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Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology
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Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology

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 (20 November 2023) | Viewed by 13044

Special Issue Editor

Dr. Heijen Jou

E-Mail Website
Guest Editor
School of Nursing, National Taipei University of Nursing and Health Science, Taipei 112, Taiwan
Interests: circulating tumor cell

Special Issue Information

Dear Colleagues,

Circulating tumor cells (CTCs) are rare cells that are shed from primary tumors or metastases. The n travel into the peripheral blood of cancer patients. They play a key role in tumor metastasis and can be used as “real-time liquid biopsies” to monitor tumor progression as well. Recent advances in CTCs technology provide researchers and clinicians with a platform for tumor heterogeneity and tumor evolution, providing a variety of useful information for precision oncology. Research related to CTCs is still at an explosive stage. This Special Issue of the International Journal of Molecular Sciences welcomes both original research articles and reviews that focusing on the studies of CTCs related to tumor heterogeneity and precision oncology to introduce the role and future development prospects of CTCs in molecular oncology. Original research and review articles on Circulating fetal cells, focusing on non-invasive prenatal diagnosis are also welcome.

Dr. Heijen Jou
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

  • circulating tumor cells (CTCs)
  • tumor heterogeneity
  • precision oncology
  • single cell sequencing
  • multi-omics
  • circulating fetal cell (CFC)
  • non-invasive prenatal diagnosis (NIPD)

Published Papers (7 papers)

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Research

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21 pages, 1408 KiB  
Article
Identification of Endometrial Cancer-Specific microRNA Biomarkers in Endometrial Fluid
by Jianing Yang, Joel E. Barkley, Bikash Bhattarai, Kameron Firouzi, Bradley J. Monk, Dean V. Coonrod and Frederic Zenhausern
Int. J. Mol. Sci. 2023, 24(10), 8683; https://doi.org/10.3390/ijms24108683 - 12 May 2023
Cited by 2 | Viewed by 1533
Abstract
Abnormal uterine bleeding is a common benign gynecological complaint and is also the most common symptom of endometrial cancer (EC). Although many microRNAs have been reported in endometrial carcinoma, most of them were identified from tumor tissues obtained at surgery or from cell [...] Read more.
Abnormal uterine bleeding is a common benign gynecological complaint and is also the most common symptom of endometrial cancer (EC). Although many microRNAs have been reported in endometrial carcinoma, most of them were identified from tumor tissues obtained at surgery or from cell lines cultured in laboratories. The objective of this study was to develop a method to detect EC-specific microRNA biomarkers from liquid biopsy samples to improve the early diagnosis of EC in women. Endometrial fluid samples were collected during patient-scheduled in-office visits or in the operating room prior to surgery using the same technique performed for saline infusion sonohysterography (SIS). The total RNA was extracted from the endometrial fluid specimens, followed by quantification, reverse transcription, and real-time PCR arrays. The study was conducted in two phases: exploratory phase I and validation phase II. In total, endometrial fluid samples from 82 patients were collected and processed, with 60 matched non-cancer versus endometrial carcinoma patients used in phase I and 22 in phase II. The 14 microRNA biomarkers, out of 84 miRNA candidates, with the greatest variation in expression from phase I, were selected to enter phase II validation and statistical analysis. Among them, three microRNAs had a consistent and substantial fold-change in upregulation (miR-429, miR-183-5p, and miR-146a-5p). Furthermore, four miRNAs (miR-378c, miR-4705, miR-1321, and miR-362-3p) were uniquely detected. This research elucidated the feasibility of the collection, quantification, and detection of miRNA from endometrial fluid with a minimally invasive procedure performed during a patient in-office visit. The screening of a larger set of clinical samples was necessary to validate these early detection biomarkers for endometrial cancer. Full article
(This article belongs to the Special Issue Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology)
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13 pages, 3673 KiB  
Article
Isolation of TTF-1 Positive Circulating Tumor Cells for Single-Cell Sequencing by Using an Automatic Platform Based on Microfluidic Devices
by Hei-Jen Jou, Hsin-Cheng Ho, Kuan-Yeh Huang, Chen-Yang Chen, Sheng-Wen Chen, Pei-Hsuan Lo, Pin-Wen Huang, Chung-Er Huang and Ming Chen
Int. J. Mol. Sci. 2022, 23(23), 15139; https://doi.org/10.3390/ijms232315139 - 01 Dec 2022
Cited by 2 | Viewed by 1918
Abstract
Single-cell sequencing provides promising information in tumor evolution and heterogeneity. Even with the recent advances in circulating tumor cell (CTC) technologies, it remains a big challenge to precisely and effectively isolate CTCs for downstream analysis. The Cell RevealTM system integrates an automatic [...] Read more.
Single-cell sequencing provides promising information in tumor evolution and heterogeneity. Even with the recent advances in circulating tumor cell (CTC) technologies, it remains a big challenge to precisely and effectively isolate CTCs for downstream analysis. The Cell RevealTM system integrates an automatic CTC enrichment and staining machine, an AI-assisted automatic CTC scanning and identification system, and an automatic cell picking machine for CTC isolation. H1975 cell line was used for the spiking test. The identification of CTCs and the isolation of target CTCs for genetic sequencing were performed from the peripheral blood of three cancer patients, including two with lung cancer and one with both lung cancer and thyroid cancer. The spiking test revealed a mean recovery rate of 81.81% even with extremely low spiking cell counts with a linear relationship between the spiked cell counts and the recovered cell counts (Y = 0.7241 × X + 19.76, R2 = 0.9984). The three cancer patients had significantly higher TTF-1+ CTCs than healthy volunteers. All target CTCs were successfully isolated by the Cell Picker machine for a subsequent genetic analysis. Six tumor-associated mutations in four genes were detected. The present study reveals the Cell RevealTM platform can precisely identify and isolate target CTCs and then successfully perform single-cell sequencing by using commercially available genetic devices. Full article
(This article belongs to the Special Issue Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology)
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Review

