The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance
Abstract
:1. Introduction
2. CTC Biology and Tumor Metastases
2.1. Do CTCs Have Cancer Stem Cell Features?
2.2. Are Single CTCs or CTC Clusters Involved in Metastasis Formation?
2.3. CTC Dissemination and Dormancy
2.4. How CTCs Escape the Immune System Surveillance and Therapy?
2.4.1. CTCs Escape the Innate Immune System Response
2.4.2. CTCs Escape the Adoptive Immune System Response
2.4.3. CTCs Induce Resistance to Chemotherapy
3. CTC Enrichment Strategies
3.1. Biological Feature-Based CTC Enrichment
3.1.1. Positive Enrichment
3.1.2. Negative Enrichment
3.2. Physical Feature-Based CTC Enrichment
3.2.1. Density-Based Enrichment
3.2.2. Size-Based Enrichment
3.2.3. Dielectrophoresis
3.2.4. Inertial Focusing
3.3. Combined Methods
3.4. Challenge with DTC Isolation
4. CTC Clinical Relevance
4.1. How CTCs Improve Metastasis Prediction and Diagnosis?
4.2. Can CTC Profiling Guide the Therapeutic Strategy?
4.2.1. CTC Proteomic Analysis
4.2.2. CTC Genomic Analysis
4.3. Which One Is Better, CTC or ctDNA?
4.4. CTC Targeting for Metastasis Therapy
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Enrichment Method | Selection Criteria | Detection Method | Advantages | Disadvantages | Ref. |
---|---|---|---|---|---|
(a) Biological-based methods for CTC enrichment | |||||
Immunoaffinity-positive enrichment | |||||
CellSearch® | EpCAM | Flow cytometry | ● FDA-approved method, ● Clinically relevant automated system, ● Quantitative, ● Easy, ● Highly robust and reproducible | ● Do not detect EpCAM-negative CTCs, ● Expensive and subjective image evaluation, ● Cell preservative limits RNA analysis | [16,18,103,135] |
CellCollector® | EpCAM | Immunocytochemical staining | ● Can isolate rare CTCs in early cancer stages, ● Provide more CTCs, ● No need of blood sampling, ● Detect CTCs in vivo | ● Cannot isolate EMT-CTCs, ● CTCs cannot be released from the wire | [115,116] |
MagWIRE system | EpCAM | qPCR | ● Large-scale CTC capture in vivo, ● Very fast processing, ● Completely self-contained, ● Flexible | ●Require additional biocompatibility testing, ● Capture EpCAM-positive CTCs only, ● Possible systemic exposure to excess iron | [116,117] |
rVAR2-based CTC isolation Ligand-receptor affinity | Oncofetal chondroitin sulfate (ofCS) | Flowcytometry/ddPCR/Western blotting/Four-color immunofluorescence staining | ● Not dependent on the expression of a single marker, ● Low contamination of PBMCs, ● CTC enumeration correlates with disease stage | ● Need to be followed by CTC detection methods, ● Need redesign for each tumor type, ● Not commercially available | [137] |
Immunoaffinity-negative enrichment | |||||
EasySep™ | CD45 depletion | Flow cytometry | ● Simple, ● Easy-to-use batch separation, ● Do not bias the sample according to selection markers | ● False positive results due to CD45– endothelial cells, ● Do not achieve the same high purity levels | [138] |
Quadrupole Magnetic Separator (QMS) | CD45 depletion | IF staining | ● High-throughput magnetic cell sorter, ● Continuous flow | ● RBC lysis required | [139] |
(b) Physical methods for CTC enrichment | |||||
Size and deformability | |||||
ISET technology | Size/ Deformability | IF staining | ● Easy and fast processing time, ● Sensitivity threshold of 1 CTC/mL of blood, ● Label-independent isolation, ● Isolation of intact CTCs, ● Isolation of EpCAM-negative CTCs, ● CTCs can be further analyzed by multiplexed imaging and genetic analysis | ● Low specificity, ● Retention only of CTCs larger than the leukocyte range, ● Bigger leukocytes may be captured, ● Blood cells need to be fixed, ● False-positive results, ● Low recovery and purity, ● Need the pathologists’ expertise for CTC detection | [3,16,18,140] |
