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Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 20454

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Special Issue Editor

Dr. Ewa Grzybowska

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Guest Editor

Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
Interests: breast cancer; cell migration; cell adhesion; metastasis; circulating tumor cells; HAX1; entosis; RNA-binding proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nowadays, therapeutic decisions are based overwhelmingly on the pathological and molecular characterization of the primary tumor. However, metastatic lesions can be highly heterogenous and substantially different from the primary neoplasm, which hampers the efficacy of treatments. Moreover, the inaccessibility of metastatic foci and the invasiveness of a biopsy represent challenging problems and call for some other means of secondary tumor characterization. The analysis of the circulating tumor cells (CTCs) as a surrogate for metastatic lesions is non-invasive and allows for a detailed characterization of the phenotype, genotype, heterogeneity, and expression profiling, as well as a functional analysis of tumor cells. These data should have a direct impact on the diagnosis and decision-making related to adjuvant treatment by helping with patient stratification and should also provide valuable information about the biology of metastasis. This open access Special Issue will bring together original research and review articles on CTCs, their biology, methods of enumeration and characterization, role in metastasis, and predictive value for diagnostics and therapeutic applications. It will provide a platform to share new discoveries, approaches, and technical developments in the field of CTC research for the development of the next generation of anti-metastasis treatments.

Topics of this Special Issue include, but are not limited to

Diagnostic and therapeutic applications of CTC research;
The biology of CTCs in different cancer types;
CTC mobilization by treatment;
Phenotypic/genotypic heterogeneity of CTCs;
Technical developments in the isolation, enumeration, and characterization of CTCs;
Functional analysis of CTCs, including culture and CDX;
CTC analysis in single-cell resolution;
Cell-free DNA vs. CTC;
Epithelial/hybrid/mesenchymal properties of CTCs;
CTC clusters: biology, enumeration, role in metastasis.

Dr. Ewa Grzybowska
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
metastasis
tumor heterogeneity
invasion
single-cell analysis
cancer dissemination
circulation
treatment response
CTC clusters

Published Papers (7 papers)

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Research

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15 pages, 2107 KiB

Open AccessArticle

Simple Detection and Culture of Circulating Tumor Cells from Colorectal Cancer Patients Using Poly(2-Methoxyethyl Acrylate)-Coated Plates

by Masatoshi Nomura, Yuhki Yokoyama, Daishi Yoshimura, Yasuhisa Minagawa, Aki Yamamoto, Yukiko Tanaka, Naoko Sekiguchi, Daiki Marukawa, Momoko Ichihara, Hiroaki Itakura, Kenichi Matsumoto, Yoshihiro Morimoto, Hideo Tomihara, Akira Inoue, Takayuki Ogino, Norikatsu Miyoshi, Hidekazu Takahashi, Hidenori Takahashi, Mamoru Uemura, Shogo Kobayashi, Tsunekazu Mizushima, Takahisa Anada, Masaki Mori, Yuichiro Doki, Masaru Tanaka, Hidetoshi Eguchi and Hirofumi Yamamoto Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(4), 3949; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043949 - 16 Feb 2023

Cited by 4 | Viewed by 2493

Abstract

Here we aimed to establish a simple detection method for detecting circulating tumor cells (CTCs) in the blood sample of colorectal cancer (CRC) patients using poly(2-methoxyethyl acrylate) (PMEA)-coated plates. Adhesion test and spike test using CRC cell lines assured efficacy of PMEA coating. A total of 41 patients with pathological stage II–IV CRC were enrolled between January 2018 and September 2022. Blood samples were concentrated by centrifugation by the OncoQuick tube, and then incubated overnight on PMEA-coated chamber slides. The next day, cell culture and immunocytochemistry with anti-EpCAM antibody were performed. Adhesion tests revealed good attachment of CRCs to PMEA-coated plates. Spike tests indicated that ~75% of CRCs from a 10-mL blood sample were recovered on the slides. By cytological examination, CTCs were identified in 18/41 CRC cases (43.9%). In cell cultures, spheroid-like structures or tumor-cell clusters were found in 18/33 tested cases (54.5%). Overall, CTCs and/or growing circulating tumor cells were found in 23/41 CRC cases (56.0%). History of chemotherapy or radiation was significantly negatively correlated with CTC detection (p = 0.02). In summary, we successfully captured CTCs from CRC patients using the unique biomaterial PMEA. Cultured tumor cells will provide important and timely information regarding the molecular basis of CTCs. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0)

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Figure 1

14 pages, 2644 KiB

Open AccessArticle

The Association of Integrins β3, β4, and αVβ5 on Exosomes, CTCs and Tumor Cells with Localization of Distant Metastasis in Breast Cancer Patients

by Evgeniya S. Grigoryeva, Luibov A. Tashireva, Olga E. Savelieva, Marina V. Zavyalova, Nataliya O. Popova, Gleb A. Kuznetsov, Elena S. Andryuhova and Vladimir M. Perelmuter

