Ann Surg Oncol DOI 10.1245/s10434-014-4019-5
ORIGINAL ARTICLE – MEDICAL ONCOLOGY
Clinicopathological Significance of CXCR4 Expression in Renal Cell Carcinoma: A Meta-Analysis Bo Tang, MD1,2, Fang Tang, MD3, Yang Li, BSc4, Shengguang Yuan, MD1, Bo Li, MSc2, Zhenran Wang, MD1, and Songqing He, MD1,2 1
Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People’s Republic of China; 2Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People’s Republic of China; 3Department of Pathology, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People’s Republic of China; 4Department of Medical Oncology, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People’s Republic of China
ABSTRACT Background. Emerging evidence indicates that C-X-C chemokine receptor type 4 (CXCR4) is a candidate oncogene in several types of human tumors including renal cell carcinoma (RCC). We conducted a meta-analysis to quantitatively evaluate the association of CXCR4 expression with the incidence of RCC and clinicopathological characteristics. Methods. We searched PubMed, Embase, and ISI Web of Knowledge to identify studies written in English. Methodological quality of the studies was also evaluated. Odds ratio and hazard ratio were calculated and summarized. Results. Final analysis was performed of 994 RCC patients from 11 eligible studies. We observed that CXCR4 expression was significantly higher in RCC than in normal renal tissues. CXCR4 expression was not found to be associated with sex status or clinical staging. However, CXCR4 expression was clearly associated with Fuhrman grading, metastatic status, and overall survival in RCC patients. Conclusions. The results of this meta-analysis suggest that CXCR4 expression is associated with an increased risk and worsen survival in RCC patients. The aberrant CXCR4 expression plays an important role in the carcinogenesis and metastasis of RCC.
Bo Tang and Fang Tang have contributed equally to the manuscript. Ó Society of Surgical Oncology 2014 First Received: 25 June 2014 S. He, MD e-mail: [email protected]
Renal cell carcinoma (RCC) accounts for approximately 4 % of all adult malignancies.1 Despite the advances in early detection multimodal therapeutic modalities, more than onethird of the patients present with locally advanced or metastatic disease at the time of diagnosis, and the 5-years survival rate of metastatic RCC is only 10 %.2,3 Therefore, investigations of the mechanism of initiation, progression, and identification of prognostic markers are still needed. The C-X-C chemokine receptor type 4 (CXCR-4), also known as fusin or CD184, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1), also called CXCL12.4,5 A number of studies have shown that CXCR4 is also overexpressed in RCC and may account for its progression, metastasis, and prognosis.6–9 However, controversies still exist due to the limited number of patients in individual studies. In addition, the roles of CXCR4 expression in RCC and clinical significance have not been thoroughly investigated. In this study, we analyzed and updated the published clinical investigations regarding the effect of CXCR4 on patients with RCC. MATERIALS AND METHODS Search Strategy and Selection Criteria We searched PubMed, Embase, and ISI Web of Knowledge to identify studies from January 1, 2000 to May 31, 2014 using the search terms: ‘‘kidney,’’ ‘‘renal,’’ ‘‘cancer or tumor or neoplasm or carcinoma,’’ ‘‘expression,’’ ‘‘CXCR4 or C-X-C chemokine receptor type 4,’’ and ‘‘prognosis or prognostic or outcome.’’ The criteria that an eligible study had to meet were as follows: (1) CXCR4 expression evaluated in primary RCC