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22 pages, 736 KiB  
Review
Circulating Tumour Cells: Detection and Application in Advanced Non-Small Cell Lung Cancer
by Kalliopi Andrikou, Tania Rossi, Alberto Verlicchi, Ilaria Priano, Paola Cravero, Marco Angelo Burgio, Lucio Crinò, Sara Bandini, Paola Ulivi and Angelo Delmonte
Int. J. Mol. Sci. 2023, 24(22), 16085; https://doi.org/10.3390/ijms242216085 - 08 Nov 2023
Cited by 1 | Viewed by 1250
Abstract
Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide. Tissue biopsy is the current gold standard for the diagnosis and molecular profiling of NSCLC. However, this approach presents some limitations due to inadequate tissue sampling, and intra- and intertumour heterogenicity. [...] Read more.
Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide. Tissue biopsy is the current gold standard for the diagnosis and molecular profiling of NSCLC. However, this approach presents some limitations due to inadequate tissue sampling, and intra- and intertumour heterogenicity. Liquid biopsy is a noninvasive method to determine cancer-related biomarkers in peripheral blood, and can be repeated at multiple timepoints. One of the most studied approaches to liquid biopsies is represented by circulating tumour cells (CTCs). Several studies have evaluated the prognostic and predictive role of CTCs in advanced NSCLC. Despite the limitations of these studies, the results of the majority of studies seem to be concordant regarding the correlation between high CTC count and poor prognosis in patients with NSCLC. Similarly, the decrease of CTC count during treatment may represent an important predictive marker of sensitivity to therapy in advanced NSCLC. Furthermore, molecular characterization of CTCs can be used to provide information on tumour biology, and on the mechanisms involved in resistance to targeted treatment. This review will discuss the current status of the clinical utility of CTCs in patients with advanced NSCLC, highlighting their potential application to prognosis and to treatment decision making. Full article
(This article belongs to the Special Issue Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology)
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25 pages, 3966 KiB  
Review
Deciphering the Biology of Circulating Tumor Cells through Single-Cell RNA Sequencing: Implications for Precision Medicine in Cancer
by Santhasiri Orrapin, Patcharawadee Thongkumkoon, Sasimol Udomruk, Sutpirat Moonmuang, Songphon Sutthitthasakul, Petlada Yongpitakwattana, Dumnoensun Pruksakorn and Parunya Chaiyawat
Int. J. Mol. Sci. 2023, 24(15), 12337; https://doi.org/10.3390/ijms241512337 - 02 Aug 2023
Cited by 4 | Viewed by 1917
Abstract
Circulating tumor cells (CTCs) hold unique biological characteristics that directly involve them in hematogenous dissemination. Studying CTCs systematically is technically challenging due to their extreme rarity and heterogeneity and the lack of specific markers to specify metastasis-initiating CTCs. With cutting-edge technology, single-cell RNA [...] Read more.
Circulating tumor cells (CTCs) hold unique biological characteristics that directly involve them in hematogenous dissemination. Studying CTCs systematically is technically challenging due to their extreme rarity and heterogeneity and the lack of specific markers to specify metastasis-initiating CTCs. With cutting-edge technology, single-cell RNA sequencing (scRNA-seq) provides insights into the biology of metastatic processes driven by CTCs. Transcriptomics analysis of single CTCs can decipher tumor heterogeneity and phenotypic plasticity for exploring promising novel therapeutic targets. The integrated approach provides a perspective on the mechanisms underlying tumor development and interrogates CTCs interactions with other blood cell types, particularly those of the immune system. This review aims to comprehensively describe the current study on CTC transcriptomic analysis through scRNA-seq technology. We emphasize the workflow for scRNA-seq analysis of CTCs, including enrichment, single cell isolation, and bioinformatic tools applied for this purpose. Furthermore, we elucidated the translational knowledge from the transcriptomic profile of individual CTCs and the biology of cancer metastasis for developing effective therapeutics through targeting key pathways in CTCs. Full article
(This article belongs to the Special Issue Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology)
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16 pages, 1077 KiB  
Review
Assessing the Role of MicroRNAs in Predicting Breast Cancer Recurrence—A Systematic Review
by Luis Bouz Mkabaah, Matthew G. Davey, James C. Lennon, Ghada Bouz, Nicola Miller and Michael J. Kerin
Int. J. Mol. Sci. 2023, 24(8), 7115; https://doi.org/10.3390/ijms24087115 - 12 Apr 2023