Spiral- Slits Chip | Size and deformability | RT-PCR | ● Avoid clogging, ● Continuous separation, ● Minimal contamination, ● Detection with optical spectroscopy, ● Fast processing | ● False-positive results, ● Need optimizing the structure geometry, ● Low sensitivity | [141] |
Cluster-Chip | Strength of cell-cell junctions | RNA sequencing | ● Label-free isolation ● Potential study of tumor-immune system interactions ● Chemistry-free approach | ● Lack of biological characterization and clinical significance, ● Not commercially available, ● Shear stress is needed to release the majority of clusters from micropillars | [31] |
Nanotube-CTC-chip | Preferential adherence or phenotype | IF staining | ● Antigen/Size-independent CTC capture, ● Better capture sensitivity from droplets, ● No cell loss, ● Surface architecture lends itself to easier CTC downstream analysis, ● CTC isolation with high purity and 100% sensitivity, ● Can capture CTCs with different phenotypes | ● Need development for surface architecture, ● Not commercially available, ● Cannot isolate EMT-CTCs, ● Long set-up times | [141] |
Dielectric properties | |||||
DEPArray™ | Electrical signature | ● DEP cages allow the recovery and manipulation of viable single cells | ● Requires pre-enrichment | [142] | |
ApoStream® | Conductivity Morphology and Membrane surface area | IF staining | ● Label-independent isolation, ● Continuous flow, ● Captures viable cells | ● Cells need to be pre-purified because whole blood has high electrical conductivity | [18,143,144] |
Density | |||||
OncoQuick® | Density and filtration | - | ● Porous membrane prevent mixing, ● Simple, ● Inexpensive | ● Relative low yield and enrichment | [120] |
Ficoll-Paque® | Density | RT-PCR | ● Inexpensive, ● Easy-to-use | ● Significant CTC loss | [145] |
Inertial Focusing | |||||
Labyrinth device | Size | IF staining | Can capture viable cells, label free | Prior RBC depletion required | [130] |
Multi-flow microfluidic device | Size and inertial forces | IF staining | Predictable and tunable cutoff size, isolation of CTC clusters, one-step isolation | Relative low flow rate, | [128] |
Micro-ellipse filters | Size, deformability and inertial forces | IF staining | Robust, large sample processing, on-chip culture | RBC lysis required | [129] |
ClearCell® FX | Size and inertial forces | Flow cytometry | ● Can captures viable cells, ● Easy to manufacture, ● Can process a 7.5 mL sample in 8 min, ● Exerts minimal stress on captured cells | ● RBC lysis required | [131] |
Vortex | Size | IF staining | ● No RBC lysis required, ● Can capture viable cells, ● Easy to manufacture, ● Detect clusters | ● Low sensitivity and reproducibility | [132] |
Photoacoustic flow cytometry | |||||
Ultrasound and a pulsed near-infrared laser | - | Flow cytometry | ● Can count CTCs in blood vessels up to 3 mm deep, ● Label-free | ● Only used for CTC count, ● No molecular analysis | [146] |
(c) Combined methods | |||||
GEDI chip | Size and immunoaffinity | cDNA sequencing and immunostaining | ● Relative high yield and enrichment | ● Requires surface chemistry modifications, ● Requires high-resolution imaging method | [147] |
