Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Literature Search and Data Sources
2.2. Inclusion and Exclusion Criteria
2.3. Data Extraction
2.4. Quality Assessment
2.5. Statistical Analysis
3. Results
3.1. Study Characteristics
3.2. EMT-CTCs Phenotype
3.2.1. Types of EMT Markers on CTCs in HCC
3.2.2. Association of EMT-CTC Subtypes with Clinicopathological Factors in Preoperative Studies
3.2.3. Association of EMT-CTC Subtypes with Clinicopathological Factors in Longitudinal and Postoperative Studies
3.2.4. Pooled Data from All EMT-CTC Subtype Analysis Reporting on Prognostic Factors for Relapse after the Curative Resection and Meta-Analysis Results
Study | Preoperative Analysis | Postoperative Analysis | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Outcomes | Schulze, 2013 [20] | Court, 2018 [23] | Ou, 2018 [24] | Qi, 2018 [25] | Chen, 2019 [28] | Bai, 2020 [29] | Qi, 2020 [30] | Lei, 2021 [31] | Wang, 2018 [26] | Xie, 2021 [32] | ||
Epithelial-CTCs | ||||||||||||
TFS | Median | pos | 10 | |||||||||
neg | 8 | |||||||||||
p-value | 0.6745 | |||||||||||
ER | HR | 1.000 | 1.295 | |||||||||
95% CI | 0.993–1.007 | 0.827–2.026 | ||||||||||
p-value | 0.970 | 0.258 | ||||||||||
OS | Median | pos | 15.3 | |||||||||
neg | 24.9 | |||||||||||
p-value | 0.017 | |||||||||||
TTR RFS | HR | 1.446 | ||||||||||
95% CI | 0.667–3.133 | |||||||||||
p-value | 0.006 | |||||||||||
Means/SD | pos | 11.32 ± 2.83 | ||||||||||
neg | 12.7 ± 3.1 | |||||||||||
p-value | 0.523 | |||||||||||
Hybrid-CTCs | ||||||||||||
TFS | Median | pos | 6 | 7 | ||||||||
neg | 7 | 24.5 | ||||||||||
p-value | 0.692 | 0.003 | ||||||||||
ER | HR | 1.068 | 2.935 | |||||||||
95% CI | 0.577–1.976 | 1.306–6.594 | ||||||||||
p-value | 0.835 | 0.009 | ||||||||||
TTR RFS | HR | 2.368 | ||||||||||
95% CI | 0.808–6.937 | |||||||||||
p-value | 0.006 | |||||||||||
Median | pos | 14 | ||||||||||
neg | NR | |||||||||||
p-value | 0.006 | |||||||||||
Means/SD | pos | 12.14 ± 2.29 | ||||||||||
neg | 10.82 ± 4.42 | |||||||||||
p-value | 0.638” | |||||||||||
Mesenchymal-CTCs | ||||||||||||
PFS TFS | HR | 2.16 * | ||||||||||
95% CI | 1.38–4.42 | |||||||||||
p-value | 0.002 | |||||||||||
Median | pos | 5 | 5 | |||||||||
neg | 13.3 | 17 | ||||||||||
p-value | 0.009 | <0.0001 | ||||||||||
ER | HR | 1.019 1.019 * | 1.182 | 4.740 3.453 * | 4.039 | |||||||
95% CI | 1.010–1.027 1.006–1.032 * | 0.764–1.83 | 2.041–11.01 1.393–8.559 * | 0.921–17.703 | ||||||||
p-value | <0.001 0.003 * | 0.452 | <0.001 | 0.064 | ||||||||
OS | HR | 2.21 * | ||||||||||
95% CI | 1.38–3.56 | |||||||||||
p-value | 0.001 | |||||||||||
TTR RFS | HR | 3.14 | 4.546 | |||||||||
95% CI | 1.50–6.57 | 2.203–9.381 | ||||||||||
p-value | 0.002 | 0.006 | ||||||||||
Median | pos | 6.4 | ||||||||||
neg | NR | |||||||||||
p-value | <0.006 | |||||||||||
Means/ SD | pos | 9.21 ± 3.16 | ||||||||||
neg | 13.8 ± 2.6 | |||||||||||
p-value | 0.654 |
3.3. CCSCs Phenotype
3.3.1. Types of CSC Markers on CTCs in HCC
3.3.2. The Clinical Significance of CCSCs Subtype Associated with Clinicopathological Factors, Metastasis, and Recurrence
3.3.3. Pooled Data from CCSC Subtype Analysis Reporting on Prognostic Factors for Relapse after the Curative Resection
4. Discussion
Expert Opinion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Author Year | Country | HCC Cohort | Blood (mL) | Time Collection | Treatment | Enrichment Platform | Category Technique | Downstream Methods | EMT Marker | Clinical Significances | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|
Li et al., 2013 [19] | China | 60 | 10 | Preoperative | - | DG-IM | Positive | IF | Twist, vimentin | PVTT, tumor size, TNM | - |
Schulze et al., 2013 [20] | Germany | 59 | 7.5 | Preoperative | Any therapies | CellSearch | Positive | IF | EpCAM | BCLC, MaVI, MiVI, | OS |
Liu et al., 2016 [21] | China | 33 | 5 | - | - | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | Tumor number | MET |
Chen et al., 2017 [22] | China | 99 | 5 | Preoperative | Surgical resection, radiochemical | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | BCLC stages, metastasis | |
Court et al., 2018 [23] | USA | 61 | 4 | Preoperative | Any therapies | NanoVelcro | Positive, MF-IC | IF | Vimentin | Tumor stage PVI | PFS, OS, TTR |
