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Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 February 2021) | Viewed by 17333

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Dr. Ewa A. Grzybowska

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Cancer Center Institute, Roentgena 5, 02-781 Warsaw, Poland
Interests: circulating tumor cells; breast cancer; tumor heterogeneity; invasion
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 A. 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 (6 papers)

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Research

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18 pages, 2404 KiB

Open AccessArticle

Heterogeneous Manifestations of Epithelial–Mesenchymal Plasticity of Circulating Tumor Cells in Breast Cancer Patients

by Liubov A. Tashireva, Olga E. Savelieva, Evgeniya S. Grigoryeva, Yuri V. Nikitin, Evgeny V. Denisov, Sergey V. Vtorushin, Marina V. Zavyalova, Nadezhda V. Cherdyntseva and Vladimir M. Perelmuter

Int. J. Mol. Sci. 2021, 22(5), 2504; https://doi.org/10.3390/ijms22052504 - 2 Mar 2021

Cited by 16 | Viewed by 2308

Abstract

To date, there is indisputable evidence of significant CTC heterogeneity in carcinomas, in particular breast cancer. The heterogeneity of CTCs is manifested in the key characteristics of tumor cells related to metastatic progression – stemness and epithelial–mesenchymal (EMT) plasticity. It is still not clear what markers can characterize the phenomenon of EMT plasticity in the range from epithelial to mesenchymal phenotypes. In this article we examine the manifestations of EMT plasticity in the CTCs in breast cancer. The prospective study included 39 patients with invasive carcinoma of no special type. CTC phenotypes were determined by flow cytometry before any type of treatment. EMT features of CTC were assessed using antibodies against CD45, CD326 (EpCam), CD325 (N-cadherin), CK7, Snail, and Vimentin. Circulating tumor cells in breast cancer are characterized by pronounced heterogeneity of EMT manifestations. The results of the study indicate that the majority of heterogeneous CTC phenotypes (22 out of 24 detectable) exhibit epithelial–mesenchymal plasticity. The variability of EMT manifestations does not prevent intravasation. Co-expression of EpCAM and CK7, regardless of the variant of co-expression of Snail, N-cadherin, and Vimentin, are associated with a low number of CTCs. Intrapersonal heterogeneity is manifested by the detection of several CTC phenotypes in each patient. Interpersonal heterogeneity is manifested by various combinations of CTC phenotypes in patients (from 1 to 17 phenotypes). Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 2.0)

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16 pages, 2590 KiB

Open AccessArticle

Assessment of the Efficacy and Clinical Utility of Different Circulating Tumor Cell (CTC) Detection Assays in Patients with Chemotherapy-Naïve Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

by Maria A. Papadaki, Ippokratis Messaritakis, Oraianthi Fiste, John Souglakos, Eleni Politaki, Athanasios Kotsakis, Vassilis Georgoulias, Dimitrios Mavroudis and Sofia Agelaki

Int. J. Mol. Sci. 2021, 22(2), 925; https://doi.org/10.3390/ijms22020925 - 18 Jan 2021

