Prognostic Significance of CXCR4 in Colorectal Cancer: An Updated Meta-Analysis and Critical Appraisal
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Study Eligibility
2.3. Data Extraction
2.4. Hazard Ratio Interpretation
2.5. Statistical Analysis
3. Results
3.1. Study Characteristics
3.2. CXCR4 Expression Methodology
3.3. Association between CXCR4 Expression and Clinico-Pathological Characteristics of Colorectal Cancer Patients
3.4. Time to Outcome According to CXCR4 Expression
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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First Author | Methods | Fresh Tissue Evaluation | Detection Correlated with TTO | Differential Nuclear, Cytoplasmic, Membrane IHC Staining | IHC Distribution Correlated with Prognosis | Scores | No. of Positive Cells for Expression Evaluation | Inclusion of “Staining Intensity” |
---|---|---|---|---|---|---|---|---|
Kim J. | IHC, RT-PCR | Yes | RT-PCR | NA | NA | Low vs.High | mRNA median CXCR4 expression | No |
Ottaiano A. | IHC | No | IHC | Yes | Overall expression | Neg/Low vs. High | ≤50% vs.>50% | No |
Yoshitake N. | IHC, Western Blot | No | IHC | Yes | Overall expression | Neg vs. Pos | No CXCR4 immunoreactivity vs others | No |
Speetjens F.M. | RT-PCR | No | RT-PCR | NA | NA | Low vs. High | mRNA median CXCR4 expression | No |
Speetjens F.M. | IHC | No | IHC | Yes | Nuclear expression | Weak vs. Strong | Examples are included in the work | Yes |
Ingold B. | IHC | No | IHC | No | Overall expression | 0, 1+, 2+, 3+ | NA | Yes Absent, faint cytoplasmic, moderate cytoplasmic and slight membranous, strong cytoplasmic and strong membranous |
Wang S.C. | IHC, RT-PCR | No | IHC | Yes | Nuclear expression | 0, 1+, 2+, 3+ | 0; <30%; 30–50%; >50% | Yes Weak, medium, strong, very strong |
Yopp A.C. | IHC | No | IHC | Yes | Overall expression | Neg vs. Pos | ≤10% vs.>10% | No |
Sakai N. | IHC, fluorescence microscopy | No | IHC | Cyto | Cytoplasm | Low vs. High | NA | Yes Relative to the staining intensity of hepatocytes |
Sakai N. | IHC, fluorescence microscopy | No | IHC | Nucleus | Nuclear | Neg vs. Pos | NA | Yes Relative to the staining intensity of hepatocytes |
Du C. | IHC | No | IHC | Not Specified | Overall expression | 0, 1+, 2+: Low3+: High | <1%; 1–50% (1+ and 2+); >50% | Yes Negative, weak, strong |
Gao Y. | IHC, RT-PCR | No | IHC | No | Overall expression | Sporadic, focal, diffuse | <10%, ≥11<50%, ≥50% | Yes Negative, weak, moderate, strong |
Stanisavljevic L. (cohort 1) | IHC, ISH | No | IHC | Yes | Nuclear expression | Low vs. High | 0–20%, >20% | No |
Stanisavljevic L. (cohort 2) | IHC | No | IHC | Yes | Nuclear expression | Low vs. High | 0–20%, >20% | No |
D′Alterio C. | IHC, RT-PCR | No | IHC | Yes | Overall expression | Negative/Low vs. High | 0–50%, >50% | No |
Wu W. | IHC, RT-PCR | No | RT-PCR | NA | NA | Low vs. High | mRNA median CXCR4 expression | No |
