Urine Extracellular Vesicle GATA2 mRNA Discriminates Biopsy Result in Men with Suspicion of Prostate Cancer

AbstractNeuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.

Download Full-text

The Emerging Role of Extracellular Vesicle-Mediated Drug Resistance in Cancers: Implications in Advanced Prostate Cancer

BioMed Research International ◽

10.1155/2015/454837 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 20

Author(s):

Carolina Soekmadji ◽

Colleen C. Nelson

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Multidrug Resistance ◽

Advanced Prostate Cancer ◽

Control Cell ◽

Extracellular Vesicle ◽

Multidrug Resistance Proteins ◽

Acquired Drug Resistance ◽

Resistance Proteins

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

Download Full-text

Independent Validation of a Diagnostic Noninvasive 3-MicroRNA Ratio Model (uCaP) for Prostate Cancer in Cell-Free Urine

Clinical Chemistry ◽

10.1373/clinchem.2018.296681 ◽

2019 ◽

Vol 65 (4) ◽

pp. 540-548 ◽

Cited By ~ 6

Author(s):

Jacob Fredsøe ◽

Anne K I Rasmussen ◽

Emma B Laursen ◽

Yunpeng Cai ◽

Kenneth A Howard ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Biopsy ◽

Specific Antigen ◽

Transrectal Ultrasound ◽

Area Under The Curve ◽

Extracellular Vesicle ◽

Urine Samples ◽

Ratio Model ◽

Psa Testing ◽

Diagnostic Potential

Abstract BACKGROUND Detection of prostate cancer (PC) based on serum prostate-specific antigen (PSA) testing leads to many unnecessary prostate biopsies, overdiagnosis, and overtreatment of clinically insignificant tumors. Thus, novel and more accurate molecular biomarkers are required. METHODS Using reverse transcription quantitative PCR, we measured the concentrations of 45 preselected microRNAs (miRNAs) in extracellular vesicle-enriched cell-free urine samples from 4 independent patient cohorts from Spain and Denmark, including 758 patients with clinically localized PC, 289 noncancer controls with benign prostatic hyperplasia (BPH), and 233 patients undergoing initial transrectal ultrasound (TRUS)-guided prostate biopsy owing to PC suspicion (101 with benign and 132 with malignant outcome). Diagnostic potential was assessed by ROC and decision curve analysis. RESULTS We identified and successfully validated 8 upregulated and 21 downregulated miRNAs in urine from PC patients. Furthermore, we validated a previously identified 3-miRNA diagnostic ratio model, uCaP (miR-222–3p*miR-24–3p/miR-30c-5p). High uCaP scores were distinctive of PC in urine samples from BPH vs PC patients in 3 independent cohorts [area under the curve (AUC) = 0.84, 0.71, 0.72]. Additionally, uCaP predicted TRUS biopsy results with greater accuracy than PSA (AUC uCaP = 0.644; AUC PSA = 0.527) for patients within the diagnostic gray zone (PSA ≤ 10 ng/mL). CONCLUSIONS We successfully validated a urine-based diagnostic 3-miRNA signature for PC (uCaP) in 3 independent patient cohorts from 2 countries. In the future, the simple and noninvasive uCaP test may be used to help more accurately select patients for prostate biopsy. Prospective clinical validation is warranted.

Download Full-text

PD53-03 URINARY EXTRACELLULAR VESICLE MRNA PANEL TO DIAGNOSE PROSTATE CANCER

The Journal of Urology ◽

10.1097/ju.0000000000000955.03 ◽

2020 ◽

Vol 203 ◽

pp. e1097

Author(s):

FuBo Wang* ◽

Jin Ji ◽

Zhi Cao ◽

Huan Xu ◽

YaLong Xu ◽

...

