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Circulating Tumor Cells' Heterogeneity and Precision Oncology

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 60456

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Special Issue Editors

Prof. Dr. Paola Gazzaniga

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Guest Editor

Chief Liquid Biopsy Unit, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
Interests: liquid biospy-driven clinical trials; cancer heterogeneity; clonal evolution; precision oncology; biomarkers
Special Issues, Collections and Topics in MDPI journals

Dr. Chiara Nicolazzo

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Guest Editor

Cancer Liquid Biopsy Unit, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
Interests: circulating tumor cells; circulating tumor DNA; liquid biopsy; liquid biopsy devices; in vitro models; tumor biology; drug resistance; molecular oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is as an invasive species, which is defined as any kind of living organism that is not native to an ecosystem, reproduces quickly, and spreads aggressively, with the potential to cause harm. In order to efficiently colonize a wide range of different microenvironments, cancer cells maintain a high degree of cellular heterogeneity. Such a plastic adaptation to different microenvironments, which leads to the existence of different ecological niches occupied by phenotypically and genetically distinct cancer cell species, plays a crucial role in regulating disease progression and therapeutic response. When cancer cells enter blood (circulating tumor cells, CTCs), they become familiar with the selective pressure of microenvironmental factors that are totally novel for cells arising from a solid tumor mass, leading to the generation of heterogeneous CTCs subpopulations, each with specific genomic features.

This Special Issue aims to deepen the genomic and transcriptional heterogeneity of the CTC compartment, and its significance for clinical decision making. We welcome submissions that will contribute to understanding how the blood microenvironment might shape the CTCs genome and how the maintainace of heterogeneity at a CTC level might impact on precision medicine in oncology.

This is a conjunct Special Issue of Cancers and Diagnostics. Authors are free to choose the journal they would like to submit to based on their submission topic.

Prof. Dr. Paola Gazzaniga
Dr. Chiara Nicolazzo
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

Circulating tumor cells
Microenvironment
Heterogeneity
Precision oncology

Published Papers (14 papers)

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Research

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18 pages, 2482 KiB

Open AccessArticle

A Multi-Analyte Approach for Improved Sensitivity of Liquid Biopsies in Prostate Cancer

by Lilli Hofmann, Katja Sallinger, Christoph Haudum, Maria Smolle, Ellen Heitzer, Tina Moser, Michael Novy, Kevin Gesson, Thomas Kroneis, Thomas Bauernhofer and Amin El-Heliebi

Cancers 2020, 12(8), 2247; https://doi.org/10.3390/cancers12082247 - 11 Aug 2020

Cited by 15 | Viewed by 3403

Abstract

Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we (1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, (2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR-splice variant 7) in lysed whole blood, and (3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44–53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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12 pages, 1702 KiB

Open AccessArticle

Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer

by Thomas M. Deutsch, Stefan Stefanovic, Manuel Feisst, Chiara Fischer, Fabian Riedel, Carlo Fremd, Christoph Domschke, Klaus Pantel, Andreas D. Hartkopf, Marc Sutterlin, Sara Y. Brucker, Andreas Schneeweiss and Markus Wallwiener

Cancers 2020, 12(4), 1055; https://doi.org/10.3390/cancers12041055 - 24 Apr 2020

Cited by 19 | Viewed by 3059

Abstract

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch^® system. A cut-off analysis was performed using Youden’s J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4–92) vs. 7 (2–43) months (p < 0.001). Median intact CTC count at enrollment was 15.0 (5–2760) vs. 30.5 (5–200000) cells (p = 0.39) and 2.5 (0–420) vs. 8.5 (0–15000) cells after one cycle of systemic therapy (p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0–1500) vs. 9 (0–800) cells (p = 0.475) and 1 (0–200) vs. 3 (0–250) cells after one cycle of systemic therapy (p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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19 pages, 1641 KiB

