Strategy For Treatment Of Prostate Cancer Research Articles

Combinatorial approaches of nanotherapeutics for inflammatory pathway targeted therapy of prostate cancer.

Prostate cancer (PC) is the most prevalent male urogenital cancer worldwide. PC patients presenting an advanced or metastatic cancer succumb to the disease, even after therapeutic interventions including radiotherapy, surgery, androgen deprivation therapy (ADT), and chemotherapy. One of the hallmarks of PC is evading immune surveillance and chronic inflammation, which is a major challenge towards designing effective therapeutic formulations against PC. Chronic inflammation in PC is often characterized by tumor microenvironment alterations, epithelial-mesenchymal transition and extracellular matrix modifications. The inflammatory events are modulated by reactive nitrogen and oxygen species, inflammatory cytokines and chemokines. Major signaling pathways in PC includes androgen receptor, PI3K and NF-κB pathways and targeting these inter-linked pathways poses a major therapeutic challenge. Notably, many conventional treatments are clinically unsuccessful, due to lack of targetability and poor bioavailability of the therapeutics, untoward toxicity and multidrug resistance. The past decade witnessed an advancement of nanotechnology as an excellent therapeutic paradigm for PC therapy. Modern nanovectorization strategies such as stimuli-responsive and active PC targeting carriers offer controlled release patterns and superior anti-cancer effects. The current review initially describes the classification, inflammatory triggers and major inflammatory pathways of PC, various PC treatment strategies and their limitations. Subsequently, recent advancement in combinatorial nanotherapeutic approaches, which target PC inflammatory pathways, and the mechanism of action are discussed. Besides, the current clinical status and prospects of PC homing nanovectorization, and major challenges to be addressed towards the advancement PC therapy are also addressed.

SY29-1 Future treatment strategies for prostate cancer guided by PSMA-PET

In recent years, prostate specific membrane antigen (PSMA) PET has attracted attention in the diagnosis of recurrence and metastasis of prostate cancer. PSMA is a membrane protein which shows increased expression in more than 90% of prostate cancer, and is known to exhibit high expression in many metastatic and recurrent lesions. In Osaka University Hospital, a clinical research using [18F]PSMA-1007 PET has been conducted since September 2019, and more than 150 scans has been performed so far in patients with prostate cancer with various stages.

Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment.

IntroductionSince the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines.Materials and methodsTo longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses.ResultsA total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate.ConclusionWhile the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Facile construction of dual-drug loaded nanoparticles for improvement synergistic chemotherapy in prostate cancer

Recently, functionalized materials have been extensively investigated and reported as drug delivery carriers. Furthermore, many groups have concentrated their efforts on establishing unique and effective therapeutic modalities, such as photothermal and photodynamic therapy, which have displayed promising anticancer ability. In the suggested techniques, the described treatments demonstrated better cooperative behavior and the capacity to substitute for the negative effects of traditional monotherapy. Herein, we developed a thermosensitive dual-targeting drug delivery system traction to improve the administration of capecitabine and two photosensitizers (indocyanine green (ICG) and methylene blue (MB). Capecitabine and photosensitizers were incorporated into nanoparticles using the thin film hydration process. Meanwhile, the dynamic identification of tumor cells may be achieved by modifying the targeted peptide cRGD and the folate targeting molecule coated on the surface of the nanoparticles. According to DLS experiments, the fabricated nanoparticles possessed an excellent dispersive index and a homogeneous size of ∼103.12 nm. Compared to free nanoparticles, the nanoparticles demonstrated dose-dependent in vitro cytotoxic properties in DU145 and PC3 cells. Based on the results examined from a confocal laser scanning microscope, the modified nanoparticles were more efficiently endocytosed by DU145 cancer cells compared to PC3 cells. On DU145 cells, the photothermal conversion-triggered release of drug and phototherapies resulted in an apoptotic rate of ∼80%. Additionally, the apoptosis cell death mechanism was displayed that the nanoparticles significantly induce apoptosis in the DU145 and PC3 cancer cells. The impressive findings concluded that the developed delivery system had put in a lot of work and established many changes to achieve precise interaction and provide a potential prostate cancer treatment strategy.

Evaluation of G2013 (α-L-guluronic acid) efficacy on PC-3 cells through inhibiting the expression of inflammatory factors.