B. Tang et al.
tissues, (2) researchers revealed the relationship between CXCR4 expression and RCC clinicopathological parameters and prognosis, and (3) studies provided sufficient information to estimate hazard ratio (HR) about overall survival (OS) and 95 % confidence interval (CI). Data Extraction and Methodological Assessment The following information was recorded for each study: the first author’s name, sample source, number of cases, clinicopathological parameters, cancer stage, immunohistochemical staining method, antibody source, percentage rate of expression, and follow-up. Heterogeneity of investigation was evaluated to determine whether the data of the various studies could be analyzed for a meta-analysis. Statistical Analysis The statistical analysis was conducted using the STATA 12.0 (Stata Corporation, TX) and Review Manager 5.2 (Cochrane Collaboration, Oxford, UK). Heterogeneity among studies was evaluated with Cochran’s Q test10 and the I2 statistic.11,12 When heterogeneity was not an issue (I2 values \50 %), a fixed effect model was used to calculate parameters. If there was substantial heterogeneity (I2 values C50 %), a random-effects model was used to pool data to attempt to identify potential sources of heterogeneity based on subgroup analyses. p values \0.05 were considered statistically significant. Publication bias was assessed by using a method reported by Egger et al.13 We also explored reasons for FIG. 1 Flow chart of study selection
statistical heterogeneity using meta-regression, subgroup analysis, and sensitivity analysis. RESULTS There were 11 studies included in the final meta-analysis,9,14–23 as shown in Fig. 1. A total of 994 RCC patients were enrolled. Their basic characteristics were summarized in Table 1. Positive CXCR4 expression was defined by immunohistochemistry (IHC). There was a difference in defining the cut-off value of positive CXCR4 expression. The pooled OR from 5 studies, including 336 RCC and 266 normal renal tissue, is shown in Fig. 2a (OR = 112.9, 95 % CI 4.16–3,063.42; p = 0.005), which indicates that CXCR4 expression was significantly higher in RCC than in normal renal tissues, and CXCR4 plays an important role in the pathogenesis of RCC. The pooled OR from four studies, including 320 males and 200 females, is shown in Fig. 2b (OR = 0.95, 95 % CI 0.64–1.41; p = 0.80), indicating that CXCR4 expression was not strongly associated with gender in RCC patients. The pooled OR from five studies, including 258 grade III and IV, 424 grade I and II, is shown in Fig. 2c (OR = 2.67, 95 % CI 1.08–6.59; p = 0.03), which indicates that CXCR4 expression was significantly higher in RCC patients of low than high Fuhrman grades. As shown in Fig. 3a, aberrant CXCR4 expression was not significantly higher in advanced RCC (III and IV) than that in early staged RCC (I and II) (OR = 1.25, 95 % CI 0.63–1.48; p = 0.52). As shown in Fig. 3b, aberrant CXCR4 expression was significantly higher in metastatic
Semiquantitative scoring system
Semiquantitquantitave scoring system
DISCUSSION
Clear cell (48)
IHC
R&D
Cytoplasm and/or nucleus
RCC than in nonmetastatic RCC (OR = 2.03, 95 % CI 1.09–3.80; p = 0.03). The pooled HR for OS showed that CXCR4 expression was associated with worse survival in RCC patients as shown in Fig. 3c (HR = 5.09, 95 % CI 2.80–9.24; p \ 0.00001). A sensitivity analysis, in which one study was removed at a time, was conducted to assess the result stability. The pooled ORs and HRs were not significantly changed, indicating the stability of our analyses. The funnel plots were largely symmetric (Fig. 4), suggesting that there were no publication biases in the meta-analysis of CXCR4 expression and clinicopathological features.
IHC immunohistochemistry
China Hao et al.,23 2010
48
[50 %
Cytoplasm R&D IHC Switzerland 195 Staller et al.,9 2003
Clear cell (195)
Cytoplasm
Nucleus, cytoplasm and membrane C25 % Abcam
Capralogics, Inc. IHC
IHC Clear cell (104)
Clear cell (113) 113
104 France
Germany
2013 Li et al.,
Wehler et al.,22 2008
Semiquantitative scoring system Cytoplasm Santa Cruz IHC Clear cell (10) 10 Germany Schrader et al.,20 2002
21
C10 % Cytoplasm and membrane
Chemicon International Membrane, cytoplasm and nucleus Semiquantitative scoring system
Santa Cruz IHC
IHC Clear cell (43)
Not known
China Wang et al.,19 2009
40 China Zhao et al.,18 2011
43
Semiquantitative scoring system
[20 %
Nuclear and membrane
Cytoplasm and membrane R&D
R&D IHC
Clear cell (150) others (32) IHC
Clear cell (117) 117 China Li et al.,16 2011
182
Predominantly nucleolus
Huang et al.,
D’Alterio et al.,17 2010 Italy
The staining score
C30 %
Cytoplasm Not known
R&D IHC
IHC Not known
Clear cell (81) others (16) 97 China
45 China 2014
Wang et al.,15 2012
Patients Histology (cases) Country
14
Study (year)
TABLE 1 Basic characteristics of the included studies
Methods Antibody source
CXCR4 distribution
Definition of CXCR4 positive
Clinicopathological Significance of CXCR4 Expression in RCC
