Clusters, Assemblies and Aggregates of Tumor Cells in the Blood of Breast Cancer Patients; Composition, Mode of Action, Detection and Impact on Metastasis and Survival
Abstract
:1. Introduction
2. Types of CTC Clusters and Cellular Assemblies Present in the Circulation
2.1. CTC Clusters
2.2. CTC-Neutrophil Clusters
2.3. Neutrophil Extracellular Traps (NETs)
2.4. Macrophage-Tumor Cell Fusion
3. The Origin of CTC Clusters
3.1. Clusters Shedding vs. Intravascular Aggregation
3.2. Edge vs. Center
4. Markers and Phenotypes of CTC Clusters
4.1. Stemness
4.2. Epithelial-Mesenchymal Plasticity
4.3. Cell-Cell Junctions
5. Methods of Detection; Pros and Cons
6. CTC Clusters and Their Impact on Survival
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CAF | cancer associated fibroblast |
CK | cytokeratins |
CTC | circulating tumor cell |
DEP | dielectrophoresis |
ECM | extracellular matrix |
EpCAM | Epithelial Cell Adhesion Molecule |
EMP | epithelial-mesenchymal plasticity |
EMT | epithelial-mesenchymal transition |
HER2 | human epidermal growth factor receptor |
HR | hormone receptors |
MBC | metastatic breast cancer |
NET | neutrophil extracellular traps |
TAN | tumor-associated neutrophils |
TME | tumor microenvironment |
TNBC | triple negative breast cancer |
WBC | white blood cells |
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Description | Markers |
---|---|
CTC | CK+ (cytokeratins 8+, 18+, 19+), CD45−, EpCAM+, DAPI+ |
CTC-neutrophil cluster | CK+/− (cytokeratins 8+, 18+, 19+), CD45+/−, EpCAM+/−, DAPI+, MPO (neutrophil myeloperoxidase)+/− |
CTC-macrophage fusion | CK+ (cytokeratins 8+, 18+, 19+), CD45+, EpCAM+, DAPI+, CD14+ |
NET | MPO (neutrophil myeloperoxidase)+, H3Cit (citrullinated histone H3)+, DAPI+ |
Category | Methods (Examples) | Key Features | Ref. |
---|---|---|---|
Biological properties | CellSearch, AdnaTest, EasySep, Dynabeads, MINDEC | Immunoaffinity-based (marker-dependent isolation), sensitivity in a range from 27% (CellSearch) up to 70% (CellSearch)–73% (AdnaTest), specificity 89–99% (CellSearch), clinically validated (CellSearch), EpCAM(−) cells may be lost, not optimal for cluster isolation | [60,61,62,63] |
RareCyto, CytoTrack | Imaging-based approaches (marker-dependent identification), detection of EpCAM(+) and EpCAM(−) cells, clusters can be observed (Figure 1) | [81,82] | |
Physical properties | OncoQuick, Ficoll Paque | Density-gradient centrifugation, marker-independent, low purity of CTCs | [69,70] |
Parsortix, Labyrinth, JETTA, DLD, Straight Microfluidic Chips | Mircrofluidics (size and deformity based, marker-independent isolation), high sensitivity (92%, Parsortix) and specificity (100%, Parsortix), subsequent analysis of cells possible, suitable for CTC cluster analysis, some specially designed for this purpose (DLD, Straight Microfluidic Chips) | [71,72,73,74,75] | |
CellSieve, ISET, ScreenCell, FMSA | Filter-based methods, marker-independent, some allow post-capture culture and microscopic examination (ScreenCell), sensitivity 76%, specificity 82% (ISET), size-dependent methods favor cluster isolation, but applied pressure may disrupt clusters | [64,65,66,67,68] | |
Mixed properties | CTC-iChip, OncoCEE, Cmx platform, HB-CTC-Chip | Immunoaffinity with Microfluidics, high sensitivity (95%, OncoCEE) and specificity (92%, OncoCEE), suitable for CTC cluster analysis | [76,77,78,79,80] |
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Smietanka, U.; Szostakowska-Rodzos, M.; Tabor, S.; Fabisiewicz, A.; Grzybowska, E.A. Clusters, Assemblies and Aggregates of Tumor Cells in the Blood of Breast Cancer Patients; Composition, Mode of Action, Detection and Impact on Metastasis and Survival. Int. J. Transl. Med. 2021, 1, 55-68. https://doi.org/10.3390/ijtm1010005
Smietanka U, Szostakowska-Rodzos M, Tabor S, Fabisiewicz A, Grzybowska EA. Clusters, Assemblies and Aggregates of Tumor Cells in the Blood of Breast Cancer Patients; Composition, Mode of Action, Detection and Impact on Metastasis and Survival. International Journal of Translational Medicine. 2021; 1(1):55-68. https://doi.org/10.3390/ijtm1010005
Chicago/Turabian StyleSmietanka, Urszula, Małgorzata Szostakowska-Rodzos, Sylwia Tabor, Anna Fabisiewicz, and Ewa A. Grzybowska. 2021. "Clusters, Assemblies and Aggregates of Tumor Cells in the Blood of Breast Cancer Patients; Composition, Mode of Action, Detection and Impact on Metastasis and Survival" International Journal of Translational Medicine 1, no. 1: 55-68. https://doi.org/10.3390/ijtm1010005
APA StyleSmietanka, U., Szostakowska-Rodzos, M., Tabor, S., Fabisiewicz, A., & Grzybowska, E. A. (2021). Clusters, Assemblies and Aggregates of Tumor Cells in the Blood of Breast Cancer Patients; Composition, Mode of Action, Detection and Impact on Metastasis and Survival. International Journal of Translational Medicine, 1(1), 55-68. https://doi.org/10.3390/ijtm1010005