Int. J. Mol. Sci. 2023, 24(3), 2929; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032929 - 02 Feb 2023

Cited by 7 | Viewed by 2006

Abstract

Integrins are cell adhesion receptors, which play a role in breast cancer invasion, angiogenesis, and metastasis. Moreover, it has been shown that exosomal integrins provide organotropic metastasis in a mouse model. In our study, we aimed to investigate the expression of integrins β3, β4, and αVβ5 on exosomes and tumor cells (circulating tumor cells and primary tumor) and their association with the localization of distant metastasis. We confirmed the association of exosomal integrin β4 with lung metastasis in breast cancer patients. However, we were unable to evaluate the role of integrin β3 in brain metastasis due to the rarity of this localization. We established no association of exosomal integrin αVβ5 with liver metastasis in our cohort of breast cancer patients. The further evaluation of β3, β4, and αVβ5 integrin expression on CTCs revealed an association of integrin β4 and αVβ5 with liver, but not the lung metastases. Integrin β4 in the primary tumor was associated with liver metastasis. Furthermore, an in-depth analysis of phenotypic characteristics of β4+ tumor cells revealed a significantly increased proportion of E-cadherin+ and CD44+CD24- cells in patients with liver metastases compared to patients with lung or no distant metastases. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0)

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16 pages, 3262 KiB

Open AccessArticle

Detection of Circulating Tumor Cells Using the Attune NxT

by Mandy Gruijs, Carolien Zeelen, Tessa Hellingman, Jasper Smit, Frank J. Borm, Geert Kazemier, Chris Dickhoff, Idris Bahce, Joop de Langen, Egbert F. Smit, Koen J. Hartemink and Marjolein van Egmond

Int. J. Mol. Sci. 2023, 24(1), 21; https://doi.org/10.3390/ijms24010021 - 20 Dec 2022

Cited by 3 | Viewed by 2792

Abstract

Circulating tumor cells (CTCs) have been detected in many patients with different solid malignancies. It has been reported that presence of CTCs correlates with worse survival in patients with multiple types of cancer. Several techniques have been developed to detect CTCs in liquid biopsies. Currently, the only method for CTC detection that is approved by the Food and Drug Administration is CellSearch. Due to low abundance of CTCs in certain cancer types and in early stages of disease, its clinical application is currently limited to metastatic colorectal cancer, breast cancer and prostate cancer. Therefore, we aimed to develop a new method for the detection of CTCs using the Attune NxT—a flow cytometry-based application that was specifically developed to detect rare events in biological samples without the need for enrichment. When healthy donor blood samples were spiked with variable amounts of different EpCAM+EGFR+ tumor cell lines, recovery yield was on average 75%. The detection range was between 1000 and 10 cells per sample. Cell morphology was confirmed with the Attune CytPix. Analysis of blood samples from metastatic colorectal cancer patients, as well as lung cancer patients, demonstrated that increased EpCAM+EGFR+ events were detected in more than half of the patient samples. However, most of these cells showed no (tumor) cell-like morphology. Notably, CellSearch analysis of blood samples from a subset of colorectal cancer patients did not detect CTCs either, suggesting that these blood samples were negative for CTCs. Therefore, we anticipate that the Attune NxT is not superior to CellSearch in detection of low amounts of CTCs, although handling and analysis of samples is easier. Moreover, morphological confirmation is essential to distinguish between CTCs and false positive events. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0)

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16 pages, 2566 KiB

Open AccessArticle

Targeting PIK3CA Actionable Mutations in the Circulome: A Proof of Concept in Metastatic Breast Cancer

by Barbara Cardinali, Giuseppa De Luca, Roberta Tasso, Simona Coco, Anna Garuti, Giulia Buzzatti, Andrea Sciutto, Luca Arecco, Federico Villa, Franca Carli, Daniele Reverberi, Rodolfo Quarto, Mariella Dono and Lucia Del Mastro

Int. J. Mol. Sci. 2022, 23(11), 6320; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116320 - 05 Jun 2022

Cited by 4 | Viewed by 2383

Abstract

The study of circulating cancer-derived components (circulome) is considered the new frontier of liquid biopsy. Despite the recognized role of circulome biomarkers, their comparative molecular profiling is not yet routine. In advanced breast cancer (BC), approximately 40% of hormone-receptor-positive, HER2-negative BC cases harbor druggable PIK3CA mutations suitable for combined alpelisib/fulvestrant treatment. This pilot study investigates PIK3CA mutations in circulating tumor DNA (ctDNA), tumor cells (CTCs), and extracellular vesicles (EVs) with the aim of determining which information on molecular targetable profiling could be recollected in each of them. The in-depth molecular analysis of four BC patients demonstrated, as a proof-of-concept study, that it is possible to retrieve mutational information in the three components. Patient-specific PIK3CA mutations were found in both tissue and ctDNA and in 3/4 cases, as well as in CTCs, in the classical population (large-sized CD45−/EpCAM+/− cells), and/or in the “non-conventional” sub-population (smaller-sized CD44+/EpCAM−/CD45− cells). Consistent mutational profiles of EVs with CTCs suggest that they may have been released by CTCs. This preliminary evidence on the molecular content of the different circulating biomaterials suggests their possible function as a mirror of the intrinsic heterogeneity of BC. Moreover, this study demonstrates, through mutational assessment, the tumor origin of the different CTC sub-populations sustaining the translational value of the circulome for a more comprehensive picture of the disease. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0)