Open AccessArticle

Dysmetabolic Circulating Tumor Cells Are Prognostic in Metastatic Breast Cancer

by Giulia Brisotto, Eva Biscontin, Elisabetta Rossi, Michela Bulfoni, Aigars Piruska, Simon Spazzapan, Cristina Poggiana, Riccardo Vidotto, Agostino Steffan, Alfonso Colombatti, Wilhelm T. S. Huck, Daniela Cesselli, Rita Zamarchi, Matteo Turetta and Fabio Del Ben

Cancers 2020, 12(4), 1005; https://doi.org/10.3390/cancers12041005 - 19 Apr 2020

Cited by 6 | Viewed by 3290

Abstract

Circulating tumor cells (CTCs) belong to a heterogeneous pool of rare cells, and a unequivocal phenotypic definition of CTC is lacking. Here, we present a definition of metabolically-altered CTC (MBA-CTCs) as CD45-negative cells with an increased extracellular acidification rate, detected with a single-cell droplet microfluidic technique. We tested the prognostic value of MBA-CTCs in 31 metastatic breast cancer patients before starting a new systemic therapy (T0) and 3–4 weeks after (T1), comparing results with a parallel FDA-approved CellSearch (CS) approach. An increased level of MBA-CTCs was associated with: i) a shorter median PFS pre-therapy (123 days vs. 306; p < 0.0001) and during therapy (139 vs. 266 days; p = 0.0009); ii) a worse OS pre-therapy (p = 0.0003, 82% survival vs. 20%) and during therapy (p = 0.0301, 67% survival vs. 38%); iii) good agreement with therapy response (kappa = 0.685). The trend of MBA-CTCs over time (combining data at T0 and T1) added information with respect to separate evaluation of T0 and T1. The combined results of the two assays (MBA and CS) increased stratification accuracy, while correlation between MBA and CS was not significant, suggesting that the two assays are detecting different CTC subsets. In conclusion, this study suggests that MBA allows detection of both EpCAM-negative and EpCAM-positive, viable and label-free CTCs, which provide clinical information apparently equivalent and complementary to CS. A further validation of proposed method and cut-offs is needed in a larger, separate study. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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12 pages, 777 KiB

Open AccessArticle

Clinical Relevance of Circulating Tumor Cells in Esophageal Cancer Detected by a Combined MACS Enrichment Method

by Anna Woestemeier, Katharina Harms-Effenberger, Karl-F. Karstens, Leonie Konczalla, Tarik Ghadban, Faik G. Uzunoglu, Jakob R. Izbicki, Maximilian Bockhorn, Klaus Pantel and Matthias Reeh

Cancers 2020, 12(3), 718; https://doi.org/10.3390/cancers12030718 - 18 Mar 2020

Cited by 14 | Viewed by 3064

Abstract

Introduction. Current modalities to predict tumor recurrence and survival in esophageal cancer are insufficient. Even in lymph node-negative patients, a locoregional and distant relapse is common. Hence, more precise staging methods are needed. So far, only the CellSearch system was used to detect circulating tumor cells (CTC) with clinical relevance in esophageal cancer patients. Studies analyzing different CTC detection assays using advanced enrichment techniques to potentially increase the sensitivity are missing. Methods. In this single-center, prospective study, peripheral blood samples from 90 esophageal cancer patients were obtained preoperatively and analyzed for the presence of CTCs by Magnetic Cell Separation (MACS) enrichment (combined anti-cytokeratin and anti-epithelial cell adhesion molecules (EpCAM)), with subsequent immunocytochemical staining. Data were correlated with clinicopathological parameters and patient outcomes. Results. CTCs were detected in 25.6% (23/90) of the patients by combined cytokeratin/EpCAM enrichment (0–150 CTCs/7.5 mL). No significant correlation between histopathological parameters and CTC detection was found. Survival analysis revealed that the presence of more than two CTCs correlated with significantly shorter overall survival (OS) and progression-free survival (PFS). Conclusion. With the use of cytokeratin as an additional enrichment target, the CTC detection rate in esophageal cancer patients can be elevated and displays the heterogeneity of cytokeratin (CK) and EpCAM expression. The presence of >2CTCs correlated with a shorter relapse-free and overall survival in a univariate analysis, but not in a multivariate setting. Moreover, our results suggest that the CK7/8⁺/EpCAM⁺ or CK7/8⁺/EpCAM⁻ CTC subtype does not lead to an advanced tumor staging tool in non-metastatic esophageal cancer (EC) patients. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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14 pages, 1412 KiB