Given multiple treatment strategies for prostate cancer, its mortality rate is still high; therefore, novel treatment strategies seem necessary. G2013 or α-L-guluronic acid is a new patented drug with immunomodulatory and anti-inflammatory properties. This study aimed to evaluate the property of G2013 on inflammatory molecules involved in tumorigenesis of prostate cancer. MTT assay was used to assess the effect of the drug on the proliferation of PC-3 cells. Expression of interleukin 8 (IL-8), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), myeloid differentiation factor 88 (MYD-88), cyclooxygenase 2 (COX-2), matrix metalloproteinase-2 (MMP-2), and MMP-9genes were studied in the PC-3 cells treated with 25 (low dose) or 50 (high dose) µg/mL of G2013 for 24h using quantitative real-time polymerase chain reaction (qRT-PCR) technique. Protein expression of NF-κB and protein activities of MMP-2 and MMP-9 were assayed using flow cytometry and gelatin zymography, respectively. The expression of COX-2 (p=0.007 at low dose), MMP-2 (p=0.023 at low dose, p=0.002 at high dose), NF-κB (p=0.004 at low dose) and IL-8 (p<0.0001 in both doses) genes, NF-κB protein (p<0.0001 in both doses), and MMP-2 activity (p<0.0001 in both doses) were significantly reduced in the presence of G2013 as compared to the control group. Cancer cell proliferation was also inhibited under 10-500µg/mL G2013 treatment. Our results revealed that G2013has the potential to inhibit PC-3 cell proliferation and reduce the expression of tumour-promoting mediators, COX-2, MMP-2, NF-κB, and IL-8 involved in the progression and metastasis of prostate cancer.

Metformin exerts anti-AR-negative prostate cancer activity via AMPK/autophagy signaling pathway

BackgroundEncouraged by the goal of developing an effective treatment strategy for prostate cancer, this study explored the mechanism involved in metformin-mediated inhibition of AR-negative prostate cancer.MethodsCell behaviors of DU145 and PC3 cells were determined by CCK8 test, colony formation experiment and scratch test. Flow cytometry was used to detect cell cycle distribution. Cell autophagy was induced with metformin, and an autophagy inhibitor, 3-MA, was used to assess the level of autophagy. Detection of LC3B by immunofluorescence was conducted to determine autophagy level. Cell proliferation, autophagy and cell cycle were examined by performing Western blot. DU145 and PC3 cell lines were transfected with AMPK siRNA targeting AMPK-α1 and AMPK-α2. Tumor formation experiment was carried out to evaluate the anti-prostate cancer effect of metformin in vivo.ResultsThe inhibitory effect of metformin on the proliferation of prostate cancer cell lines was confirmed in this study, and the mechanism of such an effect was related to autophagy and the block of cell cycle at G0/G1 phase. Metformin also induced the activation of AMPK, markedly promoted expression of LC3II, and down-regulated the expression of p62/SQSTM1. Animal experiments showed that the tumor volume of metformin group was smaller, meanwhile, the levels of p-AMPK (Thr172) and LC3B were up-regulated and the Ki-67 level was down-regulated, without abnormalities in biochemical indicators.ConclusionThis study found that autophagy induction might be the mechanism through which metformin suppressed the growth of AR-negative prostate cancer. Moreover, the activation of AMPK/autophagy pathway might be a therapeutically effective for treating AR-negative prostate cancer in the future.

Insights into homeobox B9: a propeller for metastasis in dormant prostate cancer progenitor cells

BackgroundMetastasis is the major cause of treatment failure and cancer-related deaths in prostate cancer (PCa) patients. Our previous study demonstrated that a CD44+ subpopulation isolated from PCa cells or tumours possesses both stem cell properties and metastatic potential, serving as metastatic prostate cancer stem cells (mPCSCs) in PCa metastasis. However, the underlying mechanisms remain unknown.MethodsIn this study, we established PCa models via the orthotopic and subcutaneous implantation of different human PCa cancer cell lines, and compared the metastatic efficacy, after which process function analysis of target genes was pinpointed.ResultsSeveral novel differentially expressed genes (DEGs) between orthotopic and ectopic tumours were identified. Among them, human homeobox B9 (HOXB9) transcription factor was found to be essential for PCa metastasis, as evidenced by the diminished number of lung metastatic foci derived from orthotopic implantation with HOXB9-deficient CWR22 cells, compared with the control. In addition, HOXB9 protein expression was upregulated in PCa tissues, compared with paracancer and benign prostate hyperplasia tissues. It was also positively correlated with Gleason scores. Gain- and loss-of-function assays showed that HOXB9 altered the expression of various tumour metastasis- and cancer stem cell (CSC) growth-related genes in a transforming growth factor beta (TGFβ)-dependent manner. Moreover, HOXB9 was overexpressed in an ALDH+CD44+CXCR4+CD24+ subpopulation of PCa cells that exhibited enhanced TGFβ-dependent tumorigenic and metastatic abilities, compared with other isogenic PCa cells. This suggests that HOXB9 may contribute to PCa tumorigenesis and metastasis via TGFβ signalling. Of note, ALDH+CD44+CXCR4+CD24+-PCa cells exhibited resistance to castration and antiandrogen therapy and were present in human PCa tissues.ConclusionTaken together, our study identified HOXB9 as a critical regulator of metastatic mPCSC behaviour. This occurs through altering the expression of a panel of CSC growth- and invasion/metastasis-related genes via TGFβ signalling. Thus, targeting HOXB9 is a potential novel therapeutic PCa treatment strategy.

