scholarly journals Extracellular Vesicles in Liquid Biopsies: Potential for Disease Diagnosis

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Jialing Liu ◽  
Ye Chen ◽  
Fang Pei ◽  
Chongmai Zeng ◽  
Yang Yao ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Minimally Invasive ◽  
Extracellular Vesicles ◽  
Liquid Biopsy ◽  
Enzymatic Degradation ◽  
Disease Diagnosis ◽  
Sample Collection ◽  
Liquid Biopsies ◽  
Promising Tool ◽  
Extracellular Environment

Liquid biopsy is conducted through minimally invasive or noninvasive procedures, and the resulting material can be subjected to genomic, proteomic, and lipidomic analyses for early diagnosis of cancers and other diseases. Extracellular vesicles (EVs), one kind of promising tool for liquid biopsy, are nanosized bilayer particles that are secreted by all kinds of cells and that carry cargoes such as lipids, proteins, and nucleic acids, protecting them from enzymatic degradation in the extracellular environment. In this review, we provide a comprehensive introduction to the properties and applications of EVs, including their biogenesis, contents, sample collection, isolation, and applications in diagnostics based on liquid biopsy.

Protein biomarkers in breast cancer-derived extracellular vesicles for use in liquid biopsies

2021 ◽  
Author(s):  
Dan Li ◽  
Wenjia Lai ◽  
Di Fan ◽  
Qiaojun Fang
Keyword(s):  
Breast Cancer ◽  
Early Diagnosis ◽  
Extracellular Vesicles ◽  
Liquid Biopsy ◽  
Breast Cancer Diagnosis ◽  
Extracellular Vesicle ◽  
Detection Methods ◽  
Protein Markers ◽  
Liquid Biopsies ◽  
Diagnosis And Prognosis

Breast cancer is the most common malignant disease in women worldwide. Early diagnosis and treatment can greatly improve the management of breast cancer. Liquid biopsies are becoming convenient detection methods for diagnosing and monitoring breast cancer due to their non-invasiveness and ability to provide real-time feedback. A range of liquid biopsy markers, including circulating tumor proteins, circulating tumor cells, and circulating tumor nucleic acids, have been implemented for breast cancer diagnosis and prognosis, with each having its own advantages and limitations. Circulating extracellular vesicles are messengers of intercellular communication that are packed with information from mother cells and are found in a wide variety of bodily fluids; thus, they are emerging as ideal candidates for liquid biopsy biomarkers. In this review, we summarize extracellular vesicle protein markers that can be potentially used for the early diagnosis and prognosis of breast cancer or determining its specific subtypes.

scholarly journals Single Step In Situ Detection of Surface Protein and MicroRNA in Clustered Extracellular Vesicles Using Flow Cytometry

2021 ◽  
Vol 10 (2) ◽  
pp. 319
Author(s):  
Hee Cheol Yang ◽  
Won Jong Rhee
Keyword(s):  
Extracellular Vesicles ◽  
Liquid Biopsy ◽  
Molecular Beacon ◽  
Disease Diagnosis ◽  
Single Step ◽  
Flow Cytometer ◽  
Surface Proteins ◽  
Biomarker Detection ◽  
In Situ Detection

Because cancers are heterogeneous, it is evident that multiplexed detection is required to achieve disease diagnosis with high accuracy and specificity. Extracellular vesicles (EVs) have been a subject of great interest as sources of novel biomarkers for cancer liquid biopsy. However, EVs are nano-sized particles that are difficult to handle; thus, it is necessary to develop a method that enables efficient and straightforward EV biomarker detection. In the present study, we developed a method for single step in situ detection of EV surface proteins and inner miRNAs simultaneously using a flow cytometer. CD63 antibody and molecular beacon-21 were investigated for multiplexed biomarker detection in normal and cancer EVs. A phospholipid-polymer-phospholipid conjugate was introduced to induce clustering of the EVs analyzed using nanoparticle tracking analysis, which enhanced the detection signals. As a result, the method could detect and distinguish cancer cell-derived EVs using a flow cytometer. Thus, single step in situ detection of multiple EV biomarkers using a flow cytometer can be applied as a simple, labor- and time-saving, non-invasive liquid biopsy for the diagnosis of various diseases, including cancer.

scholarly journals Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice?

