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Circulating Tumor Cells: From the Laboratory to the Cancer Clinic

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

Deadline for manuscript submissions: closed (20 February 2022) | Viewed by 32350

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Special Issue Editor

Prof. Dr. Noriyoshi Sawabata

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Guest Editor

Department of General Thoracic Surgery, Nara Medical University Hospital, 840 Shijo-Cho, Kashihara, Nara 634-8522, Japan
Interests: surgery; lung cancer; isolated tumor cell; circulating tumor cell
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In solid cancer, treatment performance is improved by multidisciplinary treatment by drug therapy, surgery, and radiation therapy, but it often relapses, and it is difficult to obtain healing for everything. Patient burden is increasing due to the high-powered treatment that progresses year by year, and it is necessary to optimize treatment and improve efficiency. There are few cancer cells circulating in the peripheral blood of patients with solid cancer, which is called the circulating cancer cell circulating tumor cell (CTC). The presence of CTC is considered an indicator of recurrence and poor prognosis, and the loss of CTC may improve the therapeutic effect. CTC can be a criterion for determining whether treatment should be adapted. By moving the primary nest, blood, and bone marrow as cancer stem cells or cancer progenitor cells, and by clarifying the biological properties of CTC, effective treatment methods targeting CTC can be obtained. Against this background, we have configured the Special Issue “From the Laboratory to the Cancer Clinic” for CTC.

Prof. Dr. Noriyoshi Sawabata
Guest Editor

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Keywords

Circulating tumor cell
Solid cancer
Cancer stem cell
Epithelial-mesenchymal transition
Liqide biopsy

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 173 KiB

Open AccessEditorial

Circulating Tumor Cells: From the Laboratory to the Cancer Clinic; A Closing Comment

by Noyiyoshi Sawabata

Cancers 2023, 15(3), 939; https://doi.org/10.3390/cancers15030939 - 2 Feb 2023

Cited by 1 | Viewed by 1375

Abstract

Cancer recurrence not only shortens the life span of cancer patients, but also leads to a decrease in QOL, so it needs to be controlled [...] Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

3 pages, 173 KiB

Open AccessEditorial

Circulating Tumor Cells: From the Laboratory to the Cancer Clinic

by Noriyoshi Sawabata

Cancers 2020, 12(10), 3065; https://doi.org/10.3390/cancers12103065 - 20 Oct 2020

Cited by 5 | Viewed by 2152

Abstract

Circulating tumor cells (CTCs) are cells that are separated from the primary tumor, move through the bloodstream, and spread from the original tumor to other sites, causing cancer metastasis [...] Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

Research

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11 pages, 1374 KiB

Open AccessArticle

Pure Solid Pattern of Non-Small Cell Lung Cancer and Clustered Circulating Tumor Cells

by Noriyoshi Sawabata, Takeshi Kawaguchi, Takashi Watanabe, Daiki Yohikawa, Noriko Ouji-Sageshima and Toshihiro Ito

Cancers 2022, 14(18), 4514; https://doi.org/10.3390/cancers14184514 - 17 Sep 2022

Cited by 4 | Viewed by 2113

Abstract

There are two solid patterns of non-small cell lung cancer (NSCLC) on computed tomography (CT): pure or mixed with ground-glass opacities (GGOs). They predict the degree of invasiveness, which may suggest the presence of clustered circulating tumor cells (CTCs), a predictor of poor prognosis. In this study, we assessed the implications of the solid patterns on CT and the preoperative clustered CTCs in surgically resected NSCLC. CTCs were detected using a size selection method. The correlation between the presence of preoperative clustered CTCs and the solid pattern and the prognostic implications were evaluated using co-variables from the clinical-pathological findings. Of the 142 cases, pure solid lesions (Group PS) and mixed GGOs (Group G) were observed in 92 (64.8%) and 50 (35.2%) patients, respectively. In Groups PS and G, clustered CTCs were detected in 29 (31.5%) and 1 (2.0%) patient (p < 0.01), respectively. The PS appearance was an independent predictor of preoperative clustered CTCs in the multivariable analysis, and preoperative clustered CTCs were an independent predictor of poor recurrence-free survival; the solid pattern was not an independent variable. Thus, the PS pattern of NSCLC on CT is an indicator of preoperative clustered CTCs, which is an independent poor prognosis predictor. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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13 pages, 2559 KiB