Cited by 11 | Viewed by 2870

Abstract

We herein investigated the detection frequency and clinical relevance of circulating tumor cells (CTCs) in chemotherapy-naïve stage IIIB/IV non-small cell lung cancer (NSCLC), by using the CellSearch and real-time CEACAM5mRNA assays. Blood samples from 43 patients were obtained at different time points during first-line chemotherapy. CellSearch revealed the detection of ≥1 CTCs in 41.9%, 40.9%, and 16.7% of patients at baseline, post-1st, and post-2nd treatment cycle, respectively, and of ≥5 CTCs in 11.6%, 9.1%, and 5.6%, respectively. CEACAM5mRNA+ CTCs were detected in 29.3% and 16% of patients pre- and post-treatment, respectively. The positivity concordance between the two assays was 2.2%. CTC-detection by CellSearch (≥5 CTCs: p = 0.004), CEACAM5mRNA (p = 0.010), or by any assay (p = 0.000) was associated with disease progression. Reduced survival was demonstrated for patients harboring ≥5 CTCs (progression-free survival; PFS: p = 0.000; overall survival; OS: p = 0.009), CEACAM5mRNA+ CTCs (PFS: p = 0.043; OS: p = 0.039), and CTCs by any assay (PFS: p = 0.005; OS: p = 0.006, respectively). CTC-detection by any assay independently predicted for increased risk of relapse (hazard ratio; HR: 3.496; p = 0.001) and death (HR: 2.866; p = 0.008). CellSearch-positivity either pre-, post-1st, or post-2nd cycle, was predictive for shorter PFS (p = 0.036) compared to negativity in all time points. Persistent CEACAM5mRNA-positivity pre- and post-treatment was associated with reduced PFS (p = 0.036) and OS (p = 0.026). In conclusion, CTC detection and monitoring using the CellSearch and CEACAM5mRNA assays provides valuable and complementary clinical information for chemo-naïve advanced or metastatic NSCLC. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 2.0)

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16 pages, 3643 KiB

Open AccessArticle

Analysis of the Circulating Tumor Cell Capture Ability of a Slit Filter-Based Method in Comparison to a Selection-Free Method in Multiple Cancer Types

by Hidenori Takagi, Liang Dong, Morgan D. Kuczler, Kara Lombardo, Mitsuharu Hirai, Sarah R. Amend and Kenneth J. Pienta

Int. J. Mol. Sci. 2020, 21(23), 9031; https://doi.org/10.3390/ijms21239031 - 27 Nov 2020

Cited by 5 | Viewed by 2699

Abstract

Circulating tumor cells (CTCs) are a promising biomarker for cancer liquid biopsy. To evaluate the CTC capture bias and detection capability of the slit filter-based CTC isolation platform (CTC-FIND), we prospectively compared it head to head to a selection-free platform (AccuCyte^®-CyteFinder^® system). We used the two methods to determine the CTC counts, CTC positive rates, CTC size distributions, and CTC phenotypes in 36 patients with metastatic cancer. Between the two methods, the median CTC counts were not significantly different and the total counts were correlated (r = 0.63, p < 0.0001). The CTC positive rate by CTC-FIND was significantly higher than that by AccuCyte^®-CyteFinder^® system (91.7% vs. 66.7%, p < 0.05). The median diameter of CTCs collected by CTC-FIND was significantly larger (13.0 μm, range 5.2–52.0 vs. 10.4 μm, range 5.2–44.2, p < 0.0001). The distributions of CTC phenotypes (CK+EpCAM+, CK+EpCAM− or CK−EpCAM+) detected by both methods were similar. These results suggested that CTC-FIND can detect more CTC-positive cases but with a bias toward large size of CTCs. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 2.0)

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16 pages, 3476 KiB

Open AccessArticle

Fluid Shear Stress Induces EMT of Circulating Tumor Cells via JNK Signaling in Favor of Their Survival during Hematogenous Dissemination

by Ying Xin, Keming Li, Mo Yang and Youhua Tan

Int. J. Mol. Sci. 2020, 21(21), 8115; https://doi.org/10.3390/ijms21218115 - 30 Oct 2020

Cited by 39 | Viewed by 3912

Abstract

Tumor cells metastasize to distal organs mainly through hematogenous dissemination, where they experience considerable levels of fluid shear stress. Epithelial–mesenchymal transition (EMT) plays a critical role in tumor metastasis. However, how fluid shear stress influences the EMT phenotype of circulating tumor cells (CTCs) in suspension has not been fully understood. The role of shear-induced EMT in cell survival under blood shear flow remains unclear. This study shows that the majority of breast CTCs underwent apoptosis under shear flow and the surviving cells exhibited mesenchymal phenotype, suggesting that fluid shear stress induces EMT. Mechanistically, fluid shear stress-activated Jun N-terminal kinase (JNK) signaling, inhibition/activation of which suppressed/promoted the EMT phenotype. In particular, shear flow facilitated the JNK-dependent transition of epithelial CTCs into the mesenchymal status and maintained the pre-existing mesenchymal cells. Importantly, the induction of EMT suppressed the pro-apoptosis gene p53 upregulated modulator of apoptosis (PUMA) and enhanced the survival of suspended CTCs in fluid shear stress, which was rescued by overexpressing PUMA or silencing JNK signaling, suggesting that shear-induced EMT promotes CTC survival through PUMA downregulation and JNK activation. Further, the expressions of EMT markers and JUN were correlated with poor patient survival. In summary, our findings have demonstrated that fluid shear stress induces EMT in suspended CTCs via JNK signaling that promotes their survival in shear flow. This study thus unveils a new role of blood shear stress in CTC survival and facilitates the development of novel therapeutics against tumor metastasis. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 2.0)

