes can be overcome by ectopically overexpressed c-Myc. Mechanistically, RP11-1023L17.1 represses FBXO32 mRNA expression, thereby enhancing c-Myc protein stability by blocking FBXO32-mediated c-Myc degradation. Our findings reveal the previously unrecognized roles of RP11-1023L17.1 in c-Myc-dependent PCa tumorigenesis.

Gene variation impact on prostate cancer progression: Lymphocyte modulator, activation, and cell adhesion gene variant contribution.

BackgroundThe view of prostate cancer (PCa) progression as a result of the interaction of epithelial cancer cells with the host's immune system is supported by the presence of tumor infiltrating lymphocytes (TILs). TILs fate and interaction with the tumor microenvironment is mediated by accessory molecules such as CD5 and CD6, two signal‐transducing coreceptors involved in fine‐tuning of T cell responses. While the nature of the CD5 ligand is still controversial, CD6 binds CD166/ALCAM, a cell adhesion molecule involved in progression and dissemination of epithelial cancers, including PCa. The purpose of the present study was to determine the role of CD5, CD6, and CD166/ALCAM gene variants in PCa.MethodsFunctionally relevant CD5 (rs2241002 and rs2229177), CD6 (rs17824933, rs11230563, and rs12360861) and CD166/ALCAM (rs6437585, rs579565, rs1044243, and rs35271455) single nucleotide polymorphisms (SNPs) were genotyped in germline DNA samples from 376 PCa patients. Their association with PCa prognostic factors, namely biochemical recurrence (BCR) and International Society of Urological Pathology (ISUP) grade was analyzed by generalized linear models and survival analyses.ResultProportional hazards regression showed that the minor CD6 rs12360861AA and CD166/ALCAM rs579565AA genotypes were associated with earlier BCR, with hazard ratios of 2.65 (95% CI: 1.39–5.05, p = 0.003) and 1.86, (95% CI: 1.02–3.39, p = 0.043), respectively. Individually, none of the analyzed SNPs was significantly associated with ISUP grade, but haplotype analyses revealed association of the CD5 rs2241002C‐rs2229177T haplotype with ISUP grade ≥2, with odds ratio of 1.52 (95% CI: 1.05–2.21, p = 0.026).ConclusionThe results show the impact on PCa aggressiveness and recurrence brought about by gene variants involved in modulation of lymphocyte activation (CD5, CD6) and immune‐epithelial cell adhesion (CD166/ALCAM) in PCa aggressiveness and recurrence, thus supporting a role for host immune response in PCa pathophysiology.

Detection and characterization of latency stage of EBV and histopathological analysis of prostatic adenocarcinoma tissues

The pathophysiology of prostate cancer involves both genetic and acquired factors, including pathogens, such as viruses. A limited number of studies have shown the presence of Epstein-Barr virus (EBV) in prostate cancer tissues. However, there is a dearth of data exploring EBV latency profile in prostate cancer, and the relationship of EBV with histopathological features of prostate cancer. In this study, prostate cancer and benign prostatic hyperplasia (BPH) samples were screened for the presence of EBV, followed by the characterization of the EBV latency profile and analysis of histopathological parameters in EBV-positive and EBV-negative groups. A conventional PCR strategy was employed using virus-specific primers to screen EBV in 99 formalin-fixed paraffin-embedded (FFPE) prostate cancer and 33 BPH samples received for histopathological analysis during the years 2019–2020. Subsequently, cDNA samples were used in a qPCR array to analyze the expression of EBV latency-associated genes to map the latency profile EBV maintains in the samples. Finally, statistical analyses were performed to determine the correlation between EBV and several histopathological features of the samples. EBV was detected in 39% of prostate cancer and 24% of BPH samples. The histopathological analysis of prostate cancer samples identified all samples as prostatic adenocarcinoma of acinar type, while statistical analyses revealed EBV-positive samples to exhibit significantly higher (p < 0.05) Gleason major and total Gleason scores as compared to EBV-negative samples. In the EBV-positive samples, variable expression patterns of latency-associated genes were observed, where most of the samples exhibited EBV latency II/III-like profiles in prostate cancer, while latency-II-like profiles in BPH samples. This study suggests a high prevalence of EBV in prostate samples, where EBV exhibited latency II/III-like profiles. Furthermore, EBV-positive samples exhibited a higher Gleason score suggesting a possible link between EBV and the onset/progression of prostate cancers. However, future functional studies are required to understand the role of the EBV gene expression profile in the onset/progression of prostate cancer.