Ou et al., 2018 [24] | China | 165 | 5 | Preoperative | Surgical resection | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | Tumor number, TNM, BCLC | RFS |
Qi et al., 2018 [25] | China | 112 | 5 | Preoperative, Postoperative | Surgical resection | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | BCLC | MET, ER |
Wang et al., 2018 [26] | China | 62 | 5 | Postoperative | Surgical resection | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19 twist, vimentin | - | ER |
Yin et al., 2018 [27] | China | 80 | 5 | Preoperative | Surgical resection, TACE | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19 twist, vimentin | Tumor number, tumor size, PVTT, TNM | MET, RECUR |
Chen et al., 2019 [28] | China | 143 | 5 | Preoperative, Postoperative | Surgical resection, ablation | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | NS | TTR |
Bai et al., 2020 [29] | China | 99 | 5 | Preoperative | Surgical resection | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | BCLC, tumor size, PVTT | PFS |
Qi et al., 2020 [30] | China | 136 | 5 | Preoperative | Surgical resection | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | - | TFS, INR, EXR, RECUR |
Lei et al., 2021 [31] | China | 160 | 15 | Preoperative | Surgical resection | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, bimentin | Tumor size, BCLC | ER |
Xie et al., 2021 [32] | China | 56 | 5 | Preoperative, Postoperative | Liver transplant | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | - | RECUR ER |
Zhang et al., 2021 [33] | China | 105 | 5 | Preoperative | Surgical resection | CanPatrol | Negative, FT | FISH | EpCAM, CK8/18/19, twist, vimentin | CK19 | - |
Author Year | Country | HCC Cohort | Blood (mL) | Time Collection | Treatment | Enrichment Platform | Category Technique | Downstream Methods | CCSC Marker | Clinical Significances | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|
Fan et al., 2011 [34] | China | 82 | 10 | Preoperative | Surgical resection | DG-FACS | Positive | - | CD90, CD44 | - | INR, EXR, RFS, OS |
Liu et al., 2013 [35] | China | 60 | - | - | - | FACS | Positive | - | ICAM | NS | DFS, OS |
Guo et al., 2018 [36] | China | 130 | 5 | Preoperative, Postoperative | Surgical resection | RosetteSep | Negative | qRT-PCR | EpCAM, CD133, CD90, CK19 | - | TTR, RECUR |
Wan et al., 2019 [37] | China | 42 | 10 | Preoperative | - | Labyrinth | Negative, MF | IF | CD44 | TNM | - |
Yao et al., 2019 [38] | China | 10 | 10 | Preoperative, Postoperative | Surgical resection | RosetteSep | Negative, DG-IC | RT-LAMP | CD90, CD133 | Vascular invasion | MET |
Lei et al., 2021 [31] | China | 160 | 15 | Preoperative | Surgical resection | CanPatrol | Negative, FT | FISH | Nanog | Tumor size, BCLC | ER |
Study | Preoperative Analysis | |||||
---|---|---|---|---|---|---|
Outcomes | Fan, 2011 [34] | Liu, 2013 [35] | Guo, 2018 [36] | Lei, 2021 [31] | ||
RFS DFS TTR | HR | 7.15 | 3.127 | |||
95% CI | 2.99–17.09 | 1.360–7.190 | ||||
p-value | 0.0001 | 0.007 | ||||
RR | 4.175 | |||||
95% CI | 2.143–8.133 | |||||
p-value | <0.0001 | |||||
Median | pos | 6 | ||||
neg | 46.5 | |||||
p-value | <0.0001 | |||||
RR | 4.175 | |||||
95% CI | 2.143–8.133 | |||||
p value | <0.0001 | |||||
ER | HR | 2.33 * | ||||
95% CI | 1.476–3.679 | |||||
p-value | 0.000282 | |||||
OS | HR | 2.28 | ||||
95% CI | 0.95–7.82 | |||||
p-value | 0.062 | |||||
RR | 4.735 | |||||
95% CI | 1.709–13.12 | |||||
p-value | 0.003 | |||||
Median | pos | 30 | ||||
neg | >57.1 | |||||
p-value | 0.0005 |
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Orrapin, S.; Udomruk, S.; Lapisatepun, W.; Moonmuang, S.; Phanphaisarn, A.; Phinyo, P.; Pruksakorn, D.; Chaiyawat, P. Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review. Cancers 2022, 14, 3373. https://doi.org/10.3390/cancers14143373
Orrapin S, Udomruk S, Lapisatepun W, Moonmuang S, Phanphaisarn A, Phinyo P, Pruksakorn D, Chaiyawat P. Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review. Cancers. 2022; 14(14):3373. https://doi.org/10.3390/cancers14143373
Chicago/Turabian StyleOrrapin, Santhasiri, Sasimol Udomruk, Worakitti Lapisatepun, Sutpirat Moonmuang, Areerak Phanphaisarn, Phichayut Phinyo, Dumnoensun Pruksakorn, and Parunya Chaiyawat. 2022. "Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review" Cancers 14, no. 14: 3373. https://doi.org/10.3390/cancers14143373