To date, there have been some studies describing the precise expression and prognostic impact of CXCR4 in RCC; however, the roles of CXCR4 expression in RCC and clinical significance have not been thoroughly investigated. Analyses of the pooled data showed that: (1) RCC had a higher expression than normal renal tissue; (2) CXCR4 expression was not strongly associated with gender in RCC patients; (3) CXCR4 expression was significantly higher in RCC patients of low than high Fuhrman grades; (4) CXCR4 expression was not found to be associated with the clinical staging of RCC patients; (5) aberrant CXCR4 expression was higher in metastatic RCC than in nonmetastatic RCC; and (6) in addition, RCC patients with CXCR4 expression had a lower survival rate that those without CXCR4 expression. The results from the current study demonstrated that the expression rate of CXCR4 in RCC was significantly higher than that in the normal renal tissues, indicating that CXCR4 expression was common in RCC and associated with incidence of RCC. In addition, CXCR4 expression was strongly correlated with metastatic status and prognostic outcome in RCC patients. To our knowledge, this present meta-analysis is the first study to systematically evaluate the association among CXCR4 expression and clinicopathological features and prognostic factors in RCC. Clear cell RCC is the major cell type and is more aggressive than other subtypes, however, only one study determined the CXCR4 expression differences between clear cell and other types, and found no significant difference (p = 0.236).15 CXCR4 can be considered as an oncogene, and its activation could contribute to tumor progression and poor prognosis. The six studies that were evaluated for the relationship between overall survival and CXCR4 expression in RCC showed similar results.9,14–17,21 Based on this meta-analysis, we may consider that CXCR4 expression in RCC tends to indicate a poor prognosis.
B. Tang et al.
FIG. 2 a The pooled OR from five studies including 336 RCC and 266 normal renal tissue. b A total of 520 RCC patients with either gender pooled in four studies. c The pooled OR from five studies including 258 grade III and IV, 424 grade I and II. CI confidence interval
FIG. 3 a A total of 709 RCC patients were pooled from five studies to assess whether CXCR4 expression in RCC was associated with advanced stages. b A total of 318 RCC patients were pooled from four studies to assess whether CXCR4 expression in RCC was associated
with metastatic status. c Six studies included investigating the relationship between overall survival (OS) and CXCR4 expression. CI confidence interval, RCC renal cell carcinoma, SE standard error
Clinicopathological Significance of CXCR4 Expression in RCC
A
B
0 SE(log[OR])
0
C
SE(log[OR])
0
1
0.1
0.2
2
0.2
0.4
3
0.3
0.6
4
0.4
0.8
OR 5 0.01
D 0
OR 0.5
0.1
1
10
E 0
OR 1
0.01
100
SE(log[OR])
SE(log[OR])
0.1
1
10
100
0.01
F
SE(log[OR])
0
0.2
0.1
1
10
100
SE(log[Hazard Ratio])
0.2 0.5
0.4
0.4 1
0.6
0.6 1.5
0.8
0.8
OR
OR 1 0.01
0.1
1
10
100
Hazard Ratio 1
2 0.01
0.1
1
10
100
0.01
0.1
1
10
100
FIG. 4 a The funnel plots were largely symmetric, suggesting there were no publication biases in the meta-analysis of CXCR4 expression and clinicopathological features. The funnel plot from five studies compared RCC and normal renal tissue. b The funnel plot from four studies was used to determine CXCR4 expression and the sex status in RCC patients. c The funnel plot from five studies compared CXCR4 expression between low Fuhrman grades (III and IV) and high
Fuhrman grades (I and II). d The funnel plot from five studies was used to determine CXCR4 expression in different clinical staged RCC. e The funnel plot from four studies determined the relationship between CXCR4 expression and metastatic status in RCC. f The funnel plot from six studies determined the relationship between CXCR4 expression and overall survival (OS) in RCC. X axis value of odds ratio (OR); Y axis standard errors (SE) multiply log scale of OR
CONCLUSIONS
3. Eisengart LJ, MacVicar GR, Yang XJ. Predictors of response to targeted therapy in renal cell carcinoma. Arch Pathol Lab Med. 2012;136:490–5. 4. Moriuchi M, Moriuchi H, Turner W, Fauci AS. Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV1 entry. J Immunol. 1997;159:4322–9. 5. Caruz A, Samsom M, Alonso JM, et al. Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett. 1998;426:271–8. 6. Huang CS, Tang SJ, Chung LY, et al. Galectin-1 upregulates CXCR4 to promote tumor progression and poor outcome in kidney cancer. J Am Soc Nephrol. 2014;25(7):1486–95. 7. Wang L, Huang T, Chen W, et al. Silencing of CXCR4 by RNA interference inhibits cell growth and metastasis in human renal cancer cells. Oncol Rep. 2012;28:2043–8. 8. Pan J, Mestas J, Burdick MD, et al. Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Mol Cancer. 2006;5:56. 9. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature. 2003;425:307–11. 10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.