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicle ◽

Diagnose Prostate Cancer

Download Full-text

miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4 and CHORDC1

10.1101/646380 ◽

2019 ◽

Author(s):

Fumihiko Urabe ◽

Nobuyoshi Kosaka ◽

Yurika Sawa ◽

Tomofumi Yamamoto ◽

Yusuke Yamamoto ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Extracellular Vesicle ◽

Suppressive Effect ◽

Prostate Cancer Cells ◽

Detailed Mechanism ◽

Novel Strategy ◽

Vesicle Secretion

AbstractExtracellular vesicles (EVs) are known to be involved in intercellular communication during cancer progression; thus, elucidating the detailed mechanism will contribute to the development of a novel strategy for EV-targeted cancer treatment. However, the biogenesis of EVs in cancer cells is not completely understood. MicroRNAs (miRNAs) regulate a variety of physiological and pathological phenomena; thus, miRNAs could regulate EV secretion. Here, we performed high-throughput miRNA-based screening to identify the regulators of EV secretion using an ExoScreen assay. By using this miRNA-based screening, we identified miR-26a, which was reported as a tumor suppressive miRNA, as a miRNA involved in EV secretion from prostate cancer (PCa) cells. In addition, we found that the SHC4, PFDN4, and CHORDC1 genes regulate EV secretion in PCa cells. Suppression of these genes by siRNAs significantly inhibited the secretion of EVs in PCa cells. Furthermore, the progression of PCa cells was inhibited in an in vivo study. On the other hand, injection of EVs isolated from PCa cells partially rescued this suppressive effect on tumor growth. Taken together, our findings suggest that miR-26a regulates EV secretion via targeting SHC4, PFDN4, and CHORDC1 in PCa cells, resulting in the suppression of PCa progression.

Download Full-text

Stroma‐derived extracellular vesicle mRNA signatures inform histological nature of prostate cancer

Journal of Extracellular Vesicles ◽

10.1002/jev2.12150 ◽

2021 ◽

Vol 10 (12) ◽

Author(s):

Alex P. Shephard ◽

Peter Giles ◽

Mariama Mbengue ◽

Amr Alraies ◽

Lisa K. Spary ◽

...

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicle

Download Full-text

miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4, and CHORDC1

Science Advances ◽

10.1126/sciadv.aay3051 ◽

2020 ◽

Vol 6 (18) ◽

pp. eaay3051 ◽

Cited By ~ 4

Author(s):

Fumihiko Urabe ◽

Nobuyoshi Kosaka ◽

Yurika Sawa ◽

Yusuke Yamamoto ◽

Kagenori Ito ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

High Throughput ◽

Intercellular Communication ◽

Extracellular Vesicle ◽

Prostate Cancer Cells ◽

Biological Phenomena ◽

Vesicle Secretion

Extracellular vesicles (EVs) are involved in intercellular communication during cancer progression; thus, elucidating the mechanism of EV secretion in cancer cells will contribute to the development of an EV-targeted cancer treatment. However, the biogenesis of EVs in cancer cells is not fully understood. MicroRNAs (miRNAs) regulate a variety of biological phenomena; thus, miRNAs could regulate EV secretion. Here, we performed high-throughput miRNA-based screening to identify the regulators of EV secretion using an ExoScreen assay. By using this method, we identified miR-26a involved in EV secretion from prostate cancer (PCa) cells. In addition, we found that SHC4, PFDN4, and CHORDC1 genes regulate EV secretion in PCa cells. Furthermore, the progression of the PCa cells suppressing these genes was inhibited in an in vivo study. Together, our findings suggest that miR-26a regulates EV secretion via targeting SHC4, PFDN4, and CHORDC1 in PCa cells, resulting in the suppression of PCa progression.

Download Full-text

Extracellular vesicle associated and soluble immune marker profiles of psychoneurological symptom clusters in men with prostate cancer: an exploratory study

Translational Psychiatry ◽

10.1038/s41398-021-01554-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dilorom Sass ◽

Leorey Saligan ◽

Wendy Fitzgerald ◽

Ann M. Berger ◽

Isaias Torres ◽

...