Abstract 4013: Functional heterogeneity of cancer-associated stromal subtypes in the prostate cancer microenvironment

Abstract The stromal tumor microenvironment plays a central role in the development, progression and therapy resistance of prostate cancer (PCa), the second leading cause of cancer-related death in males in western nations. Functional and single cell RNA sequencing (scRNA-seq) studies unequivocally demonstrate the coexistence of functionally and spatially distinct fibroblast and mural cell states within the tumor microenvironment of various non-prostate tumors. Stromal cellular heterogeneity in PCa however remains poorly understood. This study therefore aimed to (1) comprehensively analyze stromal cell states within the PCa microenvironment and (2) to identify and characterize onco-supportive fibromuscular entities in respect to their potential clinical exploitation. Thus, we performed bulk tissue scRNA-seq on biopsy cores from benign and cancerous prostate tissue of 4 different patients. Analyses presented here focused on the fibroblast and mural cell clusters, which each delineated further into 2 subclusters. One fibroblast subcluster showed strong similarity to published signatures of inflammatory cancer-associated fibroblasts (iCAF). A closely related but distinct fibroblast subcluster exhibited hallmarks of benign interstitial fibroblasts with enrichment of GO terms such as antigen processing and presentation. Based on expression signatures and spatial localization via immunohistochemistry, the 2 mural cell subclusters (MCAM+) were identified as vascular smooth muscle cells (vSMCs) and dedifferentiated prostate SMCs/myofibroblasts. Notably, the gene signature of this latter subcluster correlated with increasing Gleason score and decreased disease-specific survival. On the basis of scRNA-seq data from this and independent datasets, panels of subcluster-specific markers were selected for validation studies via FACS, multiplex immunohistochemistry and quantitative real time PCR. Thus far, immunohistochemical studies validated not only the in vivo presence of the 4 distinct cellular states but also revealed their distinct spatial localization. We will present molecular and functional data from these ongoing analyses in (i) immortalized fibroblast and smooth muscle cell lines, (ii) heterogeneous ex vivo outgrowth cultures of primary PCa fibroblasts/myofibroblasts and (iii) primary cells from single cell suspensions of PCa biopsies enzymatically digested using an in-house approach optimized for maximal recovery of fibromuscular cells. These studies aim to evaluate the specificity, robustness and suitability of the chosen markers to delineate distinct tumor-relevant stromal cell subtypes enabling their functional contribution to PCa pathophysiology and clinical relevance to be assessed in future experiments. Citation Format: Elisabeth Damisch, Elena Brunner, Sieghart Sopper, Isabel Heidegger, Andreas Pircher, Georgios Fotakis, Zlatko Trajanoski, Sandra Theresa Deichsler, Georg Schäfer, Natalie Sampson. Functional heterogeneity of cancer-associated stromal subtypes in the prostate cancer microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4013.

Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer

Prostate cancer (PCa) progression relies on androgen receptor (AR) function, making AR a top candidate for PCa therapy. However, development of drug resistance is common, which eventually leads to development of castration‐resistant PCa. This warrants a better understanding of the pathophysiology of PCa that facilitates the aberrant activation of key signaling pathways including AR. MicroRNAs (miRNAs) function as regulators of cancer progression as they modulate various cellular processes. Here, we demonstrate a multidimensional function of miR‐30e through the regulation of genes involved in various signaling pathways. We noted loss of miR‐30e expression in prostate tumors, which, when restored, led to cell cycle arrest, induction of apoptosis, improved drug sensitivity of PCa cells and reduced tumor progression in xenograft models. We show that experimental upregulation of miR‐30e reduces expression of mRNAs including AR, FBXO45, SRSF7 and MYBL2 and a novel long noncoding RNA (lncRNA) HELLPAR, which are involved in cell cycle, apoptosis and ubiquitination, and the effects could be rescued by inhibition of miR‐30e expression. RNA immunoprecipitation analysis confirmed direct interactions between miR‐30e and its RNA targets. We noted a newly identified reciprocal relationship between miR‐30e and HELLPAR, as inhibition of HELLPAR improved stabilization of miR‐30e. Transcriptome profiling and quantitative real‐time PCR (qRT‐PCR) validation of miR‐30e‐expressing PCa cells showed differential expression of genes involved in cell cycle progression, apoptosis and ubiquitination, which supports our in vitro study. This study demonstrates an integrated function of miR‐30e on dysregulation of miRNA/lncRNA/mRNA axes that may have diagnostic and therapeutic significance in aggressive PCa.