Open AccessArticle

Lymph Node and Bone Marrow Micrometastases Define the Prognosis of Patients with pN0 Esophageal Cancer

by Karl-F. Karstens, Tarik Ghadban, Katharina Effenberger, Guido Sauter, Klaus Pantel, Jakob R. Izbicki, Yogesh Vashist, Alexandra König and Matthias Reeh

Cancers 2020, 12(3), 588; https://doi.org/10.3390/cancers12030588 - 4 Mar 2020

Cited by 3 | Viewed by 3351

Abstract

Background: Pathological routine lymph node staging is postulated to be the main oncological prognosticator in esophageal cancer (EC). However, micrometastases in lymph nodes (LNMM) and bone marrow (BNMM) are discussed as the key events in tumor recurrence. We assessed the prognostic significance of the LNMM/BNMM status in initially pN0 staged patients with curative esophagectomy. Methods: From 110 patients bone marrow aspirates and lymph node tissues were analyzed. For LNMM detection immunohistochemistry was performed using the anticytokeratin antibody AE1/AE3. To detect micrometastases in the bone marrow a staining with the pan-keratin antibody A45-B/B3 was done. Results were correlated with clinicopathologic parameters as well as recurrence and death during follow-up time. Results: Thirty-eight (34.5%) patients showed LNMM, whereas in 54 (49.1%) patients BNMM could be detected. LNMM and BNMM positive patients showed a correlation to an increased pT category (p = 0.017). Univariate and multivariate analyses revealed that the LNMM/BNMM status and especially LNMM skipping the anatomical lymph node chain were significant independent predictors of overall survival and recurrence-free survival. Conclusions: This study indicates that routine pathological staging of EC is insufficient. Micrometastases in lymph nodes and the bone marrow seem to be the main reason for tumor recurrence and they are a strong prognosticator following curative treatment of pN0 EC. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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20 pages, 7101 KiB

Open AccessArticle

Clinical Relevance of Immune Checkpoints on Circulating Tumor Cells in Breast Cancer

by Maria A. Papadaki, Anastasios V. Koutsopoulos, Panormitis G. Tsoulfas, Eleni Lagoudaki, Despoina Aggouraki, Alexia Monastirioti, Chara Koutoulaki, Christina A. Apostolopoulou, Aikaterini C. Merodoulaki, Chara Papadaki, Dimitrios Mavroudis and Sofia Agelaki

Cancers 2020, 12(2), 376; https://doi.org/10.3390/cancers12020376 - 6 Feb 2020

Cited by 53 | Viewed by 4019

Abstract

The role of CD47 and PD-L1 expression on circulating tumor cells (CTCs) remains unclear, and it is currently unknown whether their distribution varies between the blood and tumor tissue in breast cancer (BC). In this study, CD47 and PD-L1 expression was investigated a) on peripheral blood mononuclear cell (PBMC) cytospins from early (n = 100) and metastatic (n = 98) BC patients, by triple immunofluorescence for CD47/PD-L1/Cytokeratins, and b) on matched primary and/or metastatic tumor tissue from CTC-positive patients using immunohistochemistry. CD47+and/orPD-L1+ CTCs were detected in 11%, 16.9%, and 29.6% of early, recurrent, and de novo metastatic patients (p = 0.016). In metastatic disease, CD47^highand/orPD-L1^high CTCs were associated with disease progression (p = 0.005) and shorter progression-free survival (PFS) (p = 0.010), and independently predicted for an increased risk of relapse (HR: 2.719; p = 0.008) and death (HR: 2.398; p = 0.034). PD-L1 expression rates differed between CTCs and tissue tumor cells and between peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) (positive concordance of 3.8% and 4%, respectively). CD47 expression also differed between CTCs and tumor cells (positive concordance of 11.5%). In conclusion, CTCs expressing CD47 and PD-L1 have independent poor prognostic implications in metastatic BC, indicating a potential role of innate and adaptive immune evasion mechanisms in their metastatic potential. The clinical value of the parallel assessment of the peripheral and local immune response merits further evaluation in BC. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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16 pages, 2008 KiB