Keyword(s):

Prostate Cancer ◽

Depressive Symptoms ◽

Sleep Disturbances ◽

Metastatic Prostate Cancer ◽

Extracellular Vesicle ◽

Symptom Clusters ◽

Symptom Cluster ◽

External Beam Radiation ◽

Immune Markers ◽

Bivariate Correlation

AbstractPsychoneurological symptom clusters are co-occurring and interrelated physiological symptoms that may include cancer-related fatigue, pain, depressive symptoms, cognitive disturbances, and sleep disturbances. These symptoms are hypothesized to share a common systemic proinflammatory etiology. Thus, an investigation of systemic immune biomarkers is an important approach to test this hypothesis. Here, we investigated the associations between extracellular vesicle (EV)-associated and soluble cytokines with immune markers and symptom clusters in men with non-metastatic prostate cancer. This observational study included 40 men with non-metastatic prostate cancer at the start (T1) of external beam radiation therapy (EBRT) and 3 months post treatment (T2), as well as 20 men with non-metastatic prostate cancer on active surveillance (AS) seen at one time point. Collected questionnaires assessed patient-reported fatigue, sleep disturbances, depressive symptoms, and cognitive fatigue. In total, 45 soluble and EV-associated biomarkers in plasma were determined by multiplex assays. Principal component analysis (PCA) was used to identify psychoneurological symptom clusters for each study group and their time points. Bivariate correlation analysis was run for each identified PCA cluster with the concentrations of EV-associated and soluble cytokines and immune markers. Both EV-associated and soluble forms of RANTES significantly correlated with the symptom cluster for EBRT at T1, whereas, at T2, soluble IFNα2, IL-9, and IL-17 correlated with the corresponding symptom cluster. For the AS group, soluble survivin correlated with psychoneurological symptoms. Linking specific inflammatory cytokines with psychoneurological symptom clusters in men receiving prostate cancer treatment can enhance understanding of the underlying mechanisms of this phenomenon and aid in developing targeted interventions.

Download Full-text

Clinical analysis of the extracellular vesicle-fingerprint score blood test to refine the prediction of clinically significant prostate cancer and avoid prostate biopsy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.5530 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 5530-5530 ◽

Cited By ~ 1

Author(s):

Adrian S. Fairey ◽

Robert J Paproski ◽

Desmond Pink ◽

Deborah L Sosnowski ◽

Catalina Vasquez ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Features ◽

Prostate Biopsy ◽

Clinical Care ◽

Digital Rectal Examination ◽

Extracellular Vesicle ◽

Risk Scores ◽

Gleason Grade ◽

Prostate Biopsies ◽

Clinically Significant

5530 Background: The accuracy of the extracellular vesicle-fingerprint score (EV-FPS) test to predict clinically significant prostate cancer (PCa; Gleason grade (GG) ≥ 3) from indolent disease (GG ≤ 2) and avoid unnecessary prostate biopsies was determined at the point of prostate biopsy decision. Methods: Clinical data, health information, and blood samples were collected from a prospective validation cohort of 415 men, without prior PCa diagnosis, referred to urology clinics for prostate biopsy or transurethral prostate surgery (June 2014-Dec 2016). The patient’s EV-FPS risk score was calculated by combining machine learning model-analyzed microflow cytometry data from EV biomarkers with logistic regression-analyzed patient-centric clinical features. The plasma-derived EV biomarkers were prostate-specific membrane antigen, polysialic acid and ghrelin-growth hormone receptor. The patient clinical features were; age, ethnicity, PCa family history, PSA levels, abnormal digital rectal examination (DRE) and prior negative prostate biopsy. Together, the biomarkers and clinical features provided specificity for clinically significant PCa. Results: The EV-FPS test identified clinically significant PCa patients with high accuracy (0.81 area under curve) at 95% sensitivity and 97% negative predictive value. Using a 7.85% probability cut-off after test validation; 95% of the patients with GG ≥ 3 would have been found before biopsy, 35% biopsies would have been avoided and diagnosis of GG ≥ 3 PCa would have been missed in only 5% of the cohort. Conclusions: This minimally invasive EV-FPS test accurately predicted clinically significant PCa in men with high EV-FPS risk scores, high PSA level and/or abnormal DRE. Therefore, men with low EV-FPS risk scores could potentially avoid unnecessary prostate biopsies. Clinical care cut-offs to calculate the number of biopsies that could have been avoided, and the percentage of GG ≥ 1 to GG ≥ 3 PCa that could have had a delayed diagnosis. [Table: see text]

Download Full-text