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1986
Author(s):  
Victoria Heredia-Soto ◽  
Nuria Rodríguez-Salas ◽  
Jaime Feliu
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Practice ◽  
Early Diagnosis ◽  
Minimally Invasive ◽  
Liquid Biopsy ◽  
Genetic Material ◽  
Current Status ◽  
Ductal Adenocarcinoma ◽  
Disease Monitoring ◽  
Global Status

Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC.

scholarly journals Genomic instability-derived plasma extracellular vesicle-microRNA signature as a minimally invasive predictor of risk and unfavorable prognosis in breast cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Siqi Bao ◽  
Ting Hu ◽  
Jiaqi Liu ◽  
Jianzhong Su ◽  
Jie Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Diagnosis ◽  
Minimally Invasive ◽  
Genomic Instability ◽  
Extracellular Vesicles ◽  
Disease Risk ◽  
Prognostic Indicator ◽  
Mirna Regulation ◽  
Mirna Signature ◽  
Operating Characteristics

Abstract Background Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-associated deaths in women. Recent studies have indicated that microRNA (miRNA) regulation in genomic instability (GI) is associated with disease risk and clinical outcome. Herein, we aimed to identify the GI-derived miRNA signature in extracellular vesicles (EVs) as a minimally invasive biomarker for early diagnosis and prognostic risk stratification. Experimental design Integrative analysis of miRNA expression and somatic mutation profiles was performed to identify GI-associated miRNAs. Then, we constructed a discovery and validation study with multicenter prospective cohorts. The GI-derived miRNA signature (miGISig) was developed in the TCGA discovery cohort (n = 261), and was subsequently independently validated in internal TCGA validation (n = 261) and GSE22220 (n = 210) cohorts for prognosis prediction, and in GSE73002 (n = 3966), GSE41922 (n = 54), and in-house clinical exosome (n = 30) cohorts for diagnostic performance. Results We identified a GI-derived three miRNA signature (MIR421, MIR128-1 and MIR128-2) in the serum extracellular vesicles of BC patients, which was significantly associated with poor prognosis in all the cohorts tested and remained as an independent prognostic factor using multivariate analyses. When integrated with the clinical characteristics, the composite miRNA-clinical prognostic indicator showed improved prognostic performance. The miGISig also showed high accuracy in differentiating BC from healthy controls with the area under the receiver operating characteristics curve (ROC) with 0.915, 0.794 and 0.772 in GSE73002, GSE41922 and TCGA cohorts, respectively. Furthermore, circulating EVs from BC patients in the in-house cohort harbored elevated levels of miGISig, with effective diagnostic accuracy. Conclusions We report a novel GI-derived three miRNA signature in EVs, as an excellent minimally invasive biomarker for the early diagnosis and unfavorable prognosis in BC.

scholarly journals Tandem microfluidic chip isolation of prostate and breast cancer cells from simulated liquid biopsies using CD71 as an affinity ligand

RSC Advances ◽  
2020 ◽  
Vol 10 (54) ◽  
pp. 32628-32637
Author(s):  
Bhagya Wickramaratne ◽  
Dimitri Pappas
Keyword(s):  
Breast Cancer ◽  
Minimally Invasive ◽  
Cancer Cells ◽  
Microfluidic Chip ◽  
Liquid Biopsy ◽  
Breast Cancer Cells ◽  
Patient Monitoring ◽  
Liquid Biopsies ◽  
Affinity Ligand

The use of blood as a liquid biopsy provides a minimally invasive and less traumatic approach for initial cancer screens as well as patient monitoring.

Pan-tumor analyses of kinase fusions detected in circulating tumor DNA (ctDNA) and concordance with paired tissue.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3517-3517
Author(s):  
Jessica Kim Lee ◽  
Daniel Lieber ◽  
Russell Madison ◽  
Jon Chung ◽  
Alexa Betzig Schrock ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Median Time ◽  
Liquid Biopsy ◽  
Clinical Care ◽  
Driver Mutations ◽  
Gene Fusions ◽  
Sample Collection ◽  
Liquid Biopsies ◽  
Kinase Gene ◽  
Tissue Samples