Open AccessArticle

Circulating Tumor Cells as a Marker of Disseminated Disease in Patients with Newly Diagnosed High-Risk Prostate Cancer

by Wojciech A. Cieślikowski, Joanna Budna-Tukan, Monika Świerczewska, Agnieszka Ida, Michał Hrab, Agnieszka Jankowiak, Martine Mazel, Michał Nowicki, Piotr Milecki, Klaus Pantel, Catherine Alix-Panabières, Maciej Zabel and Andrzej Antczak

Cancers 2020, 12(1), 160; https://doi.org/10.3390/cancers12010160 - 9 Jan 2020

Cited by 32 | Viewed by 3976

Abstract

The aim of this study was to investigate whether the enumeration of circulating tumor cells (CTCs) in blood can differentiate between true localized and metastatic prostate cancer. A cross-sectional study of 104 prostate cancer patients with newly diagnosed high-risk prostate cancer was conducted. In total, 19 patients presented metastatic disease and 85 were diagnosed with localized disease. Analyses included intergroup comparison of CTC counts, determined using the CellSearch^® system, EPISPOT assay and GILUPI CellCollector^®, and ROC analysis verifying the accuracy of CTC count as a maker of disseminated prostate cancer. The vast majority (94.7%) of patients with advanced-stage cancer tested positively for CTCs in at least one of the assays. However, significantly higher CTC counts were determined with the CellSearch^® system compared to EPISPOT assay and GILUPI CellCollector^®. Identification of ≥4 CTCs with the CellSearch^® system was the most accurate predictor of metastatic disease (sensitivity 0.500; specificity 0.900; AUC (95% CI) 0.760 (0.613–0.908). Furthermore, we tried to create a model to enhance the specificity and sensitivity of metastatic prediction with CTC counts by incorporating patient’s clinical data, including PSA serum levels, Gleason score and clinical stage. The composite biomarker panel achieved the following performance: sensitivity, 0.611; specificity, 0.971; AUC (95% CI), 0.901 (0.810–0.993). Thus, although the sensitivity of CTC detection needs to be further increased, our findings suggest that high CTC counts might contribute to the identification of high-risk prostate cancer patients with occult metastases at the time of diagnosis. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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Review

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23 pages, 1239 KiB

Open AccessReview

Mesenchymal Characteristics and Predictive Biomarkers on Circulating Tumor Cells for Therapeutic Strategy

by Takahiro Okabe, Shinsaku Togo, Yuichi Fujimoto, Junko Watanabe, Issei Sumiyoshi, Akira Orimo and Kazuhisa Takahashi

Cancers 2020, 12(12), 3588; https://doi.org/10.3390/cancers12123588 - 30 Nov 2020

Cited by 9 | Viewed by 3107

Abstract

Metastasis-related events are the primary cause of cancer-related deaths, and circulating tumor cells (CTCs) have a pivotal role in metastatic relapse. CTCs include a variety of subtypes with different functional characteristics. Interestingly, the epithelial–mesenchymal transition (EMT) markers expressed in CTCs are strongly associated with poor clinical outcome and related to the acquisition of circulating tumor stem cell (CTSC) features. Recent studies have revealed the existence of CTC clusters, also called circulating tumor microemboli (CTM), which have a high metastatic potential. In this review, we present current opinions regarding the clinical significance of CTCs and CTM with a mesenchymal phenotype as clinical surrogate markers, and we summarize the therapeutic strategy according to phenotype characterization of CTCs in various types of cancers for future precision medicine. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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38 pages, 1489 KiB

