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Circulating and Disseminated Tumor Cells — Novel Approaches and Future Outlook

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

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 15333

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Prof. Dr. Sabine Kasimir-Bauer

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Guest Editor

Department of Gynecology and Obstetrics, University Hospital Essen, 45147 Essen, Germany
Interests: circulating tumor cells

Special Issue Information

Dear Colleagues,

Despite major improvements in diagnosis and treatment of solid tumors, many patients show a relapse of the disease, often even years after first diagnosis, like in breast cancer. In many cases, recurrence of the disease is explained by early micrometastatic spread of circulating tumor cells (CTCs) to blood and further dissemination into secondary organs like the bone marrow (BM) to settle down there as disseminated tumor cells (DTCs). Although the clinical relevance for relapse and overall survival has been demonstrated in a variety of tumor entities based on the analysis of thousands of patients, the lack of therapeutic approaches to eliminate these cells constitutes major obstacles to the successful treatment of the disease. Whereas multi-marker detection methods are available for the characterization of CTCs, methods are lacking for DTCs because BM auto-fluorescence and endogenous immune cell properties as well as BM matrix components can generate false-positive staining.

With the rapid technical progress in the detection of these cells, a comprehensive characterization, especially of DTCs, might help to evaluate patients for additional treatment options to eliminate minimal residual disease.

This Special Issue invites experts in this field to present and discuss novel approaches to detect CTCs and DTCs as prognostic and predictive biomarkers for personalized targeted therapies in the future. Sophisticated data on functional mechanisms are also welcome.

Prof. Dr. Sabine Kasimir-Bauer
Guest Editor

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Prof. Dr. Sabine Kasimir-Bauer
Guest Editor

Manuscript Submission Information

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Published Papers (6 papers)

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Research

18 pages, 2699 KiB

Open AccessArticle

Association of Circulating Tumor Cells, Megakaryocytes and a High Immune-Inflammatory Environment in Metastatic Breast Cancer

by Cvetka Grašič Kuhar, Jernej Silvester, Marina Mencinger, Tanja Ovčariček, Maja Čemažar, Simona Miceska, Živa Modic, Anamarija Kuhar, Tanja Jesenko and Veronika Kloboves Prevodnik

Cancers 2023, 15(13), 3397; https://doi.org/10.3390/cancers15133397 - 28 Jun 2023

Cited by 4 | Viewed by 2104

Abstract

Liquid biopsy is becoming an important source of new biomarkers during the treatment of metastatic cancer patients. Using size-based microfluid technology, we isolated circulating tumor cells (CTCs) from metastatic breast cancer patients to evaluate their presence and cluster formation, as well as the presence of megakaryocytes and immune-inflammatory blood cells, and to correlate their presence with clinicopathological data and overall survival (OS). In total, 59 patients (median age 60.4 years) were included in the study: 62.7% luminal A/B-like, 20.3% HER2-positive, and 17% triple-negative. Our results showed that at least one CTC was present in 79.7% and ≥5 CTCs in 35.2% of the patients. CTC clusters were present in patients with ≥5 CTCs only (in 19.2% of them), and megakaryocytes were present in 52% of all patients. The presence of CTC clusters and megakaryocytes was positively associated with the CTC count. Patients with low pan-inflammatory value (PIV), low systemic immune-inflammatory index (SII), and low relative change from baseline (ΔPIV%, ΔSII%) were associated with significantly higher OS than their counterparts. ΔPIV%, the presence of infection in the last month, and a long duration of metastatic disease were identified as independent prognostic factors for OS. The interplay of CTCs, CTC clusters, megakaryocytes, and PIV needs to be further explored. Full article

(This article belongs to the Special Issue Circulating and Disseminated Tumor Cells — Novel Approaches and Future Outlook)

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14 pages, 6295 KiB

Open AccessArticle

Comparison of RNA Marker Panels for Circulating Tumor Cells and Evaluation of Their Prognostic Relevance in Breast Cancer

by Eva Welsch, Eva Schuster, Michael Krainer, Maximilian Marhold, Rupert Bartsch, Michael B. Fischer, Michael Hermann, Gabriele Hastermann, Heidemarie Uher, Gerhard Sliutz, Birgit Anker, Robert Zeillinger and Eva Obermayr