Our meta-analysis showed that high CXCR4 expression was associated with an increased risk and worsened survival in RCC patients. The aberrant CXCR4 expression plays an important role in the carcinogenesis and metastasis of RCC. Based on our data, CXCR4 could potentially be a prognostic biomarker for patients with RCC. Further large-scale studies, especially multicenter and well-matched cohort research, will provide more insight into the role of CXCR4 in the prognosis and clinical implementation of RCC patients. REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. 2. Custodio S, Joaquim A, Peixoto V, et al. Metastatic renal cell carcinoma: the importance of immunohistochemistry in differential diagnosis. Case Rep Oncol. 2012;5:30–4.
B. Tang et al. 11. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60. 12. DerSimonian R. Meta-analysis in the design and monitoring of clinical trials. Stat Med. 1996;15:1237–48; discussion 49–52. 13. Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ. 1997;315:629–34. 14. Huang CS, Tang SJ, Chung LY, et al. Galectin-1 Upregulates CXCR4 to Promote Tumor Progression and Poor Outcome in Kidney Cancer. J Am Soc Nephrol. 2014;7:7. 15. Wang L, Chen W, Gao L, et al. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol. 2012;10:212. 16. Li X, Huang Y, Xia J, et al. CXCR4 expression in patients with high-risk locally advanced renal cell carcinoma can independently predict increased risk of disease progression and poor overall survival. Asian Pac J Cancer Prev. 2011;12:3313–8. 17. D’Alterio C, Cindolo L, Portella L, et al. Differential role of CD133 and CXCR4 in renal cell carcinoma. Cell Cycle. 2010;9:4492–500.
18. Zhao FL, Guo W. Expression of stromal derived factor-1 (SDF-1) and chemokine receptor (CXCR4) in bone metastasis of renal carcinoma. Mol Biol Rep. 2011;38:1039–45. 19. Wang L, Yang B, Yang Q, Qiao S, Wang Y, Sun Y. Strong expression of chemokine receptor CXCR4 by renal cell carcinoma cells correlates with metastasis. Clin Exp Metastasis. 2009;26:1049–54. 20. Schrader AJ, Lechner O, Templin M, et al. CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer. 2002;86:1250–6. 21. Li G, Badin G, Zhao A, et al. Prognostic value of CXCR4 expression in patients with clear cell renal cell carcinoma. Histol Histopathol. 2013;28:1217–22. 22. Wehler TC, Graf C, Biesterfeld S, et al. Strong expression of chemokine receptor CXCR4 by renal cell carcinoma correlates with advanced disease. J Oncol. 2008;2008:626340. 23. Hao T, Zhou L, Wang X, Xuan Q, Cao Z. Expression of HIF-1 alpha and CXCR4 in renal clear cell cancer. Acta Universitis Medicinalis Anhui 2010;2:168–72.