Selective obstruction of the mTORC2 complex by a naturally occurring cholestane saponin (OSW-1) for inhibiting prostate cancer cell growth

Ornithogalum caudatum Ait (OCA) is a natural product used in Chinese traditional medicine. The cholestane saponin OSW-1 is isolated from plant OCA and has recently been shown to have potent cytotoxic effects against different types of cancers. The therapeutic efficacy of OSW-1 on prostate cancer and its underlying mechanism are yet to be established. OSW-1 inhibited the growth of prostate cancer cells by interrupting the interaction between mTOR and Rictor/mTORC2. This mechanism showed a better therapeutic outcome than that of the conventional inhibition of mTOR and provided a basis for as sisting modern prostate cancer treatment strategies.

Development and Validation of an Interpretable Artificial Intelligence Model to Predict 10-Year Prostate Cancer Mortality.

Simple SummaryThis article presents a gradient-boosted model that can predict 10-year prostate cancer mortality with high accuracy. The model was developed and validated on prospective multicenter data from the PLCO trial. Using XGBoost and Shapley values, it provides interpretability to understand its prediction. It can be used online to provide predictions and support informed decision-making in PCa treatment.Prostate cancer treatment strategies are guided by risk-stratification. This stratification can be difficult in some patients with known comorbidities. New models are needed to guide strategies and determine which patients are at risk of prostate cancer mortality. This article presents a gradient-boosting model to predict the risk of prostate cancer mortality within 10 years after a cancer diagnosis, and to provide an interpretable prediction. This work uses prospective data from the PLCO Cancer Screening and selected patients who were diagnosed with prostate cancer. During follow-up, 8776 patients were diagnosed with prostate cancer. The dataset was randomly split into a training (n = 7021) and testing (n = 1755) dataset. Accuracy was 0.98 (±0.01), and the area under the receiver operating characteristic was 0.80 (±0.04). This model can be used to support informed decision-making in prostate cancer treatment. AI interpretability provides a novel understanding of the predictions to the users.

Normal Basal Epithelial Cells Stimulate the Migration and Invasion of Prostate Cancer Cell RM-1 by TGF-β1/STAT3 Axis in vitro.

AimBasal epithelial cells are absent in distant prostate cancer. This study aimed to investigate whether basal epithelial cells could suppress migration and invasion of prostate cancer cells to become a new treatment strategy for prostate cancer.Main MethodsBasal epithelial cells were identified by immunofluorescence with anti-p63. Wound healing assays or transwell assays were used to explore the effects of basal epithelial cells, TGF-β1, SB431542 (inhibitor of TGF-β type I receptor) or stattic (inhibitor of phosphorylated STAT3) on migration or invasion of mouse prostate cancer cell (RM-1). Concentration of TGF-β1 was measured by ELISA assay. HE staining was used to investigate cell morphology. Immunocytochemistry with anti-p63 was used to identify basal epithelial cells. Levels of STAT3, p-STAT3 (Ser727) and proteins associated with EMT were measured with Western blot assay. Cell proliferation was measured with MTT or CCK8 assay.ResultsNormal basal epithelial cells acquired from mouse prostate were specific to anti-p63 and more than 90%. Basal epithelial cells and RM-1 could both secrete TGF-β1. Basal epithelial cells and TGF-β1 promoted the migration and invasion of RM-1 through changing the cell morphology and up-regulating expression of ZEB1, N-cadherin, vimentin, snail and p-STAT3 (Ser727), at the same time down-regulating E-cadherin of RM-1. SB431542 strongly suppressed migration, invasion as well as the expressions of EMT relevant proteins and p-STAT3 (Ser727) of co-cultured RM-1. In addition, stattic suppressed proliferation, migration and invasion of non-treated RM-1 and co-cultured RM-1.ConclusionOur study suggests that normal basal epithelial cells might stimulate the migration and invasion of RM-1 by TGF-β1/STAT3 axis which could be suppressed by inhibitor of TGF-β receptor and inhibitor of p-STAT3. So, basal epithelial cells might not become a treatment strategy for prostate cancer, but our results could provide some researching references for other diseases which include basal epithelial cells such as prostatic intraepithelial neoplasia, prostatic hyperplasia, cervical cancer, or urinary bladder cancer.