3517 Background: Oncogenic kinase gene fusions are targetable with approved and investigational therapies and can also emerge as acquired resistance (AR) to targeted therapy. To understand the clinical validity of liquid biopsy comprehensive genomic profiling (CGP) to detect kinase fusions, we compared patient-matched plasma and tissue-based CGP. Methods: Hybrid capture-based CGP was performed on 28,743 plasma and 325,131 tumor tissue samples in the course of clinical care. Complete exonic regions of 13 kinases involved in oncogenic fusions plus select introns in ALK, EGFR, FGFR2/3, PDGFRA, RET, and ROS1 were sequenced to capture fusions with well characterized breakpoints. ctDNA fraction was estimated by maximum somatic allele frequency (MSAF). Results: 86% of cases had detectable ctDNA in plasma (MSAF > 0). Kinase fusions were detected in 2.1% of ctDNA cases (478/23,294) and were most prevalent in patients (pts) with bladder cancer (4.5%), non-small cell lung cancer (NSCLC) (4.3%), and cholangiocarcinoma (3.9%). The most commonly rearranged kinases were ALK (60%, 162/271) and RET (19%, 51/271) in NSCLC, FGFR2 (85%, 11/13) in cholangiocarcinoma, and FGFR3 (88%, 7/8) in bladder cancer. ALK fusions were detected in 26% (54/207) of fusion+ non-NSCLC cases. Paired tissue and ctDNA samples where ≥1 sample harbored a kinase fusion were available for 147 pts; median time between sample collection was 150 days (interquartile range: 444 days). Positive percent agreement (PPA) to tissue and liquid biopsies was 76% and 80%. Median MSAF in concordant and discordant ctDNA samples was 2.3% and 0.41% (p = 0.04) and median time between specimen collection for concordant and discordant pairs was 110 and 344 days (p = 0.04). PPA to tissue and liquid was 86% and 88% for pairs collected < 60 days apart (n = 53), versus 70% and 74% for pairs collected > 60 days apart. 6 pts with paired samples all collected > 196 days apart (median 593 days) had initial tissue samples with EGFR driver mutations and had an acquired kinase fusion (4 ALK, 1 FGFR2, 1 FGFR3) in the 2nd ctDNA sample, likely representing AR. Conclusions: Kinase gene fusions identified by tissue-based CGP were detected by liquid biopsy CGP in 85% of temporally-matched plasma samples. Kinase fusion detection by liquid biopsy CGP is feasible and had high PPA to tissue-based CGP. Subsequent sampling by liquid biopsy identified acquired fusions in EGFR driver positive cases consistent with known mechanisms of resistance to EGFR inhibitors suggesting utility of liquid biopsy at progression to identify targetable mechanisms of AR.

Minimally Invasive Real-Time Detection of Actionable Mutations in Patients With Metastatic Solid Tumors Using Fine-Needle and Liquid Biopsies

2018 ◽  
pp. 1-20
Author(s):  
Kyaw L. Aung ◽  
Philippe L. Bedard ◽  
Celeste Yu ◽  
Scott L. Boerner ◽  
Philip C. Zuzarte ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Real Time ◽  
Solid Tumors ◽  
Liquid Biopsy ◽  
Needle Biopsy ◽  
Interquartile Range ◽  
Liquid Biopsies ◽  
Fine Needle ◽  
Tumor Dna ◽  
Mutation Profiling

Purpose Fine-needle biopsy (FNB) and liquid biopsy are minimally invasive methods of tumor sampling that provide feasible means to assess tumor genotypes in real time. However, more data are needed to establish the strength of these methods by benchmarking against the current gold standard methods, core-needle biopsy (CNB) or surgical excision of the tumor. Patients and Methods Eligible patients with advanced solid tumors were prospectively recruited. We performed mutation profiling using matched tumor DNA obtained by CNB, FNB and liquid biopsy, and matrix-assisted laser desorption/ionization time-of-flight custom mass-spectrometry or targeted next-generation DNA sequencing. The actionability of detected mutations was determined using the OncoKB Web tool. Agreement between mutations detected in CNBs, FNBs, and circulating tumor DNA (ctDNA) was examined. Results Forty-one patients underwent tumor biopsy. Thirty CNBs (73%) and 34 FNBs (83%) had sufficient tumor and DNA for mutation profiling. Median DNA yield from CNB and FNB were 775 ng (interquartile range, 240 to 347 4ng) and 649 ng (interquartile range, 180 to1350 ng), respectively. Of 29 CNB/FNB pairs available for comparison, actionable mutation results were concordant in 28 (96%). Six of nine actionable mutations (67%) that were found by CNB, FNB, or both were detectable in ctDNA. Two additional actionable mutations were found exclusively in ctDNA. Conclusion Optimally processed FNB and liquid biopsy can be used routinely for tumor mutation profiling to identify actionable mutations.

scholarly journals Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 721 ◽  
Author(s):  
Ainhoa Lapitz ◽  
Ander Arbelaiz ◽  
Colm J. O’Rourke ◽  
Jose L. Lavin ◽  
Adelaida La Casta ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Liquid Biopsy ◽  
Disease Diagnosis ◽  
Messenger Rnas ◽  
Expression Array ◽  
Dismal Prognosis ◽  
Transmission Electron ◽  
Tumor Expression ◽  
Serum And Urine

: Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cells-derived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers.

scholarly journals A Two-Dimensional Affinity Capture and Separation Mini-Platform for the Isolation, Enrichment, and Quantification of Biomarkers and Its Potential Use for Liquid Biopsy

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 255 ◽  
Author(s):  
Norberto A. Guzman ◽  
Daniel E. Guzman
Keyword(s):  
Capillary Electrophoresis ◽  
Extracellular Vesicles ◽  
Liquid Biopsy ◽  
Biological Fluids ◽  
Disease Diagnosis ◽  
Analytical Sensitivity ◽  
Biomarker Detection ◽  
Affinity Capture ◽  
Circulating Cells ◽  
Cell Extracts

