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The Analysis of Circulating Tumor Cells (CTCs): New Insights into...
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The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 7608

Special Issue Editors

Prof. Dr. Vassilis Georgoulias

E-Mail Website
Guest Editor
Hellenic Oncology Research Group (HORG), 11471 Athens, Greece
Interests: circulating tumor cells; liquid biopsy; NSCLC; breast cancer
Dr. Galatea Kallergi

E-Mail Website
Guest Editor
Department of Biology, University of Patras, 26504 Patras, Greece
Interests: liquid biopsy; signal transduction pathways in metastasis
Special Issues, Collections and Topics in MDPI journals
Dr. Athina N. Markou

E-Mail Website
Guest Editor
Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece
Interests: circulating tumor cells; miRNAs; cfDNA; gene expression; methylation; mutations; development of sensitive molecular assays
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumor cells that allow the primary tumor to enter circulation and finally metastasize are known as circulating tumor cells (CTCs). CTCs have developed ways to survive in the hostile microenvironment of the bloodstream. More specifically, they can alter their genetic and phenotypic characteristics by expressing specific proteins, and hence create beneficial niches, acquire drug resistance, escape immune response, and enhance their invasive abilities. All these genotypic and phenotypic alterations constitute epithelial to mesenchymal transition (EMT) and contribute to tumor progression and metastasis. Phenotypic characterization of these cells could give useful information regarding prognosis, response to treatment, and early diagnosis. Subclones of CTCs have been proved to hold stronger prognostic and predictive value for patients than the total number of tumor cells in the bloodstream. Therefore, the phenotypic classification of these cells could be of clinical relevance for targeting metastatic dissemination not just in the early clinical setting but also during evolution of advanced disease. Moreover, the study of CTCs is not only instrumental as a basic research tool but also allows the serial monitoring of tumor genotypes and may therefore provide predictive and prognostic biomarkers for clinicians.

This Special Issue of Cancers focuses on investigations regarding the biology and clinical relevance of circulating tumor cells, encompassing new research articles and timely reviews.

Prof. Dr. Vassilis Georgoulias
Dr. Galatea Kallergi
Dr. Athina N. Markou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • CTC
  • DTC
  • ctDNA
  • minimal residual disease
  • MRD
  • liquid biopsy
  • circulating biomarkers
  • single cell analysis

Published Papers (5 papers)

