J Cancer Res Clin Oncol (2014) 140:1003–1009 DOI 10.1007/s00432-014-1630-6
Original Article - Clinical Oncology
The prognostic role of matrix metalloproteinase 2 in gastric cancer: a systematic review with meta‑analysis Weisong Shen · Hongqing Xi · Bo Wei · Lin Chen
Received: 23 February 2014 / Accepted: 24 February 2014 / Published online: 8 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The prognostic role of matrix metalloproteinase 2 (MMP-2) in gastric cancer remains controversial. We systematically reviewed the evidence for assessment of MMP-2 expression in gastric cancer to elucidate this issue. Method Pubmed, Embase and Web of Science were searched to identify eligible studies to evaluate the association of MMP-2 expression and overall survival and clinicopathological features of gastric cancer. Results MMP-2 overexpression was significantly correlated with poor OS of gastric cancer patients (HR 1.92, 95 % CI 1.48–2.48). Subgroup analysis indicated that MMP-2 overexpression had an unfavorable impact on OS in Asian countries (HR 2.23, 95 % CI 1.57–3.17) and European countries (HR 1.43, 95 % CI 1.13–1.80). Furthermore, MMP-2 overexpression was significantly associated with TNM stage (TIII/TIV vs TI/TII: OR 2.17, 95 % CI 1.64–2.87), the depth of invasion (T3/T4 vs T1/T2: OR 2.59, 95 % CI 1.63–4.12), lymph node metastasis (positive vs negative: OR 2.21, 95 % CI 1.69–2.88), and distant metastasis (positive vs negative: OR 4.44, 95 % CI 1.24–15.94). Conclusion This meta-analysis indicated that MMP-2 overexpression might be a predictive factor for poor prognosis for gastric cancer. Keywords Gastric cancer · Matrix metalloproteinase 2 · Prognosis · Meta-analysis
W. Shen · H. Xi · B. Wei · L. Chen (*) Department of General Surgery, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853, China e-mail: [email protected]
Abbreviations MMP-2 Matrix metalloproteinase 2 HR Hazard ratio OR Odds ratio OS Overall survival
Introduction Gastric cancer is one of the main malignant tumors. Despite the recent reduction in incidence, gastric cancer is still the second most frequent cause of cancer-related death worldwide (Ferlay et al. 2010). Most patients at the time of diagnosis are at advanced stage and have poor prognosis. It is, therefore, very important to identify prognostic factors for gastric cancer which can help us find a better treatment and preventive measures for extending the life of gastric cancer patients. Traditional clinicopathological characteristics, for example tumor size and stage, do not fully predict individual clinical outcome, and much better prognostic factors are needed (Zhao et al. 2010; Kim et al. 2011; Seshadri et al. 2011). To improve clinical care, biological prognostic markers are highly desirable and must be identified in gastric cancer. Several molecular markers, for example E-cadherin, epidermal growth factor (EGF), p53, and vascular endothelial growth factor (VEGF), have been proved to be associated with prognosis for gastric cancer patients (Xing et al. 2013; Yasui et al. 1988; Deveci and Deveci 2007; Fondevila et al. 2004). Among biomarkers, Matrix metalloproteinase (MMPs) expression has recently attracted increasing research attention. MMPs are a family of enzymes that are found in extracellular milieu of various tissues which play important roles in degrading extracellular matrix (ECM) and angiogenesis in tumor invasion and metastasis (Kubben
13
1004
et al. 2006). Over expression of MMPs can promote tumor cell detachments and metastasis which have been associated with malignancy with poor clinical outcome (McCawley and Matrisian 2000; Stetler-Stevenson 2001; Rundhaug 2005). Matrix metalloproteinase 2 (MMP-2) is correlated with poor prognosis in many cancer types including adrenocortical cancer, breast cancer, and thyroid malignancies (Kjellman et al. 1999; Dalberg et al. 2000). MMP-2 has been reported to be associated with tumor invasion and lymph node metastasis of gastric carcinoma by mediating the degradation of ECM components (Nomura et al. 1996; Sundblad and Ricci 1998; Monig et al. 2001; Takahashi et al. 2002). Several studies have described the relationship between MMP-2 expression and prognosis in gastric cancer (Zhou et al. 2010; Mrena et al. 2006; Peng et al. 2010; Dicken et al. 2006; Chen et al. 2013; Allgayer et al. 1998; Alakus et al. 2008; Hwang et al. 2010; Wang et al. 2013). However, the results were inconsistent. Meta-analysis is a popular and powerful tool which overcomes the limitation of small sample sizes by combining results from several individual studies to generate a best assessment (Nordmann et al. 2012). Therefore, we conducted the present meta-analysis to appraise the prognostic value of MMP-2 in gastric cancer.