Cancers 2023, 15(4), 1271; https://doi.org/10.3390/cancers15041271 - 16 Feb 2023

Cited by 5 | Viewed by 2491

Abstract

Liquid biopsy is a promising tool for therapy monitoring of cancer patients, but a need for further research in this field exists in order to improve sensitivity, specificity, standardization and minimize costs. In our present study, we evaluated two panels of transcripts related with the presence of circulating tumor cells (CTCs) (Panel 1: CK19, EpCAM, SCGB2A2 and Panel 2: EMP2, SLC6A8, HJURP, MAL2, PPIC and CCNE2) in two cohorts of breast cancer patients (metastatic and early). A blood cell fraction possibly containing CTCs was isolated with density gradient centrifugation, followed by RNA isolation and qPCR using TaqMan^® or RT-qPCR using hybridization probes. The positivity rates of the investigated panels were similar, albeit higher in metastatic (69.4% Panel 1, 75.0% Panel 2; total 86.1%) compared to early (18.9% Panel 1, 23.3% Panel 2; total 31.1%) breast cancer patients. CK19, SCGB2A2, EMP2, HJURP, MAL2, and CCNE2 individually correlated with shorter overall survival in the metastatic patient cohort. The findings highlight the additional value of Panel 2 markers, which are in contrast to CK19 and EpCAM not solely linked to an epithelial phenotype. Full article

(This article belongs to the Special Issue Circulating and Disseminated Tumor Cells — Novel Approaches and Future Outlook)

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11 pages, 910 KiB

Open AccessArticle

The Impact of Surgery on Circulating Malignant Tumour Cells in Oral Squamous Cell Carcinoma

by Justin Curtin, Peter Thomson, Gordon Wong, Alfred Lam and Siu-Wai Choi

Cancers 2023, 15(3), 584; https://doi.org/10.3390/cancers15030584 - 18 Jan 2023

Cited by 2 | Viewed by 1783

Abstract

Importance: The extent to which surgical management of oral squamous cell carcinoma (OSCC) disseminates cancer is currently unknown. Objective: To determine changes in numbers of malignant cells released into systemic circulation immediately following tumour removal and over the first seven post-operative days. Design: An observational study from March 2019 to February 2021. Setting: This study was undertaken at Queen Mary University Hospital, Hong Kong. Participants: Patients with biopsy-proven oral SCC were considered for eligibility. Patients under 18 years of age, pregnant or lactating women and those unable to understand the study details or unable to sign the consent form were excluded. Twenty-two patients were enrolled (12 male and 10 female) with mean age of 65.5 years. Intervention: Primary tumour management was performed in accord with multi-disciplinary team agreement. Anaesthesia and post-operative care were unaltered and provided in accord with accepted clinical practice. Main Outcomes and Measures: Three types of malignant cells detected in peripheral blood samples were enumerated and sub-typed based on the presence of chromosomal aneuploidy and immunohistochemical characteristics. To test the hypothesis that malignant cells are released by surgery, the numbers of single circulating tumour cells (CTCs), circulating tumour microemboli (CTM) and circulating endothelial cells (CTECs) were recorded pre-operatively, upon tumour removal and the second and seventh post-operative days. Results: Of a potential 88 data collection points, specimens were not obtainable in 12 instances. Tumour removal resulted in a statistically significant increase in CTCs and a non-statistically significant rise in CTMs. CTCs, CTMs and CTECs were detected in the majority of patients up to the seventh post-operative day. Individual patients demonstrated striking increases in post-operative CTCs and CTECs numbers. Conclusions/Relevance: Surgical management of OSCC has a significant impact on the systemic distribution of cancer cells. Malignant cells persisted post-operatively in a manner independent of recognised staging methods suggesting differences in tumour biology between individuals. Further investigation is warranted to determine whether circulating malignant cell enumeration can be used to refine risk stratification for patients with OSCC. Full article

(This article belongs to the Special Issue Circulating and Disseminated Tumor Cells — Novel Approaches and Future Outlook)

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21 pages, 3403 KiB

Open AccessArticle

Multi-Parameter Analysis of Disseminated Tumor Cells (DTCs) in Early Breast Cancer Patients with Hormone-Receptor-Positive Tumors

by Theresa König, Senol Dogan, Anne Kathrin Höhn, Laura Weydandt, Bahriye Aktas and Ivonne Nel

Cancers 2023, 15(3), 568; https://doi.org/10.3390/cancers15030568 - 17 Jan 2023

Cited by 2 | Viewed by 1986

Abstract

Background: Patients with hormone-receptor-positive (HR+) breast cancer are at increased risk for late recurrence. One reason might be disseminated tumor cells (DTCs), which split off in the early stages of the disease and metastasize into the bone marrow (BM). Methods: We developed a novel multi-parameter immunofluorescence staining protocol using releasable and bleachable antibody–fluorochrome-conjugates. This sequential procedure enabled us to analyze six distinct phenotypical and therapy-related markers on the same DTC. We characterized BM aspirates from 29 patients with a HR+ tumor and a known positive DTC status—based on the standardized detection of epithelial cells in BM. Results: Using the immunofluorescence staining, a total of 153 DTCs were detected. Luminal A patients revealed a higher DTC count compared with luminal B. The majority of the detected DTCs were CK-positive (128/153). However, in 16 of 17 luminal A patients we found HER2-positive DTCs. We detected CK-negative DTCs (25/153) in 12 of 29 patients. Of those cells, 76% were Ki67-positive and 68% were HER2-positive. Moreover, we detected DTC clusters consisting of mixed characteristics in 6 of 29 patients. Conclusions: Using sequential multi-parameter imaging made it possible to identify distinct DTC profiles not solely based on epithelial features. Our findings indicate that characterization rather than quantification of DTCs might be relevant for treatment decisions. Full article