CTC-iChip (Microfluidic immunomagnetic-based) | Size inertial focusing Negative enrichment | Mass cytometry | ● Allows the sequential separation of different blood components through micropillar array, ● Hydrodynamic size-based sorting/magnetophoresis, ● Simplicity, ● Can sort rare CTCs | ● Samples not suitable for DNA sequencing, ● Expensive, ● Long set-up times, ● Difficult to implement in clinical settings, ● Multiple manually interconnected chips | [148] |
RosetteSep system | Negative enrichment EPISPOT (protein secretion) | IF staining | ● Captures and detects viable CTCs at the single-cell level, ● Does not need whole-genome or transcriptome amplification, ● Limited number of markers | ● Proteins must be actively secreted ● Unbiased enrichment independent of CTC/ DTC phenotype | [140,142,149] |
RosetteSep system EPIDROP | Secreted proteins Density centrifugation Immunoaffinity | IF staining | ● Simultaneous proteomic and secretomic analysis of single viable CTCs, ● Can test different drugs in a single patient, ● More reliable and sensitive than EPISPOT, ● Automatic detection of positive events using the appropriate software | ● Prototype development still in progress | [6] |
Device | Ref. | Enrichment/Detection Method | Condition | Status | Primary Endpoints | Trail |
---|---|---|---|---|---|---|
GILUPI CellCollector® | [116] | Immunoaffinity (anti-EpCAM Ab) | Locally advanced breast cancer | Completed | PFS, OS | NCT03732339 |
EMT-marker based ferrofluid device | [150] | N-cadherin or O-cadherin based analysis | Metastatic breast and prostate cancers | Completed | Clinical stage, Screening | NCT02025413 |
ISET® technology | [151] | Immunocytochemistry (PD-L1 expression analysis) FISH analysis of ALK | Lung cancer Lung Neoplasms | Recruiting Active | Not provided Validation of ALK analysis | NCT02827344 NCT02372448 |
Culture system | [152] | Affinity-based WBC deletion | Early detection of cancer | Recruiting | Early diagnosis and screening | NCT03843450 |
Flexible Micro Spring Array (FMSA) | [153] | Filtration (or size-exclusion of viable CTCs) | Stage IV colorectal cancer | Completed | PFS, OS, response to therapy | NCT01722903 |
Ficoll enrichment | [145] | Density/ PCR | Pancreatic ductal adenocarcinoma | Completed | PFS, OS, response to therapy | NCT02150746 |
CellSearch® | [154] | Immunoaffinity (anti-EpCAM Ab) | Prostate cancer Metastatic breast cancer | Recruiting Completed | EMT markers, PFS and OS CTC-Endocrine Therapy Index | NCT04021394 NCT01701050 |
CTC-Chip | [102] | Size or Immunoaffinity | Prostate cancer (Prostatectomy) | Recruiting | Examine chromosome translocation | NCT01961713 |
Parsortix™ | [155] | Cellular size and deformability | Ovarian neoplasms | Completed | Estimate risk of cancer | NCT02785731 |
IsoPic™ microfluidic system | [156] | Flow rate, surface interactions, plasticity, and elasticity | Unknown primary cancer | Recruiting | Prediction of molecularly targeted therapies | NCT04025970 |
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Dianat-Moghadam, H.; Azizi, M.; Eslami-S, Z.; Cortés-Hernández, L.E.; Heidarifard, M.; Nouri, M.; Alix-Panabières, C. The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance. Cancers 2020, 12, 867. https://doi.org/10.3390/cancers12040867
Dianat-Moghadam H, Azizi M, Eslami-S Z, Cortés-Hernández LE, Heidarifard M, Nouri M, Alix-Panabières C. The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance. Cancers. 2020; 12(4):867. https://doi.org/10.3390/cancers12040867
Chicago/Turabian StyleDianat-Moghadam, Hassan, Mehdi Azizi, Zahra Eslami-S, Luis Enrique Cortés-Hernández, Maryam Heidarifard, Mohammad Nouri, and Catherine Alix-Panabières. 2020. "The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance" Cancers 12, no. 4: 867. https://doi.org/10.3390/cancers12040867