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The 5th ACTC: “Liquid Biopsy in Its Best”

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 43180

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Prof. Dr. Evi S. Lianidou

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Analysis of Circulating Tumor Cells Lab, Department of Chemistry, University of Athens, University Campus, 15771 Athens, Greece
Interests: liquid biopsy; circulating tumor cells (CTCs); circulating tumor DNA (ctDNA); circulating miRNAs; DNA methylation; gene expression; molecular assays
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Special Issue Information

Dear Colleagues,

Liquid biopsy is a fascinating and exponentially growing field that has tremendous potential to significantly change the therapeutic strategy and management of cancer patients.

This Special Issue of Cancers will consist of selected papers presented at the 5th ACTC (Advances in Circulating Tumor Cells) “Liquid Biopsy in Its Best” meeting (www.actc2021.org) that took place in Kalamata, Greece, on 22–25 September 2021.

The 5th ACTC meeting was the first in-person meeting in the liquid biopsy field after the outbreak of the COVID-19 pandemic and was held in an extremely safe environment following all safety guidelines. The meeting was attended by 210 participants that travelled to Greece from 23 countries. Once again, researchers from academia, clinical oncologists and technology providers had, after such a long time, the chance to interact, establish collaborations and present their latest data in a unique, relaxing and stimulating environment. It is great that even under these difficult conditions due to the pandemic, a critical mass of world-recognized pioneer researchers and clinical oncologists, who have made major contributions in the field, participated in the 5th ACTC Meeting through state-of-the-art presentations, stimulating discussions, and sharing unpublished data. All sessions were highly attended and interactive, and all presentations stimulated intensive discussions.

State-of-the-art research on the biology of metastasis, on the molecular characterization of CTCs, ctDNA analysis, miRNAs and extracellular vesicles was presented in parallel with clinical applications of liquid biopsies and latest technological achievements in the field. The program consisted of 29 plenary lectures, 27 selected oral presentations, and 92 posters. There were also 11 high level industry-sponsored presentations on the latest advances in liquid biopsy technologies. All sessions were highly attended. The latest findings from clinical trials based on liquid biopsy approaches were thoroughly discussed. Three travel grants and three poster awards were granted to the best submitted abstracts.

This Special Issue in Cancers will publish a selection of papers presented as oral presentations or posters at the 5th ACTC meeting. This Special Issue will focus on state-of-the-art developments in liquid biopsy technologies, on the latest findings on CTCs and ctDNA analysis, and its implementation in clinical practice.

Prof. Dr. Evi S. Lianidou
Guest Editor

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Keywords

liquid biopsy
circulating tumor cells
circulating tumor DNA
CTCs
ctDNA
circulating miRNAs
exosomes
extracellular vesicles
precision medicine

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Published Papers (13 papers)

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14 pages, 2755 KiB

Open AccessArticle

Verification of a Novel Minimally Invasive Device for the Isolation of Rare Circulating Tumor Cells (CTC) in Cancer Patients’ Blood

by Paul Friedrich Geus, Felix Hehnen, Sophia Krakowski, Klaus Lücke, Dave S. B. Hoon, Nikolaj Frost, Ulrich Kertzscher and Gabi Wendt

Cancers 2022, 14(19), 4753; https://doi.org/10.3390/cancers14194753 - 29 Sep 2022

Cited by 1 | Viewed by 2564

Abstract

Circulating tumor cells (CTCs) exist in low quantities in the bloodstream in the early stages of cancers. It, therefore, remains a technical challenge to isolate them in large enough quantities for a precise diagnosis and downstream analysis. We introduce the BMProbe™, a minimally invasive device that isolates CTCs during a 30-minute incubation in the median cubital vein. The optimized geometry of the device creates flow conditions for improved cell deposition. The CTCs are isolated using antibodies that are bound to the surface of the BMProbe™. In this study, flow experiments using cell culture cells were conducted. They indicate a 31 times greater cell binding efficiency of the BMProbe™ compared to a flat geometry. Further, the functionality of isolating CTCs from patient blood was verified in a small ex vivo study that compared the cell count from seven non-small-cell lung carcinoma (NSCLC) patients compared to nine healthy controls with 10 mL blood samples. The median cell count was 1 in NSCLC patients and 0 in healthy controls. In conclusion, the BMProbe™ is a promising method to isolate CTCs in large quantities directly from the venous bloodstream without removing blood from a patient. The future step is to verify the functionality in vivo. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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12 pages, 1925 KiB