Materials and methods Search strategy and selection criteria We conducted and reported this systematic review and meta-analysis following the PRISMA statement (Moher et al. 2009). Criteria for eligibility of a study included in this meta-analysis were to (1) evaluate the correlation between MMP-2 expression and overall survival (OS) of gastric cancer patients; (2) assess MMP-2 expression in the primary tumor tissues using immunohistochemistry (IHC); (3) provide sufficient information allowing for estimation of hazard ratios (HRs) and their 95 % confidence intervals (CIs); (4) be published as a full text in the English language. A literature search was performed in Pubmed, Embase, and Web of Science databases for clinical research published before November 2013 that assessed MMP-2 as a prognostic factor for survival of patients with primary gastric cancer using IHC. Article language was limited to English. The search used the following terms: gastric cancer, matrix metalloproteinase 2 or MMP-2 or MMP2, prognosis or prognostic, or survival. The references of all relevant articles were evaluated to find other related studies. All studies were carefully examined to avoid the inclusion of the duplicate data. Two reviewers (W.S.S. and H.Q.X) assessed the eligibility of the screened studies independently. Agreement was reached for the discrepancies by discussion.
13
J Cancer Res Clin Oncol (2014) 140:1003–1009
Data extraction and management Data were extracted independently by two investigators (W.S.S. and H.Q.X.) by means of a predefined form. Topics in this form were author’s name, year of publication, study location, number of patients, cutoff value, and tumor characteristics. Quality assessment and methodological assessment Quality assessment was performed in each of the acceptable studies in duplicate by independent reviewers (W.S.S., H.Q.X., and B.W.) using the Newcastle–Ottawa Quality Assessment Scale for cohort studies (Stang 2010). This scale is an eight-item instrument that allows for assessment of patient population and selection, study comparability, follow-up, and outcome of interest. The three investigators reported the quality stars of reviewed studies independently and reached a consensus value for each item. Methodological assessment for each of the included studies was also performed by three investigators (W.S.S., H.Q.X., and B.W.) and scored them according to the European Lung Cancer Working Party scale established by Steels et al. (Steels et al. 2001). The score assessed several aspects of methodology, grouped into four major classifications: the scientific design, the description of IHC methods, the generalizability of results, and the analysis of the study data. Each category had a maximal score of 10 points with an overall maximum theoretical score of 40 points. The final scores were expressed as percentages, with higher values reflecting a better methodological quality. Statistical analysis In this meta-analysis, univariate HR and 95 % CI were used to calculate the overall effect estimate. Some of the studies included provided HR and 95 % CI explicitly. If HR and 95 % CI were not directly reported in the included studies, we calculated the values in the original studies by using the methods illustrated by Parmar et al. (1998). Heterogeneity was assessed by use of Cochran Q and I2 statistics and considered significant at p 1 implied a worse survival for the group with overexpression of MMP-2 or the significant association between overexpression of MMP-2 and clinicopathological characteristics. We pooled HRs and ORs of the studies by using Stata 12.0 software (StatCorp, College Station, TX, USA). We also explored reasons for inter-study heterogeneity using
9
8
73
7
8
64.5
69.9
67.5
8
8
73.6
67.5
73.6
9
8
79.9
8
7
66.2
61
meta-regression analysis and subgroup analysis by study location, publication year, number of patients, and cutoff value. Sensitivity analysis was also conducted by omission of each single study to evaluate stability of the results. Publication bias was evaluated by use of Begg’s funnel plot and Egger’s linear regression test (Egger et al. 1997).