Weixler B. | IHC | No | IHC | No | Overall expression | Histoscores (a continuous variable) | (% of positive cells)x (staining intensity) | Yes Negative, 0; weak, 1; moderate, 2; strong, 3 |
Xu C. | IHC, RT-PCR | No | IHC | No | Membrane | 0, 1, 2, 3, 4 | 0%, 1–25%, 26–50%, 51–75%, >75% | Yes No staining, weak, moderate, strong |
Ottaiano A. | IHC, RT-PCR | No | IHC | Yes | Overall expression | Neg/Low vs. High | ≥0≤50%, >50% | No |
Author | Year | CXCR4 Scores | Age | Sex | T | Side | Lymph nodes | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Young | Old | Male | Female | ≤2 | ≥3 | Left | Right | Involved | Not Involved | |||
Kim J. | 2005 | Low 44 | 23 | 21 | 18 | 9 | - | - | 8 | 36 | ||
High 48 | 22 | 26 | 11 | 19 | - | - | 8 | 40 | ||||
Ottaiano A. | 2006 | Neg 16 | <70:10 | ≥70:6 | 6 | 10 | 5 | 11 | 0 | 15 | ||
Low 25 | <70:13 | ≥70:12 | 15 | 10 | 13 | 12 | 8 | 18 | ||||
High 31 | <70:21 | ≥70:10 | 17 | 14 | 11 | 20 | 7 | 24 | ||||
Yoshitake N. | 2008 | Negative 13 | - | - | 10 | 3 | - | - | - | - | 7 | 6 |
Positive 47 | - | - | 31 | 16 | - | - | - | - | 38 | 9 | ||
Speetjens F.M. | 2009 | Low 35 | <68.5:20 | >68.5:15 | 16 | 19 | - | - | 17 | 18 | 12 | 23 |
High 35 | <68.5:15 | >68.5:20 | 19 | 16 | - | - | 17 | 18 | 11 | 24 | ||
Speetjens F.M. | 2009 | Strong 43 | <69.7:21 | >69.7:22 | 21 | 22 | - | - | 22 | 21 | 15 | 28 |
Weak 15 | <69.7:8 | >69.7:7 | 7 | 8 | - | - | 5 | 10 | 4 | 11 | ||
Ingold B. | 2009 | Negative 267 | ≤65:115 | >65:152 | 145 | 122 | 46 | 206 | - | - | 133 | 119 |
Positive 135 | ≤65:51 | >65:84 | 69 | 66 | 23 | 108 | - | - | 72 | 59 | ||
Wang SC. | 2010 | Negative 245 | - | - | 180 | 65 | 138 | 107 | 186 | 59 | 142 | 141 |
Positive 143 | - | - | 89 | 54 | 47 | 96 | 99 | 44 | 101 | 158 | ||
Yopp A.C. | 2012 | Negative 28 | ≤60:11 | >60:17 | 13 | 15 | - | - | - | - | - | - |
Positive 47 | ≤60:21 | >60:26 | 38 | 9 | - | - | - | - | - | - | ||
Sakai N. | 2012 | Low 56 (cytoplasm) | <60:26 | ≥60:30 | 36 | 20 | - | - | - | - | - | - |
High 36 (cytoplasm) | <60:10 | ≥60:26 | 22 | 14 | - | - | - | - | - | - | ||
Du C. | 2014 | Low 89 | <65:39 | ≥65:50 | 51 | 38 | 16 | 73 | 47 | 42 | 6 | 83 |
High 56 | <65:19 | ≥65:37 | 33 | 23 | 9 | 47 | 29 | 27 | 4 | 52 | ||
Gao Y. | 2014 | Negative 512 | <55:243 | ≥55:269 | 292 | 220 | - | - | - | - | 201 | 311 |
Positive 208 | <55:89 | ≥55:119 | 120 | 88 | - | - | - | - | 138 | 70 | ||
Stanisavljevic L. | 2015 | Low 78 | - | - | 45 | 33 | 3 | 75 | - | - | - | - |
High 186 | - | - | 93 | 93 | 10 | 176 | - | - | - | - | ||
Stanisavljevic L. | 2015 | Low 35 | - | - | 20 | 15 | 6 | 29 | - | - | - | - |
High 190 | - | - | 110 | 80 | 28 | 162 | - | - | - | - | ||
D′Alterio C. | 2016 | Negative/Low 10 | - | - | - | - | - | - | - | - | - | - |
High 21 | - | - | - | - | - | - | - | - | - | - | ||
Wu W. | 2016 | Low 40 | - | - | - | - | - | - | - | - | - | - |
High 40 | - | - | - | - | - | - | - | - | - | - | ||
Weixler B. | 2017 | Low 289 | - | - | 145 | 144 | 51 | 230 | 205 | 82 | 142 | 141 |
High 267 | - | - | 117 | 150 | 60 | 204 | 190 | 77 | 101 | 158 | ||