The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer.

Our understanding of prostate cancer (PCa) has shifted from solely caused by a few genetic aberrations to a combination of complex biochemical dysregulations with the prostate metabolome at its core. The role of metabolomics in analyzing the pathophysiology of PCa is indispensable. However, to fully elucidate real-time complex dysregulation in prostate cells, an integrated approach based on metabolomics and other omics is warranted. Individually, genomics, transcriptomics, and proteomics are robust, but they are not enough to achieve a holistic view of PCa tumorigenesis. This review is the first of its kind to focus solely on the integration of metabolomics with multi-omic platforms in PCa research, including a detailed emphasis on the metabolomic profile of PCa. The authors intend to provide researchers in the field with a comprehensive knowledge base in PCa metabolomics and offer perspectives on overcoming limitations of the tool to guide future point-of-care applications.

Dysregulation of the miRNome unveils a crosstalk between obesity and prostate cancer: miR-107 asa personalized diagnostic and therapeutic tool

Prostate-specific antigen (PSA) is the gold-standard marker to screen prostate cancer (PCa) nowadays. Unfortunately, its lack of specificity and sensitivity makes the identification of novel tools to diagnose PCa an urgent medical need. In this context, microRNAs (miRNAs) have emerged as potential sources of non-invasive diagnostic biomarkers in several pathologies. Therefore, this study was aimed at assessing for the first time the dysregulation of the whole plasma miRNome in PCa patients and its putative implication in PCa from a personalized perspective (i.e., obesity condition). Plasma miRNome from a discovery cohort (18 controls and 19 PCa patients) was determined using an Affymetrix-miRNA array, showing that the expression of 104 miRNAs was significantly altered, wherein six exhibited a significant receiver operating characteristic (ROC) curve to distinguish between control and PCa patients (area under the curve [AUC] = 1). Then, a systematic validation using an independent cohort (135 controls and 160 PCa patients) demonstrated that miR-107 was the most profoundly altered miRNA in PCa (AUC = 0.75). Moreover, miR-107 levels significantly outperformed the ability of PSA to distinguish between control and PCa patients and correlated with relevant clinical parameters (i.e., PSA). These differences were more pronounced when considering only obese patients (BMI > 30). Interestingly, miR-107 levels were reduced in PCa tissues versus non-tumor tissues (n = 84) and in PCa cell lines versus non-tumor cells. In vitro miR-107 overexpression altered key aggressiveness features in PCa cells (i.e., proliferation, migration, and tumorospheres formation) and modulated the expression of important genes involved in PCa pathophysiology (i.e., lipid metabolism [i.e., FASN] and splicing process). Altogether, miR-107 might represent a novel and useful personalized diagnostic and prognostic biomarker and a potential therapeutic tool in PCa, especially in obese patients.

The Emerging Clinical Role of Spermine in Prostate Cancer.

Spermine, a member of polyamines, exists in all organisms and is essential for normal cell growth and function. It is highly expressed in the prostate compared with other organs and is detectable in urine, tissue, expressed prostatic secretions, and erythrocyte. A significant reduction of spermine level was observed in prostate cancer (PCa) tissue compared with benign prostate tissue, and the level of urinary spermine was also significantly lower in men with PCa. Decreased spermine level may be used as an indicator of malignant phenotype transformation from normal to malignant tissue in prostate. Studies targeting polyamines and key rate-limiting enzymes associated with spermine metabolism as a tool for PCa therapy and chemoprevention have been conducted with various polyamine biosynthesis inhibitors and polyamine analogues. The mechanism between spermine and PCa development are possibly related to the regulation of polyamine metabolism, cancer-driving pathways, oxidative stress, anticancer immunosurveillance, and apoptosis regulation. Although the specific mechanism of spermine in PCa development is still unclear, ongoing research in spermine metabolism and its association with PCa pathophysiology opens up new opportunities in the diagnostic and therapeutic roles of spermine in PCa management.