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Research

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15 pages, 2350 KiB  
Article
DanioCTC: Analysis of Circulating Tumor Cells from Metastatic Breast Cancer Patients in Zebrafish Xenografts
by Florian Reinhardt, Luisa Coen, Mahdi Rivandi, André Franken, Eunike Sawitning Ayu Setyono, Tobias Lindenberg, Jens Eberhardt, Tanja Fehm, Dieter Niederacher, Franziska Knopf and Hans Neubauer
Cancers 2023, 15(22), 5411; https://doi.org/10.3390/cancers15225411 - 14 Nov 2023
Viewed by 1049
Abstract
Circulating tumor cells (CTCs) serve as crucial metastatic precursor cells, but their study in animal models has been hindered by their low numbers. To address this challenge, we present DanioCTC, an innovative xenograft workflow that overcomes the scarcity of patient-derived CTCs in animal [...] Read more.
Circulating tumor cells (CTCs) serve as crucial metastatic precursor cells, but their study in animal models has been hindered by their low numbers. To address this challenge, we present DanioCTC, an innovative xenograft workflow that overcomes the scarcity of patient-derived CTCs in animal models. By combining diagnostic leukapheresis (DLA), the Parsortix microfluidic system, flow cytometry, and the CellCelector setup, DanioCTC effectively enriches and isolates CTCs from metastatic breast cancer (MBC) patients for injection into zebrafish embryos. Validation experiments confirmed that MDA-MB-231 cells, transplanted following the standard protocol, localized frequently in the head and blood-forming regions of the zebrafish host. Notably, when MDA-MB-231 cells spiked (i.e., supplemented) into DLA aliquots were processed using DanioCTC, the cell dissemination patterns remained consistent. Successful xenografting of CTCs from a MBC patient revealed their primary localization in the head and trunk regions of zebrafish embryos. DanioCTC represents a major step forward in the endeavors to study the dissemination of individual and rare patient-derived CTCs, thereby enhancing our understanding of metastatic breast cancer biology and facilitating the development of targeted interventions in MBC. Summary statement: DanioCTC is a novel workflow to inject patient-derived CTCs into zebrafish, enabling studies of the capacity of these rare tumor cells to induce metastases. Full article
(This article belongs to the Special Issue The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers)
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16 pages, 1079 KiB  
Article
Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study
by Filippos Koinis, Zafeiris Zafeiriou, Ippokratis Messaritakis, Panagiotis Katsaounis, Anna Koumarianou, Emmanouil Kontopodis, Evangelia Chantzara, Chrissovalantis Aidarinis, Alexandros Lazarou, George Christodoulopoulos, Christos Emmanouilides, Dora Hatzidaki, Galatea Kallergi, Vassilis Georgoulias and Athanasios Kotsakis
Cancers 2023, 15(18), 4511; https://doi.org/10.3390/cancers15184511 - 11 Sep 2023
Cited by 2 | Viewed by 899
Abstract
Rational: Circulating tumor cells (CTCs) appear to be a promising tool for predicting the clinical outcome and monitoring the response to treatment in patients with solid tumors. The current study assessed the clinical relevance of monitoring CTCs in patients with metastatic castration resistant [...] Read more.
Rational: Circulating tumor cells (CTCs) appear to be a promising tool for predicting the clinical outcome and monitoring the response to treatment in patients with solid tumors. The current study assessed the clinical relevance of monitoring CTCs in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel. Patients and Methods: Patients with histologically confirmed mCRPC who were previously treated with a docetaxel-containing regimen and experienced disease progression were enrolled in this multicenter prospective study. CTC counts were enumerated using the CellSearch system at baseline (before cabazitaxel initiation), after one cabazitaxel cycle (post 1st cycle) and at disease progression (PD). Patients were stratified into predetermined CTC-positive and CTC-negative groups. The phenotypic characterization was performed using double immunofluorescence staining with anti-CKs and anti-Ki67, anti-M30 or anti-vimentin antibodies. Results: The median PFS and OS were 4.0 (range, 1.0–17.9) and 14.5 (range, 1.2–33.9) months, respectively. At baseline, 48 out of 57 (84.2%) patients had ≥1 CTCs/7.5 mL of peripheral blood (PB) and 37 (64.9%) had ≥5 CTCs/7.5 mL of PB. After one treatment cycle, 30 (75%) out of the 40 patients with available measurements had ≥1 detectable CTC/7.5 mL of PB and 24 (60%) ≥ 5CTCs/7.5 mL of PB; 12.5% of the patients with detectable CTCs at the baseline sample had no detectable CTCs after one treatment cycle. The detection of ≥5CTCs/7.5 mL of PB at baseline and post-cycle 1 was associated with shorter PFS and OS (p = 0.002), whereas a positive CTC status post-cycle 1 strongly correlated with poorer OS irrespective of the CTC cut-off used. Multivariate analysis revealed that the detection of non-apoptotic (CK+/M30−) CTCs at baseline is an independent predictor of shorter OS (p = 0.005). Conclusions: In patients with mCRPC treated with cabazitaxel, CTC counts both at baseline and after the first cycle retain their prognostic significance, implying that liquid biopsy monitoring might serve as a valuable tool for predicting treatment efficacy and survival outcomes. Full article
(This article belongs to the Special Issue The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers)
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15 pages, 2281 KiB  
Article
Immune Checkpoint and EMT-Related Molecules in Circulating Tumor Cells (CTCs) from Triple Negative Breast Cancer Patients and Their Clinical Impact
by Vasileios Vardas, Anastasios Tolios, Athina Christopoulou, Vassilis Georgoulias, Anastasia Xagara, Filippos Koinis, Athanasios Kotsakis and Galatea Kallergi
Cancers 2023, 15(7), 1974; https://doi.org/10.3390/cancers15071974 - 25 Mar 2023
Cited by 4 | Viewed by 1549
Abstract
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in [...] Read more.
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in CTCs of TNBC patients. Ninety-five patients were enrolled in this study: sixty-four TNBC and thirty-one luminal. Of these patients, 60 were in the early stage, while 35 had metastatic disease. Protein expression was identified by immunofluorescence staining experiments and VyCAP analysis. All the examined proteins were upregulated in TNBC patients. The expression of the GLU+VIM+CK+ phenotype was higher (50%) in metastatic TNBC compared to early TNBC patients (17%) (p = 0.005). Among all the BC patients, a significant correlation was found between PD-L1+CD45−CK+ and CTLA-4+CD45−CK+ phenotypes (Spearman test, p = 0.024), implying an important role of dual inhibition in BC. Finally, the phenotypes GLU+VIM+CK+ and PD-L1+CD45−CK+ were associated with shorter OS in TNBC patients (OS: log-rank p = 0.048, HR = 2.9, OS: log-rank p < 0.001, HR = 8.7, respectively). Thus, PD-L1, CTLA-4, GLU, and VIM constitute significant biomarkers in TNBC associated with patients’ outcome, providing new therapeutic targets for this difficult breast cancer subtype. Full article
(This article belongs to the Special Issue The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers)
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13 pages, 1931 KiB  
Article
Preoperative Mutational Analysis of Circulating Tumor Cells (CTCs) and Plasma-cfDNA Provides Complementary Information for Early Prediction of Relapse: A Pilot Study in Early-Stage Non-Small Cell Lung Cancer
by A. N. Markou, D. Londra, D. Stergiopoulou, I. Vamvakaris, K. Potaris, I. S. Pateras, A. Kotsakis, V. Georgoulias and E. Lianidou
Cancers 2023, 15(6), 1877; https://doi.org/10.3390/cancers15061877 - 21 Mar 2023
Cited by 2 | Viewed by 2093
Abstract
Purpose: We assessed whether preoperativemutational analyses of circulating tumor cells (CTCs) and plasma-cfDNA could be used as minimally invasive biomarkers and as complimentary tools for early prediction of relapse in early-stage non-small -cell lung cancer (NSCLC). Experimental Design: Using ddPCR assays, hotspot mutations [...] Read more.
Purpose: We assessed whether preoperativemutational analyses of circulating tumor cells (CTCs) and plasma-cfDNA could be used as minimally invasive biomarkers and as complimentary tools for early prediction of relapse in early-stage non-small -cell lung cancer (NSCLC). Experimental Design: Using ddPCR assays, hotspot mutations of BRAF, KRAS, EGFR and PIK3CA were identified in plasma-cfDNA samples and size-based enriched CTCs isolated from the same blood samples of 49 early-stage NSCLC patients before surgery and in a control group of healthy blood donors (n= 22). Direct concordance of the mutational spectrum was further evaluated in 27 patient-matched plasma-cfDNA and CTC-derived DNA in comparison to tissue-derived DNA. Results: The prevalence of detectable mutations of the four tested genes was higher in CTC-derived DNA than in the corresponding plasma-cfDNA (38.8% and 24.5%, respectively).The most commonly mutated gene was PIK3CA, in both CTCs and plasma-cfDNA at baseline and at the time of relapse. Direct comparison of the mutation status of selected drug-responsive genes in CTC-derived DNA, corresponding plasma-cfDNA and paired primary FFPE tissues clearly showed the impact of heterogeneity both within a sample type, as well as between different sample components. The incidence of relapse was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA compared with patients in whom no mutation was detected (p =0.023). Univariate analysis showed a significantly higher risk of progression (HR: 2.716; 95% CI, 1.030–7.165; p =0.043) in patients with detectable mutations in plasma-cfDNA compared with patients with undetectable mutations, whereas the hazard ratio was higher when at least one mutation was detected in CTC-derived DNA or plasma-cfDNA (HR: 3.375; 95% CI, 1.098–10.375; p =0.034). Conclusions: Simultaneous mutational analyses of plasma-cfDNA and CTC-derived DNA provided complementary molecular information from the same blood sample and greater diversity in genomic information for cancer treatment and prognosis. The detection of specific mutations in ctDNA and CTCs in patients with early-stage NSCLC before surgery was independently associated with disease recurrence, which represents an important stratification factor for future trials. Full article
(This article belongs to the Special Issue The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers)
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Review