Xu C. | 2018 | Low 26 | <60:21 | ≥60:5 | 16 | 10 | 4 | 22 | - | - | 1 | 25 |
High 22 | <60:20 | ≥60:4 | 18 | 4 | 5 | 17 | - | - | 5 | 17 | ||
Ottaiano A. | 2020 | Negative/Low 26 | ≤65:12 | >65:14 | 17 | 9 | - | - | 19 | 7 | - | - |
High 52 | ≤65:20 | >65:32 | 27 | 25 | - | - | 26 | 26 | - | - |
Author | Year | Median Follow-Up (Months) | Median PFS (Months) | HR | CI | P | Median OS (Months) | HR | CI | P |
---|---|---|---|---|---|---|---|---|---|---|
Kim J. | 2005 | 28 | NR | 1.35 | 1.09–1.68 | 0.0065 | High 9; Low 23 | 2.53 | 1.19–5.40 | 0.016 |
Ottaiano A. | 2006 | 23 | NR | 3.01 | 0.88–5.21 | 0.0991 | NR | |||
Yoshitake N. | 2008 | NR | 5.08 | 0.65–40.00 | 0.123 | |||||
Speetjens F.M. | 2009 | NR | NR | 2 | 1.1–3.7 | 0.03 | NR | 1.8 | 1–3.6 | 0.07 |
Speetjens F.M. | 2009 | NR | NR | 2.6 | 1–6.2 | 0.04 | NR | 3.7 | 1.35–11 | 0.02 |
Ingold B. | 2009 | 32 | NR | 2.87 | 1.31–6.29 | 0.009 | ||||
Wang SC. | 2010 | 61 | 5 years DFS rate: High 70%; Low 55% (Nuc CXCR4) | 1.23 | 0.7–2.18 | 0.458 | ||||
Yopp A.C. | 2012 | 68 | Pos. 15 vs Neg. 73 | 2.2 | 1.2–4.2 | 0.012 | ||||
Sakai N.* | 2012 | 38 | 3 years OS rate: High 67%; Low 78% | Cyto: 0.43 | Cyto: 0.18–1.02 | Cyto: 0.056 | ||||
Sakai N.* | 2012 | 38 | 3 years OS rate: Pos 93%; Neg 67% | Nuc: 4.05 | Nuc: 1.19–13.8 | Nuc: 0.025 | ||||
Du C.* | 2014 | 68.5 | 5 years DFS rate: High 76.8%; Low 84.3% | 0.81 | 0.36–1.8 | 0.618 | ||||
Gao Y. | 2014 | NR | 1.3 | 1.38–1.85 | 0.001 | |||||
Stanisavljevic L.* | 2015 | Min from 3–5 years | 5 years DFS rate: High 65%; Low 85% | 0.42 | 0.22–0.78 | 0.006 | ||||
Stanisavljevic L.* | 2015 | Min from 3–5 years | High 82%; Low 89% | 0.89 | 0.31–2.61 | 0.838 | ||||
D′Alterio C.* | 2016 | 28 | High 14 vs. Neg/Low 46 | 3.405 | 1.70–17.33 | 0.004 | High 28; Neg/Low 46 | 0.079 | 0.062–0.480 | 0.0008 |
Wu W. | 2016 | Max 60 | NR | 5.38 | 2.42–9.13 | 0.002 | ||||
Weixler B. | 2017 | NR | 5 years OS rate: High 48%; Low 48% | 0.99 | 0.99–1.0 | 0.322 | ||||
Xu C.* | 2018 | NR | High 51; Low 54 | 0.188 | 0.03–0.75 | 0.020 | ||||
Ottaiano A. | 2020 | 53 | High 19; Neg/Low 31 | 3.18 | 2.01–5.02 | 0.0312 |
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Ottaiano, A.; Santorsola, M.; Del Prete, P.; Perri, F.; Scala, S.; Caraglia, M.; Nasti, G. Prognostic Significance of CXCR4 in Colorectal Cancer: An Updated Meta-Analysis and Critical Appraisal. Cancers 2021, 13, 3284. https://doi.org/10.3390/cancers13133284
Ottaiano A, Santorsola M, Del Prete P, Perri F, Scala S, Caraglia M, Nasti G. Prognostic Significance of CXCR4 in Colorectal Cancer: An Updated Meta-Analysis and Critical Appraisal. Cancers. 2021; 13(13):3284. https://doi.org/10.3390/cancers13133284
Chicago/Turabian StyleOttaiano, Alessandro, Mariachiara Santorsola, Paola Del Prete, Francesco Perri, Stefania Scala, Michele Caraglia, and Guglielmo Nasti. 2021. "Prognostic Significance of CXCR4 in Colorectal Cancer: An Updated Meta-Analysis and Critical Appraisal" Cancers 13, no. 13: 3284. https://doi.org/10.3390/cancers13133284