Nanovectorization of Prostate Cancer Treatment Strategies: A New Approach to Improved Outcomes.

Prostate cancer (PC) is the most frequent male cancer in the Western world. Progression to Castration Resistant Prostate Cancer (CRPC) is a known consequence of androgen withdrawal therapy, making CRPC an end-stage disease. Combination of cytotoxic drugs and hormonal therapy/or genotherapy is a recognized modality for the treatment of advanced PC. However, this strategy is limited by poor bio-accessibility of the chemotherapy to tumor sites, resulting in an increased rate of collateral toxicity and incidence of multidrug resistance (MDR). Nanovectorization of these strategies has evolved to an effective approach to efficacious therapeutic outcomes. It offers the possibility to consolidate their antitumor activity through enhanced specific and less toxic active or passive targeting mechanisms, as well as enabling diagnostic imaging through theranostics. While studies on nanomedicine are common in other cancer types, only a few have focused on prostate cancer. This review provides an in-depth knowledge of the principles of nanotherapeutics and nanotheranostics, and how the application of this rapidly evolving technology can clinically impact CRPC treatment. With particular reference to respective nanovectors, we draw clinical and preclinical evidence, demonstrating the potentials and prospects of homing nanovectorization into CRPC treatment strategies.

Artificial Intelligence Techniques for Prostate Cancer Detection through Dual-Channel Tissue Feature Engineering.

Simple SummaryArtificial intelligence techniques were used for the detection of prostate cancer through tissue feature engineering. A radiomic method was used to extract the important features or information from histopathology tissue images to perform binary classification (i.e., benign vs. malignant). This method can identify a histological pattern that is invisible to the human eye, which helps researchers to predict and detect prostate cancer. We used different performance metrics to evaluate the results of the classification. In the future, it is expected that a method like radiomic will provide a consistent contribution to analyze histopathology tissue images and differentiate between cancerous and noncancerous tumors.The optimal diagnostic and treatment strategies for prostate cancer (PCa) are constantly changing. Given the importance of accurate diagnosis, texture analysis of stained prostate tissues is important for automatic PCa detection. We used artificial intelligence (AI) techniques to classify dual-channel tissue features extracted from Hematoxylin and Eosin (H&E) tissue images, respectively. Tissue feature engineering was performed to extract first-order statistic (FOS)-based textural features from each stained channel, and cancer classification between benign and malignant was carried out based on important features. Recursive feature elimination (RFE) and one-way analysis of variance (ANOVA) methods were used to identify significant features, which provided the best five features out of the extracted six features. The AI techniques used in this study for binary classification (benign vs. malignant and low-grade vs. high-grade) were support vector machine (SVM), logistic regression (LR), bagging tree, boosting tree, and dual-channel bidirectional long short-term memory (DC-BiLSTM) network. Further, a comparative analysis was carried out between the AI algorithms. Two different datasets were used for PCa classification. Out of these, the first dataset (private) was used for training and testing the AI models and the second dataset (public) was used only for testing to evaluate model performance. The automatic AI classification system performed well and showed satisfactory results according to the hypothesis of this study.

Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer.

Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer.

GRPr-mediated photothermal and thermodynamic dual-therapy for prostate cancer with synergistic anti-apoptosis mechanism.