Biomarker detection for disease diagnosis, prognosis, and therapeutic response is becoming increasingly reliable and accessible. Particularly, the identification of circulating cell-free chemical and biochemical substances, cellular and subcellular entities, and extracellular vesicles has demonstrated promising applications in understanding the physiologic and pathologic conditions of an individual. Traditionally, tissue biopsy has been the gold standard for the diagnosis of many diseases, especially cancer. More recently, liquid biopsy for biomarker detection has emerged as a non-invasive or minimally invasive and less costly method for diagnosis of both cancerous and non-cancerous diseases, while also offering information on the progression or improvement of disease. Unfortunately, the standardization of analytical methods to isolate and quantify circulating cells and extracellular vesicles, as well as their extracted biochemical constituents, is still cumbersome, time-consuming, and expensive. To address these limitations, we have developed a prototype of a portable, miniaturized instrument that uses immunoaffinity capillary electrophoresis (IACE) to isolate, concentrate, and analyze cell-free biomarkers and/or tissue or cell extracts present in biological fluids. Isolation and concentration of analytes is accomplished through binding to one or more biorecognition affinity ligands immobilized to a solid support, while separation and analysis are achieved by high-resolution capillary electrophoresis (CE) coupled to one or more detectors. When compared to other existing methods, the process of this affinity capture, enrichment, release, and separation of one or a panel of biomarkers can be carried out on-line with the advantages of being rapid, automated, and cost-effective. Additionally, it has the potential to demonstrate high analytical sensitivity, specificity, and selectivity. As the potential of liquid biopsy grows, so too does the demand for technical advances. In this review, we therefore discuss applications and limitations of liquid biopsy and hope to introduce the idea that our affinity capture-separation device could be used as a form of point-of-care (POC) diagnostic technology to isolate, concentrate, and analyze circulating cells, extracellular vesicles, and viruses.

Prognostic and Theragnostic Applications of Circulating Tumor DNA (CtDNA) in Metastatic Castrate- resistant Prostatic Carcinoma in Veterans: A Novel Promise in Precision Oncology

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S144-S144
Author(s):  
S Dalal ◽  
D Jhala
Keyword(s):  
General Population ◽  
Minimally Invasive ◽  
Liquid Biopsy ◽  
Patient Population ◽  
Prostatic Carcinoma ◽  
Precision Oncology ◽  
Disease Course ◽  
Liquid Biopsies ◽  
Castrate Resistant

Abstract Introduction/Objective Utility of CtDNA in peripheral blood through liquid biopsies serves as a robust biomarker for precision oncology. Prostate cancer is most common cancer diagnosed in veterans, more commonly presenting at advanced stage with increased incidence of metastatic castrate-resistant prostatic carcinoma (MCRPC). Minimally invasive liquid biopsy is not limited by tumor site, type, tumor heterogeneity, and most importantly enables real time disease monitoring for best therapy decisions in MCRPC. The literature is sparse depicting the role of CtDNA in MCRPC in veteran patient population with distinct demographics/frequency of Tp53 mutations. We herein aim to study role of CtDNA in liquid biopsies for prognosis, treatment decisions and outcome in veterans with MCRPC. Methods QA documents from Foundation One (Cambridge MA, NGS) on liquid biopsies performed for the Corporal Michael J. Crescenz Veteran Affairs Medical Center (CMCVAMC) from May 2019 to April 15, 2020 were reviewed. All liquid biopsies were performed on MCRPC with evidence of tumor progression. Statistical data for adequacy, type of mutations either altering therapy, disease course or outcome was noted. Results A total of 23 liquid biopsies were performed. 21/23 (91.3%) biopsies were adequate, 19/21 (90.4%) showed signature mutations for resistance to therapy, predicting prognosis, or suggesting poor outcome with decreased overall survival. 4/21 (19%) showed androgen receptor amplification (ARV7 mutation) that helped in making treatment decisions. Increased frequency of Tp53 mutations were noted (12/21 (57.1%) compared to general population (30- 40%)) indicating worse prognosis/aggressive disease course with decreased survival. Conclusion Combined exposure of herbicide agent orange and smoking may be a fertile soil for observed differences in type and frequency of genomic alterations in veteran patient population with MCRPC. Comprehensive genomic profiling on CtDNA through minimally invasive liquid biopsy is feasible and can be successfully implemented in veterans with multiple co-morbidities. Although ARV7 mutation is much more common in general population, veterans with advanced hormone resistant prostatic carcinoma may benefit from aggressive approach in developing targeted therapy focused on DNA repair genes, especially Tp53.

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