Open AccessArticle

Characterization of RARRES1 Expression on Circulating Tumor Cells as Unfavorable Prognostic Marker in Resected Pancreatic Ductal Adenocarcinoma Patients

by Christine Nitschke, Benedikt Markmann, Marie Tölle, Jolanthe Kropidlowski, Yassine Belloum, Mara R. Goetz, Hartmut Schlüter, Marcel Kwiatkowski, Marianne Sinn, Jakob Izbicki, Klaus Pantel, Cenap Güngör, Faik G. Uzunoglu and Harriet Wikman

Cancers 2022, 14(18), 4405; https://doi.org/10.3390/cancers14184405 - 10 Sep 2022

Cited by 11 | Viewed by 2499

Abstract

Background: In pancreatic ductal adenocarcinoma (PDAC), the characterization of circulating tumor cells (CTCs) opens new insights into cancer metastasis as the leading cause of cancer-related death. Here, we focused on the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs as a novel marker for treatment failure and early relapse. Methods: The stable isotope labeling of amino acids in cell culture (SILAC)—approach was applied for identifying and quantifying new biomarker proteins in PDAC cell lines HPDE and its chemoresistant counterpart, L3.6pl-Res. Fifty-five baseline and 36 follow-up (FUP) peripheral blood samples were processed via a marker-independent microfluidic-based CTC detection approach using RARRES1 as an additional marker. Results: SILAC-based proteomics identified RARRES1 as an abundantly expressed protein in more aggressive chemoresistant PDAC cells. At baseline, CTCs were detected in 25.5% of all PDAC patients, while FUP analysis (median: 11 months FUP) showed CTC detection in 45.5% of the resected patients. CTC positivity (≥3 CTC) at FUP was significantly associated with short recurrence-free survival (p = 0.002). Furthermore, detection of RARRES1 positive CTCs was indicative of an even earlier relapse after surgery (p = 0.001). Conclusions: CTC detection in resected PDAC patients during FUP is associated with a worse prognosis, and RARRES1 expression might identify an aggressive subtype of CTCs that deserves further investigation. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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15 pages, 3744 KiB

Open AccessArticle

Characterizing Circulating Tumor Cells and Tumor-Derived Extracellular Vesicles in Metastatic Castration-Naive and Castration-Resistant Prostate Cancer Patients

by Khrystany T. Isebia, Eshwari Dathathri, Noortje Verschoor, Afroditi Nanou, Anouk C. De Jong, Frank A. W. Coumans, Leon W. M. M. Terstappen, Jaco Kraan, John W. M. Martens, Ruchi Bansal and Martijn P. Lolkema

Cancers 2022, 14(18), 4404; https://doi.org/10.3390/cancers14184404 - 10 Sep 2022

Cited by 7 | Viewed by 2430

Abstract

Circulating tumor cell (CTC)- and/or tumor-derived extracellular vesicle (tdEV) loads in the blood of metastatic castration-resistant prostate cancer (CRPC) patients are associated with worse overall survival and can be used as predictive markers of treatment response. In this study, we investigated the quantity/quality of CTCs and tdEVs in metastatic castration-naive prostate cancer (CNPC) and CRPC patients, and whether androgen deprivation therapy (ADT) affects CTCs and tdEVs. We included 104 CNPC patients before ADT initiation and 66 CRPC patients. Blood samples from 31/104 CNPC patients were obtained 6 months after ADT. CTCs and tdEVs were identified using ACCEPT software. Based on the morphology, CTCs of metastatic CNPC and CRPC patients were subdivided by manual reviewing into six subclasses. The numbers of CTCs and tdEVs were correlated in both CNPC and CRPC patients, and both CTCs (p = 0.013) and tdEVs (p = 0.005) were significantly lower in CNPC compared to CRPC patients. Qualitative differences in CTCs were observed: CTC clusters (p = 0.006) and heterogeneously CK expressing CTCs (p = 0.041) were significantly lower in CNPC patients. CTC/tdEV numbers declined 6 months after ADT. Our study showed that next to CTC-load, qualitative CTC analysis and tdEV-load may be useful in CNPC patients. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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14 pages, 1398 KiB