Increased phospholipase D activity contributes to tumorigenesis in prostate cancer cell models.

Prostate cancer (PCa) is the most frequent cancer among men and the first cause of death over 65. Approximately 90% of patients with advanced disease will develop bone metastasis, which dramatically reduces long-term survival. Therefore, effective therapies need to be developed, especially when disease is still well-localized. Phospholipase D (PLD), an enzyme that hydrolyzes phosphatidylcholine to yield phosphatidic acid, regulates several cellular functions as proliferation, survival, migration or vesicular trafficking. PLD is implicated in numerous diseases such as neurodegenerative, cardiovascular, autoimmune disorders or cancer. Indeed, PLD controls different aspects of oncogenesis including tumor progression and resistance to targeted therapies such as radiotherapy. PLD1 and PLD2 are the only isoforms with catalytic activity involved in cancer. Surprisingly, studies deciphering the role of PLD in the pathophysiology of PCa are scarce. Here we describe the correlation between PLD activity and PLD1 and PLD2 expression in PCa bone metastasis-derived cell lines C4-2B and PC-3. Next, by using PLD pharmacological inhibitors and RNA interference strategy, we validate the implication of PLD1 and PLD2 in cell viability, clonogenicity and proliferation of C4-2B and PC-3 cells and in migration capacity of PC-3 cells. Last, we show an increase in PLD activity as well as PLD2 protein expression during controlled starvation of PC-3 cells, concomitant with an augmentation of its migration capacity. Specifically, upregulation of PLD activity appears to be PKC-independent. Taken together, our results indicate that PLD, and in particular PLD2, could be considered as a potential therapeutic target for the treatment of PCa-derived bone metastasis.

Inhibition on JNK Mimics Silencing of Wnt-11 Mediated Cellular Response in Androgen-Independent Prostate Cancer Cells.

Prostate cancer (PCa) is one of the most common cancers among men, and one of the leading causes of cancer death for men. The c-Jun N-terminal kinase (JNK) pathway is required for several cellular functions, such as survival, proliferation, differentiation, and migration. Wnt-11, a member of the Wnt family, has been identified for its upregulation in PCa; however, downstream signalling of Wnt-11 remains to be fully characterized. In this study, we investigated the role of the JNK pathway as a potential downstream factor for Wnt-11 signalling. For this purpose, LNCaP, DU145, and PC-3 PCa cells and normal epithelial PNT1A cells were treated with a specific JNK kinase inhibitor: JNKVIII. Our results showed that JNK inhibition decreased mitochondrial membrane potential and promoted cell death in a cell type-dependent manner. We found that JNK inhibition led to an increase in autophagy and prevented epithelial–mesenchymal transition (EMT) in independently growing androgen cells. JNK inhibition and the silencing of Wnt-11 showed similar responses in DU145 and PC-3 cells and decreased metastasis-related biomarkers, cell migration, and invasion. Overall, our results suggest that JNK signalling plays a significant role in the pathophysiology of PCa by mediating Wnt-11 induced signals. Our data highlights that both the JNK pathway and Wnt-11 could be a useful therapeutic target for the combinatory application of current PCa.

Thiol Groups as a Biomarker for the Diagnosis and Prognosis of Prostate Cancer

Oxidative stress (OS) is associated with the onset of prostate cancer (PCa). The aims of this study are to examine whether OS biomarkers may be employed as external validating criteria for the diagnosis PCa. This case-control study recruited 204 subjects, 73 patients with PCa, 67 patients with benign prostate hyperplasia (BPH), and 64 healthy controls (HC) and assayed plasma prostate-specific antigen (PSA), protein thiol (−SH) groups, lipid hydroperoxides, carbonyl proteins (PCB), advanced oxidation protein products (AOPP), and total radical-trapping antioxidant parameter (TRAP). -SH groups were significantly and inversely associated with PSA levels. PCa was characterized by lowered -SH groups and red blood cell TRAP levels, and higher PSA, AOPP and PCB levels as compared with BPH and HC. Support vector machine with 10-fold cross-validation showed that PSA values together with -SH groups, PCB and AOPP yielded a cross-validation accuracy of 96.34% for the differentiation of PCa from BPH and HC. The area under the ROC curve using PSA and -SH differentiating PCa from BPH and controls was 0.945. Moreover, lowered -SH, but not PSA, are associated with PCa metastasis and progression. Inflammatory biomarkers were not associated with PCa or BPH. PCa, its progression and metastatic PCa are characterized by lowered antioxidant defenses, especially lowered thiol groups, and increased oxidative stress toxicity, suggesting that these processes play a key role in the pathophysiology of PCa. An algorithm based on -SH and PSA values may be used to differentiate patients with PCa from those with BPH and controls.