Open AccessEditor’s ChoiceReview

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

by Anthony Genna, Aline M. Vanwynsberghe, Amélie V. Villard, Charles Pottier, Julien Ancel, Myriam Polette and Christine Gilles

Cancers 2020, 12(6), 1632; https://doi.org/10.3390/cancers12061632 - 19 Jun 2020

Cited by 71 | Viewed by 5601

Abstract

Epithelial–mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major EMT-driven properties that may help hybrid Epithelial/Mesenchymal CTCs to survive in the bloodstream and accomplish early phases of metastatic colonization. We then discuss how interrogating EMT in CTCs as a companion biomarker could help refine cancer patient management, further supporting the relevance of CTCs in personalized medicine. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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26 pages, 2818 KiB

Open AccessReview

Detection of Circulating Tumor Plasma Cells in Monoclonal Gammopathies: Methods, Pathogenic Role, and Clinical Implications

by Luzalba Sanoja-Flores, Juan Flores-Montero, Martín Pérez-Andrés, Noemí Puig and Alberto Orfao

Cancers 2020, 12(6), 1499; https://doi.org/10.3390/cancers12061499 - 8 Jun 2020

Cited by 20 | Viewed by 5329

Abstract

Cancer dissemination and distant metastasis most frequently require the release of tumor cells into the blood circulation, both in solid tumors and most hematological malignancies, including plasma cell neoplasms. However, detection of blood circulating tumor cells in solid tumors and some hematological malignancies, such as the majority of mature/peripheral B-cell lymphomas and monoclonal gammopathies, has long been a challenge due to their very low frequency. In recent years, the availability of highly-sensitive and standardized methods for the detection of circulating tumor plasma cells (CTPC) in monoclonal gammopathies, e.g., next-generation flow cytometry (NGF), demonstrated the systematic presence of CTPC in blood in virtually every smoldering (SMM) and symptomatic multiple myeloma (MM) patient studied at diagnosis, and in the majority of patients with newly-diagnosed monoclonal gammopathies of undetermined significance (MGUS). These methods set the basis for further detailed characterization of CTPC vs. their bone marrow counterpart in monoclonal gammopathies, to investigate their role in the biology of the disease, and to confirm their strong impact on patient outcome when measured both at diagnosis and after initiating therapy. Here, we review the currently available techniques for the detection of CTPC, and determine their biological features, physiopathological role and clinical significance in patients diagnosed with distinct diagnostic categories of plasma cell neoplasms. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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24 pages, 811 KiB

Open AccessReview

Liquid Biopsy in Colorectal Carcinoma: Clinical Applications and Challenges

by Drahomír Kolenčík, Stephanie N. Shishido, Pavel Pitule, Jeremy Mason, James Hicks and Peter Kuhn

Cancers 2020, 12(6), 1376; https://doi.org/10.3390/cancers12061376 - 27 May 2020

Cited by 24 | Viewed by 4956

Abstract

Colorectal carcinoma (CRC) is characterized by wide intratumor heterogeneity with general genomic instability and there is a need for improved diagnostic, prognostic, and therapeutic tools. The liquid biopsy provides a noninvasive route of sample collection for analysis of circulating tumor cells (CTCs) and genomic material, including cell-free DNA (cfDNA), as a complementary biopsy to the solid tumor tissue. The solid biopsy is critical for molecular characterization and diagnosis at the time of collection. The liquid biopsy has the advantage of longitudinal molecular characterization of the disease, which is crucial for precision medicine and patient-oriented treatment. In this review, we provide an overview of CRC and the different methodologies for the detection of CTCs and cfDNA, followed by a discussion on the potential clinical utility of the liquid biopsy in CRC patient care, and lastly, current challenges in the field. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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17 pages, 3289 KiB

Open AccessReview

Prospects for Comprehensive Analyses of Circulating Tumor Cells in Tumor Biology

by Masahiko Aoki, Hirokazu Shoji, Ayumi Kashiro, Keiko Takeuchi, Yoshihiro Shimizu and Kazufumi Honda