Open AccessCommunication

Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach

by Cristina Catoni, Cristina Poggiana, Antonella Facchinetti, Jacopo Pigozzo, Luisa Piccin, Vanna Chiarion-Sileni, Antonio Rosato, Giovanni Minervini and Maria Chiara Scaini

Cancers 2022, 14(17), 4153; https://doi.org/10.3390/cancers14174153 - 27 Aug 2022

Cited by 4 | Viewed by 2611

Abstract

The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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15 pages, 964 KiB

Open AccessArticle

Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis—Results from the Adjuvant SUCCESS A Trial

by Elisabeth K. Trapp, Peter A. Fasching, Tanja Fehm, Andreas Schneeweiss, Volkmar Mueller, Nadia Harbeck, Ralf Lorenz, Claudia Schumacher, Georg Heinrich, Fabienne Schochter, Amelie de Gregorio, Marie Tzschaschel, Brigitte Rack, Wolfgang Janni and Thomas W. P. Friedl

Cancers 2022, 14(16), 3949; https://doi.org/10.3390/cancers14163949 - 16 Aug 2022

Cited by 12 | Viewed by 2402

Abstract

The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch^®-System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1–827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1–124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy (p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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20 pages, 3295 KiB

Open AccessArticle

Improvements in Quality Control and Library Preparation for Targeted Sequencing Allowed Detection of Potentially Pathogenic Alterations in Circulating Cell-Free DNA Derived from Plasma of Brain Tumor Patients

by Paulina Szadkowska, Adria-Jaume Roura, Bartosz Wojtas, Kamil Wojnicki, Sabina Licholai, Tomasz Waller, Tomasz Gubala, Kacper Zukowski, Michal Karpeta, Kinga Wilkus, Wojciech Kaspera, Sergiusz Nawrocki and Bozena Kaminska

Cancers 2022, 14(16), 3902; https://doi.org/10.3390/cancers14163902 - 12 Aug 2022

Cited by 6 | Viewed by 2808

Abstract

Malignant gliomas are the most frequent primary brain tumors in adults. They are genetically heterogenous and invariably recur due to incomplete surgery and therapy resistance. Circulating tumor DNA (ctDNA) is a component of circulating cell-free DNA (ccfDNA) and represents genetic material that originates from the primary tumor or metastasis. Brain tumors are frequently located in the eloquent brain regions, which makes biopsy difficult or impossible due to severe postoperative complications. The analysis of ccfDNA from a patient’s blood presents a plausible and noninvasive alternative. In this study, freshly frozen tumors and corresponding blood samples were collected from 84 brain tumor patients and analyzed by targeted next-generation sequencing (NGS). The cohort included 80 glioma patients, 2 metastatic cancer patients, and 2 primary CNS lymphoma (PCNSL) patients. We compared the pattern of genetic alterations in the tumor DNA (tDNA) with that of ccfDNA. The implemented technical improvements in quality control and library preparation allowed for the detection of ctDNA in 8 out of 84 patients, including 5 out of 80 glioma patients. In 32 out of 84 patients, we found potentially pathogenic genetic alterations in ccfDNA that were not detectable in tDNA. While sequencing ccfDNA from plasma has a low efficacy as a diagnostic tool for glioma patients, we concluded that further improvements in sample processing and library preparation can make liquid biopsy a valuable diagnostic tool for glioma patients. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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12 pages, 763 KiB

