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Analysis of Circulating Tumor Cells in Patients with Non-small Cell Lung Cancer Using Epithelial Marker-Dependent and -Independent Approaches
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Introduction Epithelial circulating tumor cells (CTCs) are detectable in patients with non-small cell lung cancer (NSCLC). However, epithelial to mesenchymal transition, a widely reported prerequisite for metastasis, may lead to an underestimation of CTC number. We compared directly an epithelial marker-dependent (CellSearch) and a marker-independent (isolation by size of epithelial tumor cells [ISET]) technology platform for the ability to identify CTCs. Molecular characteristics of CTCs were also explored.Methods Paired peripheral blood samples were collected from 40 chemonäive, stages IIIA to IV NSCLC patients. CTCs were enumerated by Epithelial Cell Adhesion Molecule-based immunomagnetic capture (CellSearch, Veridex) and by filtration (ISET, RareCell Diagnostics). CTCs isolated by filtration were assessed by immunohistochemistry for epithelial marker expression (cytokeratins, Epithelial Cell Adhesion Molecule, epidermal growth factor receptor) and for proliferation status (Ki67).Results CTCs were detected using ISET in 32 of 40 (80%) patients compared with 9 of 40 (23%) patients using CellSearch. A subpopulation of CTCs isolated by ISET did not express epithelial markers. Circulating tumor microemboli (CTM, clusters of ≥ 3 CTCs) were observed in 43% patients using ISET but were undetectable by CellSearch. Up to 62% of single CTCs were positive for the proliferation marker Ki67, whereas cells within CTM were nonproliferative.Conclusions Both technology platforms detected NSCLC CTCs. ISET detected higher numbers of CTCs including epithelial marker negative tumor cells. ISET also isolated CTM and permitted molecular characterization. Combined with our previous CellSearch data confirming CTC number as an independent prognostic biomarker for NSCLC, we propose that this complementary dual technology approach to CTC analysis allows more complete exploration of CTCs in patients with NSCLC.
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“While circulating tumor cells (CTCs) are considered a form of liquid biopsy, and we (31) and others (47) have reported on approaches for molecular analysis of CTCs, NSCLC patient CTCs cannot always be reliably identified (44, 48, 49).”
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Metadata
- Authors
- Krebs, M. G., Hou, J.-M., Sloane, R., Lancashire, L., Priest, L., Nonaka, D., Ward, T. H., Backen, A., Clack, G., Hughes, A., Ranson, M., Blackhall, F. H., & Dive, C.
- Affiliations
- Manchester Academic Health Science Centre (GB)
- Cancer Research UK Manchester Institute (GB)
- The Christie NHS Foundation Trust (GB)
- University of Manchester (GB)
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Dive, Caroline
- ORCID
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 7
- Issue
- 2
- Pages
- 306-315
- ISSN
- 1556-0864 (ISSN-L)
- OpenAlex
- W2037607269
- Cited by
- 463
- References
- 40
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 22 · 2023: 23 · 2022: 29 · 2021: 45 · 2020: 39 · 2019: 38 · 2018: 40 · 2017: 47 · 2016: 51 · 2015: 34 · 2014: 27 · 2013: 31 · 2012: 18
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- AstraZeneca
- Cancer Research UK (C147/a12328)
- Academy of Medical Sciences (AMS-SGCL7-Krebs)
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- circulating tumor cells, non-small cell lung cancer, epithelial-mesenchymal transition, CellSearch, circulating tumor microemboli, epithelial markers, Ki-67 proliferation index, EpCAM, cytokeratin, epidermal growth factor receptor, CTC enumeration, prognostic factors
- MeSH terms
- Adenocarcinoma, Aged, Adenocarcinoma, Bronchiolo-Alveolar, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Separation, Epithelial Cells, Female, Humans, Lung Neoplasms, Male, Middle Aged, Neoplastic Cells, Circulating, Prognosis, Prospective Studies, Biomarkers, Tumor, Cell Proliferation
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