Open AccessArticle

Multiparametric Phenotyping of Circulating Tumor Cells for Analysis of Therapeutic Targets, Oncogenic Signaling Pathways and DNA Repair Markers

by Stephanie Staudte, Konrad Klinghammer, Philipp Sebastian Jurmeister, Paul Jank, Jens-Uwe Blohmer, Sandra Liebs, Peter Rhein, Anja E. Hauser and Ingeborg Tinhofer

Cancers 2022, 14(11), 2810; https://doi.org/10.3390/cancers14112810 - 6 Jun 2022

Cited by 5 | Viewed by 2958

Abstract

Detection of circulating tumor cells (CTCs) has been established as an independent prognostic marker in solid cancer. Multiparametric phenotyping of CTCs could expand the area of application for this liquid biomarker. We evaluated the Amnis^® brand ImageStream^®X MkII (ISX) (Luminex, Austin, TX, USA) imaging flow cytometer for its suitability for protein expression analysis and monitoring of treatment effects in CTCs. This was carried out using blood samples from patients with head and neck squamous cell carcinoma (n = 16) and breast cancer (n = 8). A protocol for negative enrichment and staining of CTCs was established, allowing quantitative analysis of the therapeutic targets PD–L1 and phosphorylated EGFR (phospho–EGFR), and the treatment response marker γH2AX as an indicator of radiation–induced DNA damage. Spiking experiments revealed a sensitivity of 73% and a specificity of 100% at a cut–off value of ≥3 CTCs, and thus confirmed the suitability of the ISX-based protocol to detect phospho–EGFR and γH2AX foci in CTCs. Analysis of PD–L1/–L2 in both spiked and patient blood samples further showed that assessment of heterogeneity in protein expression within the CTC population was possible. Further validation of the diagnostic potential of this ISX protocol for multiparametric CTC analysis in larger clinical cohorts is warranted. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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Graphical abstract

15 pages, 2464 KiB

Open AccessArticle

Immediate Sample Fixation Increases Circulating Tumour Cell (CTC) Capture and Preserves Phenotype in Head and Neck Squamous Cell Carcinoma: Towards a Standardised Approach to Microfluidic CTC Biomarker Discovery

by Karl Payne, Jill M. Brooks, Graham S. Taylor, Nikolaos Batis, Boris Noyvert, Yi Pan, Paul Nankivell and Hisham Mehanna

Cancers 2021, 13(21), 5519; https://doi.org/10.3390/cancers13215519 - 3 Nov 2021

Cited by 7 | Viewed by 3454

Abstract

Introduction: Research demonstrates strong evidence that circulating tumour cells (CTCs) can provide diagnostic and/or prognostic biomarkers in head and neck squamous cell carcinoma (HNSCC) and a potential tool for therapeutic stratification. However, the question still remains as to the optimum method of CTC enrichment and how this can be translated into clinical practice. We aimed to evaluate the Parsortix microfluidic device for CTC enrichment and characterisation in HNSCC, seeking to optimise a sample collection and processing protocol that preserves CTC integrity and phenotype. Method: Spiking experiments of the FaDu and SCC040 HNSCC cell lines were used to determine the Parsortix capture rate of rare “CTC-like” cells. Capture rates of cancer cells spiked into EDTA blood collections tubes (BCTs) were compared to the Transfix fixative BCT and Cytodelics whole blood freezing protocol. The Lexogen Quantseq library preparation was used to profile gene expression of unfixed cells before and after microfluidic enrichment and enriched cell line spiked Transfix blood samples. An antibody panel was optimised to enable immunofluorescence microscopy CTC detection in HNSCC patient Transfix blood samples, using epithelial (EpCAM) and mesenchymal (N-cadherin) CTC markers. Results: Across a spiked cell concentration range of 9–129 cells/mL, Parsortix demonstrated a mean cell capture rate of 53.5% for unfixed cells, with no significant relationship between spiked cell concentration and capture rate. Samples preserved in Transfix BCTs demonstrated significantly increased capture rates at 0 h (time to processing) compared to EDTA BCTs (65.3% vs. 51.0%). Capture rates in Transfix BCTs were maintained at 24 h and 72 h timepoints, but dropped significantly in EDTA BCTs. Gene expression profiling revealed that microfluidic enrichment of unfixed cell lines caused downregulation of RNA processing/binding gene pathways and upregulation of genes involved in cell injury, apoptosis and oxidative stress. RNA was successfully extracted and sequenced from Transfix preserved cells enriched using Parsortix, demonstrating epithelial specific transcripts from spiked cells. In a proof-of-concept cohort of four patients with advanced HNSCC, CTCs were successfully identified and visualised with epithelial and epithelial-mesenchymal phenotypes. Conclusion: We have optimised a protocol for detection of CTCs in HNSCC with the Parsortix microfluidic device, using Transfix BCTs. We report a significant benefit, both in terms of cell capture rates and preserving cell phenotype, for using a fixative BCT- particularly if samples are stored before processing. In the design of large cohort multi-site clinical trials, such data are of paramount importance. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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15 pages, 683 KiB