Conventional prostate cancer treatment strategies, including chemotherapy and radiotherapy, cannot effectively eradicate prostate cancer, especially castration resistance prostate cancer. Herein, we developed a novel nanotherapy platform that consists of synergic photothermal and photodynamic therapy via the unique properties of photothermal conversion by gold nanorods and free radicals generation by encapsulated initiators (AIPH). Mesoporous silica was employed as a coating material, and the bombesin peptide was conjugated onto the mesoporous silica coating layer as the targeting moiety to prostate cancer via its overexpressed gastrin-releasing peptide receptors. An in vitro study with the castration resistance prostate cancer cell exhibited a significant photothermal therapeutic effect as well as enhanced thermodynamic therapy via generating free radicals. P-p38 and p-JNK proteins, as key proteins involved in the cells' stress responses, were found to be upregulated by the synergetic treatment. The in vivo study demonstrated that a significant eradication of prostate tumour could be achieved by the nanoparticle therapeutic platform with a good biocompatibility profile. This work pioneers a novel approach for high-efficient castration resistance prostate cancer treatment by combining photothermal, thermodynamic, and site-specific drug delivery directed by an integrated nanoparticle system.

EGFR/FOXO3A/LXR-α Axis Promotes Prostate Cancer Proliferation and Metastasis and Dual-Targeting LXR-α/EGFR Shows Synthetic Lethality

Prostate cancer is the second leading cause of cancer-related death in men. Early prostate cancer has a high 5-year survival rate. However, the five-year survival rate is low in progressive prostate cancer, which manifests as bone metastasis. The EGF receptor overexpression increases during disease progression and in the development of castration-resistant disease, and may be a potential therapeutic target. Liver X receptors (LXRs) are ligand-dependent nuclear receptor transcription factors and consist of two subtypes, LXR-α and LXR-β, which can inhibit tumor growth in various cancer cells. We revealed that LXR-α, but not LXR-β, was reduced in prostate cancer tissues compared with adjacent normal tissues. LXRs’ agonist GW3965 enhanced the inhibitory action of LXR-α on the proliferation and metastasis of prostate cancer cells. Furthermore, our results support the notion that LXR-α is regulated by the EGFR/AKT/FOXO3A pathway. As an EGFR inhibitor, Afatinib could weaken AKT activation and increase the expression level of FOXO3A in prostate cancer. In addition, we indicated that the combination of Afatinib and GW3965 simultaneously increased and activated LXR-α, which led to an increase of tumor suppressors, and eventually inhibited tumor progression. Therefore, the combination of EGFR inhibitor and LXRs agonist may become a potential treatment strategy for prostate cancer, especially metastatic prostate cancer.

Variation in adjuvant and early salvage radiotherapy after robot-assisted radical prostatectomy for prostate cancer: a population-based cohort study

Purpose: The primary aim of the study was to assess the association between having a radiotherapy (RT) department on-site at the surgical centre and the performed postoperative treatment strategy for prostate cancer (PCa) patients. According to the current international guidelines, adjuvant radiotherapy (ART) or a regular prostate-specific antigen (PSA)-based follow-up with (early) salvage radiotherapy ((e)SRT) if needed is recommended in case of adverse pathological characteristics.Material and methods: Prospective data on consecutive robot-assisted radical prostatectomy (RARP) patients in Belgium from 2009 to 2016 were identified in the Belgian Robotic-Assisted-Laparoscopic-Prostatectomy (Be-RALP) database. Multivariable regression was used to evaluate patient- and facility-related factors associated with postoperative radiation treatment.Results: 2072 patients undergoing a RARP, suffering at least one of the following adverse pathological features, i.e., extracapsular extension (ECE), seminal vesicle invasion (SVI) or positive section margins (PSM), and with registered follow-up until 24 months were enrolled. After RARP, ART was applied to 9.1% and (e)SRT to 12.6% of the patients. Multivariable analysis demonstrated that patients were more likely to receive ART or (e)SRT if they were operated in a hospital with a RT department on-site (odds ratio, ART: 1.49 [1.07-2.07]; (e)SRT: 1.55 [1.16-2.06]). Furthermore, the presence of higher tumour category (T-category) and/or PSM on final pathology was associated with a higher chance of getting ART and (e)SRT (p < .01).Conclusion: Variations in ART and (e)SRT are not only driven by patient-related characteristics. In our nationwide cohort, the availability of a RT department on-site at the surgical centre was found to be an independent predictor for ART and (e)SRT, with a 1.5 times higher odds of receiving postoperative RT during the first 24 months after surgery.

MicroRNA‑16‑5p regulates cell survival, cell cycle and apoptosis by targeting AKT3 in prostate cancer cells.