Open AccessArticle

by A. Zafeiriadou, I. Kollias, T. Londra, E. Tsaroucha, V. Georgoulias, A. Kotsakis, E. Lianidou and A. Markou

Cancers 2022, 14(13), 3237; https://doi.org/10.3390/cancers14133237 - 30 Jun 2022

Cited by 6 | Viewed by 3325

Abstract

Purpose: Metabolic reprogramming is now characterized as one of the core hallmarks of cancer, and it has already been shown that the altered genomic profile of metabolically rewired cancer cells can give valuable information. In this study, we quantified three Metabolism-Related Gene (MRG) transcripts in the circulating tumor cells (CTCs) of early stage NSCLC patients and evaluated their associations with epithelial and EMT markers. Experimental Design: We first developed and analytically validated highly sensitive RT-qPCR assays for the quantification of HK2, MCT1 and PHGDH transcripts, and further studied the expression of MRGs in CTCs that were isolated using a size-dependent microfluidic device (Parsortix, Angle) from the peripheral blood of: (a) 46 NSCLC patients at baseline, (b) 39/46 of these patients one month after surgery, (c) 10/46 patients at relapse and (d) 10 pairs of cancerous and adjacent non-cancerous FFPE tissues from the same NSCLC patients. Epithelial and EMT markers were also evaluated. Results: MCT1 and HK2 were differentially expressed between HD and NSCLC patients. An overexpression of MCT1 was detected in 15/46 (32.6%) and 3/10 (30%) patients at baseline and at progression disease (PD), respectively, whereas an overexpression of HK2 was detected in 30.4% and 0% of CTCs in the same group of samples. The expression levels of all tested MRGs decreased in CTCs one month after surgery, but a significant increase was noticed at the time of relapse for PHGDH and MCT1 only. The expression levels of HK2 and MCT1 were associated with the overexpression of mesenchymal markers (TWIST-1 and VIM). Conclusion: An overexpression of MRGs was observed at a high frequency in the CTCs isolated from early NSCLC patients, thereby supporting the role of MRGs in metastatic processes. The glycolytic and mesenchymal subpopulation of CTCs was significantly predominant compared to CTCs that were glycolytic but not mesenchymal-like. Our data indicate that MRGs merit further evaluation through large and well-defined cohort studies. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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13 pages, 2765 KiB

Open AccessArticle

StarDist Image Segmentation Improves Circulating Tumor Cell Detection

by Michiel Stevens, Afroditi Nanou, Leon W. M. M. Terstappen, Christiane Driemel, Nikolas H. Stoecklein and Frank A. W. Coumans

Cancers 2022, 14(12), 2916; https://doi.org/10.3390/cancers14122916 - 13 Jun 2022

Cited by 33 | Viewed by 4495

Abstract

After a CellSearch-processed circulating tumor cell (CTC) sample is imaged, a segmentation algorithm selects nucleic acid positive (DAPI+), cytokeratin-phycoerythrin expressing (CK-PE+) events for further review by an operator. Failures in this segmentation can result in missed CTCs. The CellSearch segmentation algorithm was not designed to handle samples with high cell density, such as diagnostic leukapheresis (DLA) samples. Here, we evaluate deep-learning-based segmentation method StarDist as an alternative to the CellSearch segmentation. CellSearch image archives from 533 whole blood samples and 601 DLA samples were segmented using CellSearch and StarDist and inspected visually. In 442 blood samples from cancer patients, StarDist segmented 99.95% of CTC segmented by CellSearch, produced good outlines for 98.3% of these CTC, and segmented 10% more CTC than CellSearch. Visual inspection of the segmentations of DLA images showed that StarDist continues to perform well when the cell density is very high, whereas CellSearch failed and generated extremely large segmentations (up to 52% of the sample surface). Moreover, in a detailed examination of seven DLA samples, StarDist segmented 20% more CTC than CellSearch. Segmentation is a critical first step for CTC enumeration in dense samples and StarDist segmentation convincingly outperformed CellSearch segmentation. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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14 pages, 2627 KiB