Open AccessArticle

The Long-Term Prognostic Significance of Circulating Tumor Cells in Ovarian Cancer—A Study of the OVCAD Consortium

by Eva Obermayr, Angelika Reiner, Burkhard Brandt, Elena Ioana Braicu, Alexander Reinthaller, Liselore Loverix, Nicole Concin, Linn Woelber, Sven Mahner, Jalid Sehouli, Ignace Vergote and Robert Zeillinger

Cancers 2021, 13(11), 2613; https://doi.org/10.3390/cancers13112613 - 26 May 2021

Cited by 17 | Viewed by 2454

Abstract

Introduction: We previously reported the prognostic impact of circulating tumor cells (CTCs) in a multicenter study on minimal residual disease in primary ovarian cancer. With additional follow-up data, we evaluated the combined CTC approach (CTCs^combo), in particular for the patients who had survived more than five years. Material and Methods: Blood samples taken at baseline and six months after adjuvant treatment (follow-up) were assessed by quantitative PCR (qPCR) measuring PPIC transcripts and immunofluorescent staining (IF). A positive result with either IF or qPCR was classified as CTC^combo-positive. Further, PPIC was assessed in the primary tumor tissue. Results: The concordance of IF and qPCR was 65% at baseline and 83% after treatment. Results showed that 50.5% of the baseline and 29.5% of the follow-up samples were CTC^combo-positive. CTCs^combo after treatment were associated with increased mortality after adjusting for FIGO stage (HR 2.574, 95% CI: 1.227–5.398, p = 0.012), a higher risk of recurrence after adjusting for peritoneal carcinosis (HR 4.068, 95% CI: 1.948–8.498, p < 0.001), and increased mortality after five survived years. Discussion: The two-sided analytical approach revealed CTC subpopulations associated with ovarian cancer progression and may illuminate a potential treatment-related shift in molecular phenotypes. That approach can identify patients who have elevated risk of recurrence and death due to ovarian cancer and who may require risk-adapted treatment strategies. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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26 pages, 6545 KiB

Open AccessArticle

Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies

by Vladimir A. D’yakonov, Alexey A. Makarov, Lilya U. Dzhemileva, Ilfir R. Ramazanov, Elina Kh. Makarova and Usein M. Dzhemilev

Cancers 2021, 13(8), 1808; https://doi.org/10.3390/cancers13081808 - 10 Apr 2021

Cited by 17 | Viewed by 2379

Abstract

The first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61–64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoic acids with non-methylene-interrupted Z-double bonds show moderate cytotoxic activities against tumor cell lines (Jurkat, K562, U937, HL60, HeLa), human embryonic kidney cells (Hek293), normal fibroblasts and human topoisomerase I (hTop1) inhibitory activity in vitro. The synthesized acids efficiently initiate apoptosis of Jurkat tumor cells, with the cell death mechanism being activated by the mitochondrial pathway. A probable mechanism of topoisomerase I inhibition was also hypothesized on the basis of in silico studies resorting to docking. The activation and inhibition of the most versatile intracellular signaling pathways (CREB, JNK, NFkB, p38, ERK1/2, Akt, p70S6K, STAT3 and STAT5 tyrosine kinases) responsible for cell proliferation and for initiation of apoptosis were studied by multiplex assay technology (Luminex xMAP). Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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Review