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Review

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17 pages, 1359 KiB

Open AccessReview

Technologies for Viable Circulating Tumor Cell Isolation

by Maria S. Tretyakova, Maxim E. Menyailo, Anastasia A. Schegoleva, Ustinia A. Bokova, Irina V. Larionova and Evgeny V. Denisov

Int. J. Mol. Sci. 2022, 23(24), 15979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415979 - 15 Dec 2022

Cited by 5 | Viewed by 2967

Abstract

The spread of tumor cells throughout the body by traveling through the bloodstream is a critical step in metastasis, which continues to be the main cause of cancer-related death. The detection and analysis of circulating tumor cells (CTCs) is important for understanding the biology of metastasis and the development of antimetastatic therapy. However, the isolation of CTCs is challenging due to their high heterogeneity and low representation in the bloodstream. Different isolation methods have been suggested, but most of them lead to CTC damage. However, viable CTCs are an effective source for developing preclinical models to perform drug screening and model the metastatic cascade. In this review, we summarize the available literature on methods for isolating viable CTCs based on different properties of cells. Particular attention is paid to the importance of in vitro and in vivo models obtained from CTCs. Finally, we emphasize the current limitations in CTC isolation and suggest potential solutions to overcome them. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0)

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24 pages, 1370 KiB

Open AccessReview

Clinical Relevancy of Circulating Tumor Cells in Breast Cancer: Epithelial or Mesenchymal Characteristics, Single Cells or Clusters?

by Ivana Fridrichova, Lenka Kalinkova and Sona Ciernikova

Int. J. Mol. Sci. 2022, 23(20), 12141; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012141 - 12 Oct 2022

Cited by 10 | Viewed by 2516

Abstract

Metastatic breast cancer (MBC) is typically an incurable disease with high mortality rates; thus, early identification of metastatic features and disease recurrence through precise biomarkers is crucial. Circulating tumor cells (CTCs) consisting of heterogeneous subpopulations with different morphology and genetic, epigenetic, and gene expression profiles represent promising candidate biomarkers for metastatic potential. The experimentally verified role of epithelial-to-mesenchymal transition in cancer dissemination has not been clearly described in BC patients, but the stemness features of CTCs strongly contributes to metastatic potency. Single CTCs have been shown to be protected in the bloodstream against recognition by the immune system through impaired interactions with T lymphocytes and NK cells, while associations of heterotypic CTC clusters with platelets, leucocytes, neutrophils, tumor-associated macrophages, and fibroblasts improve their tumorigenic behavior. In addition to single CTC and CTC cluster characteristics, we reviewed CTC evaluation methods and clinical studies in early and metastatic BCs. The variable CTC tests were developed based on specific principles and strategies. However, CTC count and the presence of CTC clusters were shown to be most clinically relevant in existing clinical trials. Despite the known progress in CTC research and sampling of BC patients, implementation of CTCs and CTC clusters in routine diagnostic and treatment strategies still requires improvement in detection sensitivity and precise molecular characterizations, focused predominantly on the role of CTC clusters for their higher metastatic potency. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0)

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Graphical abstract

18 pages, 1222 KiB

Open AccessReview

Exploring the Clinical Utility of Pancreatic Cancer Circulating Tumor Cells

by Dannel Yeo, Althea Bastian, Heidi Strauss, Payal Saxena, Peter Grimison and John E. J. Rasko

Int. J. Mol. Sci. 2022, 23(3), 1671; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031671 - 31 Jan 2022

Cited by 18 | Viewed by 4360

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type, characterized by a dismal prognosis due to late diagnosis, frequent metastases, and limited therapeutic response to standard chemotherapy. Circulating tumor cells (CTCs) are a rare subset of tumor cells found in the blood of cancer patients. CTCs has the potential utility for screening, early and definitive diagnosis, prognostic and predictive assessment, and offers the potential for personalized management. However, a gold-standard CTC detection and enrichment method remains elusive, hindering comprehensive comparisons between studies. In this review, we summarize data regarding the utility of CTCs at different stages of PDAC from early to metastatic disease and discuss the molecular profiling and culture of CTCs. The characterization of CTCs brings us closer to defining the specific CTC subpopulation responsible for metastasis with the potential to uncover new therapies and more effective management options for PDAC. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 3.0)

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