Open AccessArticle

Urine Cell-Free MicroRNAs in Localized Prostate Cancer Patients

by Yoko Koh, Matias A. Bustos, Jamie Moon, Rebecca Gross, Romela Irene Ramos, Suyeon Ryu, Jane Choe, Selena Y. Lin, Warren M. Allen, David L. Krasne, Timothy G. Wilson and Dave S. B. Hoon

Cancers 2022, 14(10), 2388; https://doi.org/10.3390/cancers14102388 - 12 May 2022

Cited by 8 | Viewed by 2731

Abstract

Prostate cancer (PCa) is the most common cancer in men. Prostate-specific antigen screening is recommended for the detection of PCa. However, its specificity is limited. Thus, there is a need to find more reliable biomarkers that allow non-invasive screening for early-stage PCa. This study aims to explore urine microRNAs (miRs) as diagnostic biomarkers for PCa. We assessed cell-free miR (cfmiR) profiles of urine and plasma samples from pre- and post-operative PCa patients (n = 11) and normal healthy donors (16 urine and 24 plasma) using HTG EdgeSeq miRNA Whole Transcriptome Assay based on next-generation sequencing. Furthermore, tumor-related miRs were detected in formalin-fixed paraffin-embedded tumor tissues obtained from patients with localized PCa. Specific cfmiRs signatures were found in urine samples of localized PCa patients using differential expression analysis. Forty-two cfmiRs that were detected were common to urine, plasma, and tumor samples. These urine cfmiRs may have potential utility in diagnosing early-stage PCa and complementing or improving currently available PCa screening assays. Future studies may validate the findings. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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17 pages, 2185 KiB

Open AccessArticle

Clinical Validity of Circulating Tumor DNA as Prognostic and Predictive Marker for Personalized Colorectal Cancer Patient Management

by Ariane Hallermayr, Verena Steinke-Lange, Holger Vogelsang, Markus Rentsch, Maike de Wit, Christopher Haberl, Elke Holinski-Feder and Julia M. A. Pickl

Cancers 2022, 14(3), 851; https://doi.org/10.3390/cancers14030851 - 8 Feb 2022

Cited by 7 | Viewed by 3497

Abstract

Circulating tumor DNA (ctDNA) is a promising liquid biopsy (LB) marker to support clinical decisions in precision medicine. For implementation into routine clinical practice, clinicians need precise ctDNA level cutoffs for reporting residual disease and monitoring tumor burden changes during therapy. We clinically validated the limit of blank (LOB) and the limit of quantification (LOQ) of assays for the clinically most relevant somatic variants BRAF p.V600E and KRAS p.G12/p.G13 in colorectal cancer (CRC) in a study cohort encompassing a total of 212 plasma samples. We prove that residual disease detection using the LOB as a clinically verified cutoff for ctDNA positivity is in concordance with clinical evidence of metastasis or recurrence. We further show that tumor burden changes during chemotherapy and the course of disease are correctly predicted using the LOQ as a cutoff for quantitative ctDNA changes. The high potential of LB using ctDNA for accurately predicting the course of disease was proven by direct comparison to the routinely used carcinoembryonic antigen (CEA) as well as the circulating free DNA (cfDNA) concentration. Our results show that LB using validated ctDNA assays outperforms CEA and cfDNA for residual disease detection and the prediction of tumor burden changes. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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20 pages, 1020 KiB

Open AccessEditor’s ChoiceReview

Detection and Molecular Characterization of Circulating Tumour Cells: Challenges for the Clinical Setting