Prostate cancer (PCa) is a malignancy with the highest morbidity rate in 105 countries worldwide and was a major cause of cancer‑associated death in men in 2018. Accumulating evidence suggests that microRNAs (miRNAs/miRs) have important functions in the carcinogenesis of PCa, and may provide novel treatment targets. Previous studies have indicated that miR‑16‑5p is associated with PCa. However, the relevance and importance of miR‑16‑5p in PCa carcinogenesis are still not completely understood. In the current study, we aimed to investigate the role and mechanism of miR‑16‑5p in PCa carcinogenesis. The results showed that miR‑16‑5p was markedly downregulated in PCa cells, and MTS assay, colony formation, flow cytometric analyses demonstrated that miR‑16‑5p inhibited PCa cell survival, regulated cell cycle distribution and induced apoptosis. Moreover, luciferase reporter assay and western blot analysis showed that miR‑16‑5p directly targets AKT3 (AKT serine/threonine kinase 3), which is associated with PCa carcinogenesis, and the effects of the downregulation of AKT3 were similar to the effects of upregulation of miR‑16‑5p in PC‑3 cells. In conclusion, our data clarify that miR‑16‑5p has anticancer functions in PCa cells, and our findings provide experimental evidence to highlight the potential value of miR‑targeting treatment strategies for PCa.

Targeting lactate production and efflux in prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed cancer in men worldwide. Screening and management of PCa remain controversial and, therefore, the discovery of novel molecular biomarkers is urgently needed. Alteration in cancer cell metabolism is a recognized hallmark of cancer, whereby cancer cells exhibit high glycolytic rates with subsequent lactate production, regardless of oxygen availability. To maintain the hyperglycolytic phenotype, cancer cells efficiently export lactate through the monocarboxylate transporters MCT1 and MCT4. The impact of inhibiting lactate production/extrusion on PCa cell survival and aggressiveness was investigated in vitro and ex vivo using primary tumor and metastatic PCa cell lines and the chicken embryo chorioallantoic membrane (CAM) model. In this study, we showed the metastatic PCa cell line (DU125) displayed higher expression levels of MCT1/4 isoforms and glycolysis-related markers than the localized prostate tumor-derived cell line (22RV1), indicating these proteins are differentially expressed throughout prostate malignant transformation. Moreover, disruption of lactate export by MCT1/4 silencing resulted in a decrease in PCa cell growth and motility. To support these results, we pharmacological inhibited lactate production (via inhibition of LDH) and release (via inhibition of MCTs) and a reduction in cancer cell growth in vitro and in vivo was observed. In summary, our data provide evidence that MCT1 and MCT4 are important players in prostate neoplastic progression and that inhibition of lactate production/export can be explored as a strategy for PCa treatment.

Cancer-driven IgG promotes the development of prostate cancer though the SOX2-CIgG pathway.

Although androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer (PCa), recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G (CIgG) is found to be induced after ADT, identifying CIgG as a potential CRPC driver gene. The expression of CIgG and its clinical significance in PCa tissue was analyzed by The Cancer Genome Atlas database and immunohistochemistry. Subsequently, the sequence features of prostate cell line VHDJH rearrangements were analyzed. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of PCa cells in vitro and vivo. Suspended microsphere, colony formation and drug-resistant assays were performed using PC3 cells with high CIgG expression (CIgGhigh ) and low CIgG expression (CIgG-/low ), and A nonobese diabetic/severe combined immunodeficiency mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, Western blot, luciferase, and chromatin immunoprecipitation assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of PCa in vivo using a Babl/c nude mouse xenograft model. CIgG is frequently expressed in PCa and associated with clinicopathological characteristics, moreover, CIgG transcripts with unique patterns of VHDJH rearrangements are found in PCa cells. Functional analyses identified that CIgG was induced by ADT and upregulated by SOX2 (SRY (sex determining region Y)-box 2) in PCa, promoting the development of PCa. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through mitogen activated protein kinase/extracellular-signal-regulated kinase and AKT in PCa. In vivo experiments further demonstrated that depleting CIgG significantly suppressed the growth of PCa cell xenografts. Furthermore, a CIgG monoclonal antibody named RP215 exhibits tumor inhibitory effect as well. Our data suggests that CIgG could be a driver of PCa development, and that targeting the SOX2-CIgG axis may therefore inhibit PCa development after ADT.

MP75-12 THE SECOND OPINION PATHOLOGY REVIEW IMPROVES CONCORDANCE BETWEEN PROSTATE BIOPSY AND RADICAL PROSTATECTOMY SPECIMENS

INTRODUCTION AND OBJECTIVE:The Gleason scoring system is an essential tool in deciding a prostate cancer treatment strategy. However, the Gleason grade group (GGG) often differs between needle-core...