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Review

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29 pages, 1435 KiB

Open AccessReview

Circulating Tumour Cells as Prognostic Biomarkers in Colorectal Cancer: A Systematic Review

by Léa Veyrune, David N. Naumann and Niki Christou

Int. J. Mol. Sci. 2021, 22(8), 3437; https://doi.org/10.3390/ijms22083437 - 8 Apr 2021

Cited by 9 | Viewed by 2040

Abstract

Despite therapeutic advances, colorectal cancer (CRC) is still one of the deadliest cancers, partly due to local recurrence and metastatic disease. Tumour cells that spread by gaining access to peripheral blood are called circulating tumour cells (CTCs). These may be present before there are any clinical signs, but can be detected within blood samples. CTCs from patients with CRC may be isolated in a laboratory for characterization and multiple analyses. In this review, we focus on the prognostic potential of CTCs detection, by evaluating the reported progress and applications of such analyses. Our search found 77 relevant studies that reported CTC detection in CRC. Both cell count and features were reported as promising prognosis biomarkers. Since CTCs are rare and can lose their differentiation, new tools are being developed to improve detection. CTCs may have potential as prognostic biomarkers for CRC in terms of survival prediction, anticipating chemotherapy resistance, and surgical planning. CTCs are not yet used in clinical practice, and further investigations are required in order to better frame their practical value. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 2.0)

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14 pages, 2424 KiB

Open AccessReview

Circulating Tumour Cell Expression of Immune Markers as Prognostic and Therapeutic Biomarkers in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

by Karl Payne, Matthew Pugh, Jill Brooks, Nikolaos Batis, Graham Taylor, Paul Nankivell and Hisham Mehanna

Int. J. Mol. Sci. 2020, 21(21), 8229; https://doi.org/10.3390/ijms21218229 - 3 Nov 2020

Cited by 8 | Viewed by 2732

Abstract

Rates of loco-regional recurrence and distant metastasis remain high among head and neck squamous cell carcinoma (HNSCC) patients, despite advancing cancer treatment modalities and therapeutic agents. One area that has generated considerable interest is the immune landscape of the tumour, heralding a wave of immune checkpoint inhibitors with notable efficacy in recurrent/metastatic HNSCC patients. However, HNSCC remains poorly served by biomarkers that can direct treatment in a personalised fashion to target the tumour heterogeneity seen between patients. Detection and analysis of circulating tumour cells (CTCs) in HNSCC has provided a previously unseen view of the metastasis forming cells that are potentially contributing to poor clinical outcomes. In particular, identifying CTC expression of phenotypic and druggable protein markers has allowed CTC sub-populations to be defined that hold prognostic value or are potential therapeutic targets themselves. The aim of this systematic review was to examine the role of CTC immune-marker expression as prognostic/therapeutic biomarkers in HNSCC by evaluating progress to date and discussing areas for future research. Our results highlight how few studies have been able to demonstrate prognostic significance of immune-marker expression in CTCs. As expected, the immune checkpoint PD-L1 was the most widely investigated marker. However, no studies evaluated CTC target immune marker expression in immunotherapy cohorts. Despite these findings, the data presented demonstrate promise that CTCs may be a source of future biomarkers for immunotherapy and will provide valuable information regarding the potential immune evasion of these metastasis forming cells. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 2.0)

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