by Areti Strati, Athina Markou, Evgenia Kyriakopoulou and Evi Lianidou

Cancers 2023, 15(7), 2185; https://doi.org/10.3390/cancers15072185 - 6 Apr 2023

Cited by 20 | Viewed by 4443

Abstract

Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis of circulating tumour cells (CTCs) and circulating tumour-derived material, such as circulating tumour DNA (ctDNA), circulating miRNAs (cfmiRNAs) and extracellular vehicles (EVs). CTC analysis has already had an important impact on the prognosis, detection of minimal residual disease (MRD), treatment selection and monitoring of cancer patients. Numerous clinical trials nowadays include a liquid biopsy arm. CTC analysis is now an exponentially expanding field in almost all types of solid cancers. Functional studies, mainly based on CTC-derived cell-lines and CTC-derived explants (CDx), provide important insights into the metastatic process. The purpose of this review is to summarize the latest findings on the clinical significance of CTCs for the management of cancer patients, covering the last four years. This review focuses on providing a comprehensive overview of CTC analysis in breast, prostate and non-small-cell lung cancer. The unique potential of CTC single-cell analysis for understanding metastasis biology, and the importance of quality control and standardization of methodologies used in this field, is also discussed. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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16 pages, 2729 KiB

Open AccessReview

Pre-PCR Mutation-Enrichment Methods for Liquid Biopsy Applications

by Farzaneh Darbeheshti, Fangyan Yu and G. Mike Makrigiorgos

Cancers 2022, 14(13), 3143; https://doi.org/10.3390/cancers14133143 - 27 Jun 2022

Cited by 6 | Viewed by 3592

Abstract

Liquid biopsy is having a remarkable impact on healthcare- and disease-management in the context of personalized medicine. Circulating free DNA (cfDNA) is one of the most instructive liquid-biopsy-based biomarkers and harbors valuable information for diagnostic, predictive, and prognostic purposes. When it comes to cancer, circulating DNA from the tumor (ctDNA) has a wide range of applications, from early cancer detection to the early detection of relapse or drug resistance, and the tracking of the dynamic genomic make-up of tumor cells. However, the detection of ctDNA remains technically challenging, due, in part, to the low frequency of ctDNA among excessive circulating cfDNA originating from normal tissues. During the past three decades, mutation-enrichment methods have emerged to boost sensitivity and enable facile detection of low-level mutations. Although most developed techniques apply mutation enrichment during or following initial PCR, there are a few techniques that allow mutation selection prior to PCR, which provides advantages. Pre-PCR enrichment techniques can be directly applied to genomic DNA and diminish the influence of PCR errors that can take place during amplification. Moreover, they have the capability for high multiplexity and can be followed by established mutation detection and enrichment technologies without changes to their established procedures. The first approaches for pre-PCR enrichment were developed by employing restriction endonucleases directly on genomic DNA in the early 1990s. However, newly developed pre-PCR enrichment methods provide higher sensitivity and versatility. This review describes the available pre-PCR enrichment methods and focuses on the most recently developed techniques (NaME-PrO, UVME, and DEASH/MAESTRO), emphasizing their applications in liquid biopsies. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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10 pages, 1109 KiB

Open AccessPerspective

Detection and Characterization of Circulating Tumor Cells Using Imaging Flow Cytometry—A Perspective Study

by Anna Muchlińska, Julia Smentoch, Anna J. Żaczek and Natalia Bednarz-Knoll

Cancers 2022, 14(17), 4178; https://doi.org/10.3390/cancers14174178 - 29 Aug 2022

Cited by 21 | Viewed by 4112

Abstract

Tumor dissemination is one of the most-investigated steps of tumor progression, which in recent decades led to the rapid development of liquid biopsy aiming to analyze circulating tumor cells (CTCs), extracellular vesicles (EVs), and circulating nucleic acids in order to precisely diagnose and monitor cancer patients. Flow cytometry was considered as a method to detect CTCs; however, due to the lack of verification of the investigated cells’ identity, this method failed to reach clinical utility. Meanwhile, imaging flow cytometry combining the sensitivity and high throughput of flow cytometry and image-based detailed analysis through a high-resolution microscope might open a new avenue in CTC technologies and provide an open-platform system alternative to CellSearch^®, which is still the only gold standard in this field. Hereby, we shortly review the studies on the usage of flow cytometry in CTC identification and present our own representative images of CTCs envisioned by imaging flow cytometry providing rationale that this novel technology might be a good tool for studying tumor dissemination, and, if combined with a high CTC yield enrichment method, could upgrade CTC-based diagnostics. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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