ORIGINAL ARTICLE – MEDICAL ONCOLOGY
Clinicopathological Significance of CXCR4 Expression in Renal Cell Carcinoma: A Meta-Analysis Bo Tang, MD1,2, Fang Tang, MD3, Yang Li, BSc4, Shengguang Yuan, MD1, Bo Li, MSc2, Zhenran Wang, MD1, and Songqing He, MD1,2 1
Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People’s Republic of China; 2Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People’s Republic of China; 3Department of Pathology, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People’s Republic of China; 4Department of Medical Oncology, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People’s Republic of China
ABSTRACT Background. Emerging evidence indicates that C-X-C chemokine receptor type 4 (CXCR4) is a candidate oncogene in several types of human tumors including renal cell carcinoma (RCC). We conducted a meta-analysis to quantitatively evaluate the association of CXCR4 expression with the incidence of RCC and clinicopathological characteristics. Methods. We searched PubMed, Embase, and ISI Web of Knowledge to identify studies written in English. Methodological quality of the studies was also evaluated. Odds ratio and hazard ratio were calculated and summarized. Results. Final analysis was performed of 994 RCC patients from 11 eligible studies. We observed that CXCR4 expression was significantly higher in RCC than in normal renal tissues. CXCR4 expression was not found to be associated with sex status or clinical staging. However, CXCR4 expression was clearly associated with Fuhrman grading, metastatic status, and overall survival in RCC patients. Conclusions. The results of this meta-analysis suggest that CXCR4 expression is associated with an increased risk and worsen survival in RCC patients. The aberrant CXCR4 expression plays an important role in the carcinogenesis and metastasis of RCC.
Bo Tang and Fang Tang have contributed equally to the manuscript. Ó Society of Surgical Oncology 2014 First Received: 25 June 2014 S. He, MD e-mail: [email protected]
Renal cell carcinoma (RCC) accounts for approximately 4 % of all adult malignancies.1 Despite the advances in early detection multimodal therapeutic modalities, more than onethird of the patients present with locally advanced or metastatic disease at the time of diagnosis, and the 5-years survival rate of metastatic RCC is only 10 %.2,3 Therefore, investigations of the mechanism of initiation, progression, and identification of prognostic markers are still needed. The C-X-C chemokine receptor type 4 (CXCR-4), also known as fusin or CD184, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1), also called CXCL12.4,5 A number of studies have shown that CXCR4 is also overexpressed in RCC and may account for its progression, metastasis, and prognosis.6–9 However, controversies still exist due to the limited number of patients in individual studies. In addition, the roles of CXCR4 expression in RCC and clinical significance have not been thoroughly investigated. In this study, we analyzed and updated the published clinical investigations regarding the effect of CXCR4 on patients with RCC. MATERIALS AND METHODS Search Strategy and Selection Criteria We searched PubMed, Embase, and ISI Web of Knowledge to identify studies from January 1, 2000 to May 31, 2014 using the search terms: ‘‘kidney,’’ ‘‘renal,’’ ‘‘cancer or tumor or neoplasm or carcinoma,’’ ‘‘expression,’’ ‘‘CXCR4 or C-X-C chemokine receptor type 4,’’ and ‘‘prognosis or prognostic or outcome.’’ The criteria that an eligible study had to meet were as follows: (1) CXCR4 expression evaluated in primary RCC
B. Tang et al.
tissues, (2) researchers revealed the relationship between CXCR4 expression and RCC clinicopathological parameters and prognosis, and (3) studies provided sufficient information to estimate hazard ratio (HR) about overall survival (OS) and 95 % confidence interval (CI). Data Extraction and Methodological Assessment The following information was recorded for each study: the first author’s name, sample source, number of cases, clinicopathological parameters, cancer stage, immunohistochemical staining method, antibody source, percentage rate of expression, and follow-up. Heterogeneity of investigation was evaluated to determine whether the data of the various studies could be analyzed for a meta-analysis. Statistical Analysis The statistical analysis was conducted using the STATA 12.0 (Stata Corporation, TX) and Review Manager 5.2 (Cochrane Collaboration, Oxford, UK). Heterogeneity among studies was evaluated with Cochran’s Q test10 and the I2 statistic.11,12 When heterogeneity was not an issue (I2 values \50 %), a fixed effect model was used to calculate parameters. If there was substantial heterogeneity (I2 values C50 %), a random-effects model was used to pool data to attempt to identify potential sources of heterogeneity based on subgroup analyses. p values \0.05 were considered statistically significant. Publication bias was assessed by using a method reported by Egger et al.13 We also explored reasons for FIG. 1 Flow chart of study selection