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24 pages, 1041 KiB  
Review
Circulating Tumor Cells: How Far Have We Come with Mining These Seeds of Metastasis?
by Vijay Radhakrishnan, Jussuf T. Kaifi and Kanve N. Suvilesh
Cancers 2024, 16(4), 816; https://doi.org/10.3390/cancers16040816 - 17 Feb 2024
Viewed by 1193
Abstract
Circulating tumor cells (CTCs) are cancer cells that slough off from the tumor and circulate in the peripheral blood and lymphatic system as micro metastases that eventually results in macro metastases. Through a simple blood draw, sensitive CTC detection from clinical samples has [...] Read more.
Circulating tumor cells (CTCs) are cancer cells that slough off from the tumor and circulate in the peripheral blood and lymphatic system as micro metastases that eventually results in macro metastases. Through a simple blood draw, sensitive CTC detection from clinical samples has proven to be a useful tool for determining the prognosis of cancer. Recent technological developments now make it possible to detect CTCs reliably and repeatedly from a simple and straightforward blood test. Multicenter trials to assess the clinical value of CTCs have demonstrated the prognostic value of these cancer cells. Studies on CTCs have filled huge knowledge gap in understanding the process of metastasis since their identification in the late 19th century. However, these rare cancer cells have not been regularly used to tailor precision medicine and or identify novel druggable targets. In this review, we have attempted to summarize the milestones of CTC-based research from the time of identification to molecular characterization. Additionally, the need for a paradigm shift in dissecting these seeds of metastasis and the possible future avenues to improve CTC-based discoveries are also discussed. Full article
(This article belongs to the Special Issue The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers)
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