Cited by 5 | Viewed by 1740
Abstract
Identifying patients likely to develop breast cancer recurrence remains a challenge. Thus, the discovery of biomarkers capable of diagnosing recurrence is of the utmost importance. MiRNAs are small, non-coding RNA molecules which are known to regulate genetic expression and have previously demonstrated relevance [...] Read more.
Identifying patients likely to develop breast cancer recurrence remains a challenge. Thus, the discovery of biomarkers capable of diagnosing recurrence is of the utmost importance. MiRNAs are small, non-coding RNA molecules which are known to regulate genetic expression and have previously demonstrated relevance as biomarkers in malignancy. To perform a systematic review evaluating the role of miRNAs in predicting breast cancer recurrence. A formal systematic search of PubMed, Scopus, Web of Science, and Cochrane databases was performed. This search was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist. A total of 19 studies involving 2287 patients were included. These studies identified 44 miRNAs which predicted breast cancer recurrence. Results from nine studies assessed miRNAs in tumour tissues (47.4%), eight studies included circulating miRNAs (42.1%), and two studies assessed both tumour and circulating miRNAs (10.5%). Increased expression of 25 miRNAs were identified in patients who developed recurrence, and decreased expression of 14 miRNAs. Interestingly, five miRNAs (miR-17-5p, miR-93-5p, miR-130a-3p, miR-155, and miR-375) had discordant expression levels, with previous studies indicating both increased and reduced expression levels of these biomarkers predicting recurrence. MiRNA expression patterns have the ability to predict breast cancer recurrence. These findings may be used in future translational research studies to identify patients with breast cancer recurrence to improve oncological and survival outcomes for our prospective patients. Full article
(This article belongs to the Special Issue Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology)
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8 pages, 1231 KiB  
Review
Recent Advances of Microfluidic Platform for Cell Based Non-Invasive Prenatal Diagnosis
by Hei-Jen Jou, Pei-Hsuan Lo and Pei-Ying Ling
Int. J. Mol. Sci. 2023, 24(2), 991; https://doi.org/10.3390/ijms24020991 - 04 Jan 2023
Cited by 1 | Viewed by 1916
Abstract
The purpose of the present review is to try to highlight recent advances in the application of microfluidic technology on non-invasive prenatal diagnosis (NIPD). The immunoaffinity based microfluidic technology is the most common approach for NIPD, followed by size-based microfluidic methods. Immunoaffinity microfluidic [...] Read more.
The purpose of the present review is to try to highlight recent advances in the application of microfluidic technology on non-invasive prenatal diagnosis (NIPD). The immunoaffinity based microfluidic technology is the most common approach for NIPD, followed by size-based microfluidic methods. Immunoaffinity microfluidic methods can enrich and isolate circulating fetal extravillous trophoblasts (fEVTs) or fetal nucleated red blood cells (fnRBCs) for NIPD by using specific antibodies, but size-based microfluidic systems are only applied to isolate fEVTs. Most studies based on the immunoaffinity microfluidic system gave good results. Enough fetal cells were obtained for chromosomal and/or genetic analysis in all blood samples. However, the results from studies using size-based microfluidic systems for NIPD are less than ideal. In conclusion, recent advances in microfluidic devices make the immunoaffinity based microfluidic system potentially a powerful tool for cell-based NIPD. However, more clinical validation is needed. Full article
(This article belongs to the Special Issue Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology)
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Other

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12 pages, 1614 KiB  
Brief Report
Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers
by Stefania Bellone, Blair McNamara, Levent Mutlu, Cem Demirkiran, Tobias Max Philipp Hartwich, Justin Harold, Yang Yang-Hartwich, Eric R. Siegel and Alessandro D. Santin
Int. J. Mol. Sci. 2023, 24(10), 8873; https://doi.org/10.3390/ijms24108873 - 17 May 2023
Cited by 2 | Viewed by 1718
Abstract
Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology [...] Read more.
Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated “driver” target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted. Full article
(This article belongs to the Special Issue Circulating Tumor Cells, Liquid Biopsies, and Precision Oncology)
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