statistical heterogeneity using meta-regression, subgroup analysis, and sensitivity analysis. RESULTS There were 11 studies included in the final meta-analysis,9,14–23 as shown in Fig. 1. A total of 994 RCC patients were enrolled. Their basic characteristics were summarized in Table 1. Positive CXCR4 expression was defined by immunohistochemistry (IHC). There was a difference in defining the cut-off value of positive CXCR4 expression. The pooled OR from 5 studies, including 336 RCC and 266 normal renal tissue, is shown in Fig. 2a (OR = 112.9, 95 % CI 4.16–3,063.42; p = 0.005), which indicates that CXCR4 expression was significantly higher in RCC than in normal renal tissues, and CXCR4 plays an important role in the pathogenesis of RCC. The pooled OR from four studies, including 320 males and 200 females, is shown in Fig. 2b (OR = 0.95, 95 % CI 0.64–1.41; p = 0.80), indicating that CXCR4 expression was not strongly associated with gender in RCC patients. The pooled OR from five studies, including 258 grade III and IV, 424 grade I and II, is shown in Fig. 2c (OR = 2.67, 95 % CI 1.08–6.59; p = 0.03), which indicates that CXCR4 expression was significantly higher in RCC patients of low than high Fuhrman grades. As shown in Fig. 3a, aberrant CXCR4 expression was not significantly higher in advanced RCC (III and IV) than that in early staged RCC (I and II) (OR = 1.25, 95 % CI 0.63–1.48; p = 0.52). As shown in Fig. 3b, aberrant CXCR4 expression was significantly higher in metastatic
Semiquantitative scoring system
Semiquantitquantitave scoring system
DISCUSSION
Clear cell (48)
IHC
R&D
Cytoplasm and/or nucleus
RCC than in nonmetastatic RCC (OR = 2.03, 95 % CI 1.09–3.80; p = 0.03). The pooled HR for OS showed that CXCR4 expression was associated with worse survival in RCC patients as shown in Fig. 3c (HR = 5.09, 95 % CI 2.80–9.24; p \ 0.00001). A sensitivity analysis, in which one study was removed at a time, was conducted to assess the result stability. The pooled ORs and HRs were not significantly changed, indicating the stability of our analyses. The funnel plots were largely symmetric (Fig. 4), suggesting that there were no publication biases in the meta-analysis of CXCR4 expression and clinicopathological features.
IHC immunohistochemistry
China Hao et al.,23 2010
48
[50 %
Cytoplasm R&D IHC Switzerland 195 Staller et al.,9 2003
Clear cell (195)
Cytoplasm
Nucleus, cytoplasm and membrane C25 % Abcam
Capralogics, Inc. IHC
IHC Clear cell (104)
Clear cell (113) 113
104 France
Germany
2013 Li et al.,
Wehler et al.,22 2008
Semiquantitative scoring system Cytoplasm Santa Cruz IHC Clear cell (10) 10 Germany Schrader et al.,20 2002
21
C10 % Cytoplasm and membrane
Chemicon International Membrane, cytoplasm and nucleus Semiquantitative scoring system
Santa Cruz IHC
IHC Clear cell (43)
Not known
China Wang et al.,19 2009
40 China Zhao et al.,18 2011
43
Semiquantitative scoring system
[20 %
Nuclear and membrane
Cytoplasm and membrane R&D
R&D IHC
Clear cell (150) others (32) IHC
Clear cell (117) 117 China Li et al.,16 2011
182
Predominantly nucleolus
Huang et al.,
D’Alterio et al.,17 2010 Italy
The staining score
C30 %
Cytoplasm Not known
R&D IHC
IHC Not known
Clear cell (81) others (16) 97 China
45 China 2014
Wang et al.,15 2012
Patients Histology (cases) Country
14
Study (year)
TABLE 1 Basic characteristics of the included studies
Methods Antibody source
CXCR4 distribution
Definition of CXCR4 positive
Clinicopathological Significance of CXCR4 Expression in RCC
To date, there have been some studies describing the precise expression and prognostic impact of CXCR4 in RCC; however, the roles of CXCR4 expression in RCC and clinical significance have not been thoroughly investigated. Analyses of the pooled data showed that: (1) RCC had a higher expression than normal renal tissue; (2) CXCR4 expression was not strongly associated with gender in RCC patients; (3) CXCR4 expression was significantly higher in RCC patients of low than high Fuhrman grades; (4) CXCR4 expression was not found to be associated with the clinical staging of RCC patients; (5) aberrant CXCR4 expression was higher in metastatic RCC than in nonmetastatic RCC; and (6) in addition, RCC patients with CXCR4 expression had a lower survival rate that those without CXCR4 expression. The results from the current study demonstrated that the expression rate of CXCR4 in RCC was significantly higher than that in the normal renal tissues, indicating that CXCR4 expression was common in RCC and associated with incidence of RCC. In addition, CXCR4 expression was strongly correlated with metastatic status and prognostic outcome in RCC patients. To our knowledge, this present meta-analysis is the first study to systematically evaluate the association among CXCR4 expression and clinicopathological features and prognostic factors in RCC. Clear cell RCC is the major cell type and is more aggressive than other subtypes, however, only one study determined the CXCR4 expression differences between clear cell and other types, and found no significant difference (p = 0.236).15 CXCR4 can be considered as an oncogene, and its activation could contribute to tumor progression and poor prognosis. The six studies that were evaluated for the relationship between overall survival and CXCR4 expression in RCC showed similar results.9,14–17,21 Based on this meta-analysis, we may consider that CXCR4 expression in RCC tends to indicate a poor prognosis.