Jump to: Editorial, Research

12 pages, 721 KiB

Open AccessReview

Circulating Tumor Cells and the Non-Touch Isolation Technique in Surgery for Non-Small-Cell Lung Cancer

by Hiroyuki Adachi, Hiroyuki Ito and Noriyoshi Sawabata

Cancers 2022, 14(6), 1448; https://doi.org/10.3390/cancers14061448 - 11 Mar 2022

Cited by 8 | Viewed by 2581

Abstract

Circulating tumor cells (CTCs) are dislodged from the primary tumor into the bloodstream, travel within the bloodstream to distant organs, and finally extravasate and proliferate as epithelial metastatic deposits. The relationship between the existence of CTCs and tumor prognosis has been demonstrated by many researchers. In surgery for malignancies, the surgical manipulation of tumors and tissues around the tumor may lead to the release of CTCs into the bloodstream. The non-touch isolation technique (NTIT) has been advocated to prevent the release of CTCs during surgery. The concept of NTIT is the prevention of intraoperative increment of CTCs from the primary tumor by the early blockade of outflow vessels, and ‘pulmonary vein (PV)-first lobectomy’ during surgery for non-small-cell lung cancer (NSCLC) corresponds to this technique. The concept of PV-first lobectomy is well known among thoracic surgeons, but evidence of its efficacy for preventing the increase of intra- and postoperative CTCs and for improving postoperative prognosis is still uncertain. Our study summarizes evidence regarding the relationship between NTIT and CTCs in NSCLC and suggests the need for further research on CTCs and CTC-detecting modalities. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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19 pages, 849 KiB

Open AccessReview

Liquid Biopsy in Hepatocellular Carcinoma: Opportunities and Challenges for Immunotherapy

by Panagiota Maravelia, Daniela Nascimento Silva, Giulia Rovesti, Michael Chrobok, Per Stål, Yong-Chen Lu and Anna Pasetto

Cancers 2021, 13(17), 4334; https://doi.org/10.3390/cancers13174334 - 27 Aug 2021

Cited by 20 | Viewed by 5019

Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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11 pages, 258 KiB

Open AccessReview

The Emerging Role of Circulating Tumor DNA in the Management of Breast Cancer

by Mira Shoukry, Sacha Broccard, Jamie Kaplan and Emmanuel Gabriel

Cancers 2021, 13(15), 3813; https://doi.org/10.3390/cancers13153813 - 29 Jul 2021

Cited by 15 | Viewed by 2932

Abstract

With the incidence of breast cancer steadily rising, it is important to explore novel technologies that can allow for earlier detection of disease as well more a personalized and effective treatment approach. The concept of “liquid biopsies” and the data they provide have been increasingly studied in the recent decades. More specifically, circulating tumor DNA (ctDNA) has emerged as a potential biomarker for various cancers, including breast cancer. While methods such as mammography and tissue biopsies are the current standards for the detection and surveillance of breast cancer, ctDNA analysis has shown some promise. This review discusses the versatility of ctDNA by exploring its multiple emerging uses for the management of breast cancer. Its efficacy is also compared to current biomarkers and technologies. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

25 pages, 2399 KiB

Open AccessReview

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

by Iwona Kwiatkowska, Justyna Magdalena Hermanowicz, Alicja Przybyszewska-Podstawka and Dariusz Pawlak

Cancers 2021, 13(11), 2667; https://doi.org/10.3390/cancers13112667 - 28 May 2021

Cited by 9 | Viewed by 3503

Abstract

Background: The recently discovered phenomenon that cancer cells can avoid immune response has gained scientists’ interest. One of the pathways involved in this process is tryptophan (TRP) metabolism through the kynurenine pathway (KP). Individual components involved in TRP conversion seem to contribute to cancerogenesis both through a direct impact on cancer cells and the modulation of immune cell functionality. Due to this fact, this pathway may serve as a target for immunotherapy and attempts are being made to create novel compounds effective in cancer treatment. However, the results obtained from clinical trials are not satisfactory, which raises questions about the exact role of KP elements in tumorigenesis. An increasing number of experiments reveal that TRP metabolites may either be tumor promoters and suppressors and this is why further research in this field is highly needed. The aim of this study is to present KP as a modulator of cancer development through multiple mechanisms and to point to its ambiguity, which may be a reason for failures in treatment based on the inhibition of tryptophan metabolism Full article

(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)

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