Abstract D084: Overall survival (OS) of African-American (AA) and Caucasian (CAU) men who received sipuleucel-T for metastatic castration-resistant prostate cancer (mCRPC)—final PROCEED analysis

Abstract BACKGROUND: Prostate cancer risk and mortality are higher in AAs versus CAUs. Post-hoc analyses of pooled Phase 3 data (n = 737) suggested substantial OS benefit for AA men receiving sipuleucel-T (n=33) vs placebo (n = 10) (McLeod 2012). Compared with pooled placebo patients (n = 249), number needed to treat for OS benefit at 3 years was 3 for AAs and 8 for all sipuleucel-T-treated patients (n = 488) (Moses 2017). Herein we analyzed PROCEED (NCT01306890), a large real-world registry, in which all patients received sipuleucel-T. Previously presented at ASCO Annual Meeting 2019 (Sartor 2019).METHODS: In PROCEED, 1902 mCRPC patients received 1 or more sipuleucel-T infusions. OS of all AA (n=221) and CAU (n=1649) men were compared. Baseline prostate-specific antigen (PSA), the most important prognostic variable for OS after sipuleucel-T (Schellhammer 2013), substantially differed by race. Thus, OS for a PSA-matched cohort (n=219 AA; n=438 CAU) was compared and univariable/multivariable analyses were performed. Post-sipuleucel-T use of OS-prolonging anticancer interventions was also assessed. RESULTS: After a median follow-up of 46.6 mo, median OS was 35.2 (all sipuleucel-T-treated AAs) and 29.9 mo (all sipuleucel-T-treated CAUs): HR 0.81, 95% CI 0.68–0.97; P=0.03. In the PSA-matched cohort, median OS was 35.3 and 25.8 mo, respectively (HR 0.70, 95% CI 0.57–0.86; p&amp;lt;0.001). Sipuleucel-T-treated AAs with lower baseline PSA had markedly longer median OS vs sipuleucel-T-treated CAUs. Among those with PSA less than or equal to median baseline PSA (29.48 ng/ml), median OS was 54.3 mo (AA) vs. 33.4 (CAUs); HR 0.52, 95% CI 0.37–0.72; p&amp;lt;0.001. Along with other known prognostic factors, AA race was independently associated with prolonged OS on detailed multivariable analyses (HR 0.60, 95% CI 0.48–0.74; p&amp;lt;0.001) and confirmed on sensitivity analyses. Post-sipuleucel-T life-prolonging anti-cancer therapies were balanced between groups. CONCLUSIONS: Sipuleucel-T-treated AAs had significantly improved OS vs sipuleucel-T-treated CAUs. This analysis marks the largest known racial difference in OS in response to any therapy for mCRPC, a finding with implications for both prostate cancer pathophysiology and cancer immunotherapy. REFERENCES: Sartor 2012 (DOI: 10.1200/JCO.2019.37.15_suppl.5035); McLeod 2012 (DOI: 10.1016/j.juro.2012.02.1051); Moses KA et al 2017 (DOI: 10.1016/j.urology.2016.07.045); Schellhammer 2013 (DOI: 10.1016/j.urology.2013.01.061) Citation Format: Oliver Sartor, Andrew J Armstrong, Chiledum Ahaghotu, David G McLeod, Matthew R Cooperberg, David F Penson, Philip W Kantoff, Nicholas J Vogelzang, Arif Hussain, Christopher. M Pieczonka, Neal D Shore, David I Quinn, Elisabeth I Heath, Ronald F Tutrone, Paul F Schellhammer, Matthew Harmon, Nancy N Chang, Stephen J Freedland, Celestia S Higano. Overall survival (OS) of African-American (AA) and Caucasian (CAU) men who received sipuleucel-T for metastatic castration-resistant prostate cancer (mCRPC)—final PROCEED analysis [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D084.