B. Tang et al.
FIG. 2 a The pooled OR from five studies including 336 RCC and 266 normal renal tissue. b A total of 520 RCC patients with either gender pooled in four studies. c The pooled OR from five studies including 258 grade III and IV, 424 grade I and II. CI confidence interval
FIG. 3 a A total of 709 RCC patients were pooled from five studies to assess whether CXCR4 expression in RCC was associated with advanced stages. b A total of 318 RCC patients were pooled from four studies to assess whether CXCR4 expression in RCC was associated
with metastatic status. c Six studies included investigating the relationship between overall survival (OS) and CXCR4 expression. CI confidence interval, RCC renal cell carcinoma, SE standard error
Clinicopathological Significance of CXCR4 Expression in RCC
A
B
0 SE(log[OR])
0
C
SE(log[OR])
0
1
0.1
0.2
2
0.2
0.4
3
0.3
0.6
4
0.4
0.8
OR 5 0.01
D 0
OR 0.5
0.1
1
10
E 0
OR 1
0.01
100
SE(log[OR])
SE(log[OR])
0.1
1
10
100
0.01
F
SE(log[OR])
0
0.2
0.1
1
10
100
SE(log[Hazard Ratio])
0.2 0.5
0.4
0.4 1
0.6
0.6 1.5
0.8
0.8
OR
OR 1 0.01
0.1
1
10
100
Hazard Ratio 1
2 0.01
0.1
1
10
100
0.01
0.1
1
10
100
FIG. 4 a The funnel plots were largely symmetric, suggesting there were no publication biases in the meta-analysis of CXCR4 expression and clinicopathological features. The funnel plot from five studies compared RCC and normal renal tissue. b The funnel plot from four studies was used to determine CXCR4 expression and the sex status in RCC patients. c The funnel plot from five studies compared CXCR4 expression between low Fuhrman grades (III and IV) and high
Fuhrman grades (I and II). d The funnel plot from five studies was used to determine CXCR4 expression in different clinical staged RCC. e The funnel plot from four studies determined the relationship between CXCR4 expression and metastatic status in RCC. f The funnel plot from six studies determined the relationship between CXCR4 expression and overall survival (OS) in RCC. X axis value of odds ratio (OR); Y axis standard errors (SE) multiply log scale of OR
CONCLUSIONS
3. Eisengart LJ, MacVicar GR, Yang XJ. Predictors of response to targeted therapy in renal cell carcinoma. Arch Pathol Lab Med. 2012;136:490–5. 4. Moriuchi M, Moriuchi H, Turner W, Fauci AS. Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV1 entry. J Immunol. 1997;159:4322–9. 5. Caruz A, Samsom M, Alonso JM, et al. Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett. 1998;426:271–8. 6. Huang CS, Tang SJ, Chung LY, et al. Galectin-1 upregulates CXCR4 to promote tumor progression and poor outcome in kidney cancer. J Am Soc Nephrol. 2014;25(7):1486–95. 7. Wang L, Huang T, Chen W, et al. Silencing of CXCR4 by RNA interference inhibits cell growth and metastasis in human renal cancer cells. Oncol Rep. 2012;28:2043–8. 8. Pan J, Mestas J, Burdick MD, et al. Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Mol Cancer. 2006;5:56. 9. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature. 2003;425:307–11. 10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.
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