Cancers 2020, 12(5), 1135; https://doi.org/10.3390/cancers12051135 - 1 May 2020

Cited by 20 | Viewed by 3462

Abstract

The comprehensive analysis of biological and clinical aspects of circulating tumor cells (CTCs) has attracted interest as a means of enabling non-invasive, real-time monitoring of cancer patients and enhancing our fundamental understanding of tumor metastasis. However, CTC populations are extremely small when compared to other cell populations in the blood, limiting our comprehension of CTC biology and their clinical utility. Recently developed proteomic and genomic techniques that require only a small amount of sample have attracted much interest and expanded the potential utility of CTCs. Cancer heterogeneity, including specific mutations, greatly impacts disease diagnosis and the choice of available therapeutic strategies. The CTC population consists primarily of cancer stem cells, and CTC subpopulations are thought to undergo epithelial–mesenchymal transition during dissemination. To better characterize tumor cell populations, we demonstrated that changes in genomic profiles identified via next-generation sequencing of liquid biopsy samples could be expanded upon to increase sensitivity without decreasing specificity by using a combination of assays with CTCs and circulating tumor DNA. To enhance our understanding of CTC biology, we developed a metabolome analysis method applicable to single CTCs. Here, we review―omics studies related to CTC analysis and discuss various clinical and biological issues related to CTCs. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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30 pages, 354 KiB

Open AccessReview

Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient

by Giovanni Rossi, Alessandro Russo, Marco Tagliamento, Alessandro Tuzi, Olga Nigro, Giacomo Vallome, Claudio Sini, Massimiliano Grassi, Maria Giovanna Dal Bello, Simona Coco, Luca Longo, Lodovica Zullo, Enrica Teresa Tanda, Chiara Dellepiane, Paolo Pronzato and Carlo Genova

Cancers 2020, 12(5), 1125; https://doi.org/10.3390/cancers12051125 - 30 Apr 2020

Cited by 46 | Viewed by 5795

Abstract

In recent years, the evolution of treatments has made it possible to significantly improve the outcomes of patients with non-small cell lung cancer (NSCLC). In particular, while molecular targeted therapies are effective in specific patient sub-groups, immune checkpoint inhibitors (ICIs) have greatly influenced the outcomes of a large proportion of NSCLC patients. While nivolumab activity was initially assessed irrespective of predictive biomarkers, subsequent pivotal studies involving other PD-1/PD-L1 inhibitors in pre-treated advanced NSCLC (atezolizumab within the OAK study and pembrolizumab in the Keynote 010 study) reported the first correlations between clinical outcomes and PD-L1 expression. However, PD-L1 could not be sufficient on its own to select patients who may benefit from immunotherapy. Many studies have tried to discover more precise markers that are derived from tumor tissue or from peripheral blood. This review aims to analyze any characteristics of the immunogram that could be used as a predictive biomarker for response to ICIs. Furthermore, we describe the most important genetic alteration that might predict the activity of immunotherapy. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

35 pages, 1965 KiB

Open AccessReview

The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance

by Hassan Dianat-Moghadam, Mehdi Azizi, Zahra Eslami-S, Luis Enrique Cortés-Hernández, Maryam Heidarifard, Mohammad Nouri and Catherine Alix-Panabières

Cancers 2020, 12(4), 867; https://doi.org/10.3390/cancers12040867 - 3 Apr 2020

Cited by 63 | Viewed by 7159

Abstract

Metastases and cancer recurrence are the main causes of cancer death. Circulating Tumor Cells (CTCs) and disseminated tumor cells are the drivers of cancer cell dissemination. The assessment of CTCs’ clinical role in early metastasis prediction, diagnosis, and treatment requires more information about their biology, their roles in cancer dormancy, and immune evasion as well as in therapy resistance. Indeed, CTC functional and biochemical phenotypes have been only partially characterized using murine metastasis models and liquid biopsy in human patients. CTC detection, characterization, and enumeration represent a promising tool for tailoring the management of each patient with cancer. The comprehensive understanding of CTCs will provide more opportunities to determine their clinical utility. This review provides much-needed insights into this dynamic field of translational cancer research. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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