(This article belongs to the Special Issue Circulating and Disseminated Tumor Cells — Novel Approaches and Future Outlook)

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16 pages, 2480 KiB

Open AccessArticle

Phenotypic Characterization of Circulating Tumor Cells Isolated from Non-Small and Small Cell Lung Cancer Patients

by Argyro Roumeliotou, Evangelia Pantazaka, Anastasia Xagara, Foteinos-Ioannis Dimitrakopoulos, Angelos Koutras, Athina Christopoulou, Theodoros Kourelis, Nada H. Aljarba, Saad Alkahtani, Filippos Koinis, Athanasios Kotsakis and Galatea Kallergi

Cancers 2023, 15(1), 171; https://doi.org/10.3390/cancers15010171 - 28 Dec 2022

Cited by 8 | Viewed by 2915

Abstract

In the present study, we evaluated the expression of JUNB and CXCR4 in circulating tumor cells (CTCs) of lung cancer patients and investigated whether these proteins have prognostic clinical relevance. Peripheral blood from 30 patients with non-small-cell lung cancer (NSCLC) was filtered using ISET membranes, and cytospins from 37 patients with small-cell lung cancer (SCLC) were analyzed using confocal and VyCAP microscopy. Both JUNB and CXCR4 were expressed in the vast majority of lung cancer patients. Interestingly, the phenotypic patterns differed between NSCLC and SCLC patients; the (CK+/JUNB+/CXCR4+) phenotype was present in 50% of NSCLC vs. 71% of SCLC patients. Similarly, the (CK+/JUNB+/CXCR4–) was present in 44% vs. 71%, the (CK+/JUNB–/CXCR4+) in 6% vs. 71%, and the (CK+/JUNB–/CXCR4–) phenotype in 38% vs. 84%. In NSCLC, the presence of ≥1 CTCs with the (CK+/JUNB+/CXCR4+) phenotype was associated with worse progression-free survival (PFS) (p = 0.007, HR = 5.21) while ≥2 with poorer overall survival (OS) (p < 0.001, HR = 2.16). In extensive stage SCLC patients, the presence of ≥4 CXCR4-positive CTCs was associated with shorter OS (p = 0.041, HR = 5.01). Consequently, JUNB and CXCR4 were expressed in CTCs from lung cancer patients, and associated with patients’ survival, underlying their key role in tumor progression. Full article

(This article belongs to the Special Issue Circulating and Disseminated Tumor Cells — Novel Approaches and Future Outlook)

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14 pages, 10532 KiB

Open AccessArticle

Neoadjuvant Chemotherapy of Patients with Early Breast Cancer Is Associated with Increased Detection of Disseminated Tumor Cells in the Bone Marrow

by Léa Volmer, André Koch, Sabine Matovina, Dominik Dannehl, Martin Weiss, Ganna Welker, Markus Hahn, Tobias Engler, Markus Wallwiener, Christina Barbara Walter, Ernst Oberlechner, Sara Yvonne Brucker, Klaus Pantel and Andreas Hartkopf

Cancers 2022, 14(3), 635; https://doi.org/10.3390/cancers14030635 - 27 Jan 2022

Cited by 8 | Viewed by 3326

Abstract

Preclinical data suggest that neoadjuvant chemotherapy (NAT) may promote micrometastatic spread. We aimed to compare the detection rate and prognostic relevance of disseminated tumor cells (DTCs) from the bone marrow (BM) of patients with early-stage breast cancer (EBC) after NAT with that of therapy-naive EBC patients. DTCs were identified from BM samples, collected during primary surgery. Patients who received NAT were compared to patients who received chemotherapy after surgery. In total, 809 patients were analyzed. After NAT, 45.4% of patients were DTC-positive as compared to 19.9% of patients in the adjuvant chemotherapy group (p < 0.001). When sampled in patients who had undergone NAT, the detection of DTCs in the BM was significantly increased (OR: 3.1; 95% confidence interval (CI): 2.1–4.4; p < 0.001). After NAT, DTC-positive patients with ≥2 DTCs per 1.5 × 10⁶ mononuclear cells in their BM had an impaired disease-free survival (HR: 4.8, 95% CI: 0.9–26.6; p = 0.050) and overall survival (HR: 4.2; 95% CI: 1.4–12.7; p = 0.005). The higher rate of DTC-positive patients after NAT as compared to a treatment-naive comparable control cohort suggests that NAT supports tumor cell dissemination into the bone marrow. DTC positivity in BM predicted relapse in various distant organs, implying that tumor cell dissemination was not restricted to the bone marrow. Full article

(This article belongs to the Special Issue Circulating and Disseminated Tumor Cells — Novel Approaches and Future Outlook)

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