Result
T, the depth of invasion; N, lymph node status; M, distant metastasis; –, missing data and do not be analyzed in meta-analysis
25
– 22/18
85/104 – 103/86
21/19
107/82 81
China
40
China Hwang et al. (2010)
Wang et al. (2013)
189
35
25/15
–
50
25 –
– –
–
–
–
–
–
52.5
39.7 Germany
116
Germany Allgayer et al. (1998)
Alakus et al. (2008)
139
38
38 53/28
189/169 13/345
15/66
221/135
60/21
238/120
77/4
67.3
45.7 China
81
China Chen et al. (2013)
Chen et al. (2013)
358
40
33 –
26/11 8/29
–
27/10
–
–
– 74.6
54.1 37
Dicken et al. (2006)
114
China
Canada
Peng et al. (2010)
57
25 196/133
– –
83/236
122/78
183/145
148/52
216/113 73.6
73.9
Mrena et al. (2006)
200 China
Finland
Zhou et al. (2010)
329
Quality stars (NOS) M Positive/negative T T3T4/T1T2 MMP-2 expression (%) Number of patients Study location Study
Table 1 Major features of the included studies
1005
Study selection and characteristics
N Positive/negative
TNM stage TIII TIV/TI TII
Cutoff (%)
Methodological scores (%)
J Cancer Res Clin Oncol (2014) 140:1003–1009
A total of 154 reports were retrieved from a search of the above databases using search strategies as described. After exclusion of the reports that were out of the scope of our systematic review, 34 reports assessing prognostic value for survival of MMP-2 status in patients with gastric cancer were considered eligible for inclusion in the evaluation. By full-text review, 13 were excluded because the estimation of HRs in these reports was not allowed due to the insufficient data provided by the authors, 4 were excluded because the authors determined the MMP-2 status from other than tumor tissues, 3 were excluded because the reports were not published in English, and 5 were excluded because the authors assessed MMP-2 expression using a method other than IHC; especially, Chen’ report includes two studies (Chen et al. 2013). Therefore, 10 studies meeting the inclusion criteria were finally enrolled in this systematic review and meta-analysis. The characteristics of the 10 eligible studies are summarized in Table 1. Six studies evaluated patients from China, two from Germany, one from Finland, one from Canada. The ten studies comprised 1,603 patients, with sample sizes ranging from 37 to 358 patients. Three of these studies enrolled less than 100 patients and 7 studies included more than 100 patients (Table 1). Study results report and meta‑analysis As indicated in Table 1, 6 of 10 studies revealed that MMP-2 overexpression was a poor prognostic factor for survival of patients and 4 of 10 studies reported that MMP-2 overexpression did not have an unfavorable impact on survival (Fig. 1). Figure 2 demonstrates a forest plot of the individual HRs and results from the meta-analysis. Overall, MMP-2 overexpression in the primary tumor had significant association with an enhanced mortality risk of gastric cancer patients in the random-effects model (combined HR 1.92, 95 % CI 1.48–2.48), despite the exhibition of heterogeneity among studies (I2 62.6 %, p = 0.004). For the exploration of the source of heterogeneity, meta-regression analysis and subgroup analysis was conducted by study location,
13
1006
J Cancer Res Clin Oncol (2014) 140:1003–1009
OR 2.30, 95 % CI 1.77–2.97), and distant metastasis (positive vs negative: OR 4.44, 95 % CI 1.24–15.94). Moreover, diffuse-type gastric cancer had a significant MMP-2 overexpression as compared to intestinal-type (OR 1.50, 95 % CI 1.13–1.99) according to Lauren classification. The meta-analysis of TNM stage and lauren classification with MMP-2 overexpression did not exhibit inter-study heterogeneity (I2 15–23 %), whereas the analysis of other clinicopathological parameters exhibited heterogeneity (I2 54–79 %). The assessment of publication bias showed that the Egger’s tests (p = 0.464) and Begg’s tests (p = 0.721) were not significant (p > 0.05) for studies included in analysis of OS. The funnel plots for publication bias also demonstrated a certain degree of symmetry (Fig. 3). Sensitivity analysis also indicated that omitting any single study did not affect the pooled HR significantly.
Fig. 1 Flow chart of included studies
publication year, number of patients, and cutoff value. The results showed that study location had significant association with the heterogeneity (p = 0.008), while other factors did not (Table 2). Moreover, subgroup analysis indicated a significant relation between MMP-2 overexpression, and OS was also exhibited in Asian countries (HR 2.23, 95 % CI 1.57–3.17) and European countries (HR 1.43, 95 % CI 1.13–1.80). Moreover, subgroup analysis on other factors comprising publication year, number of patients, and cutoff value did not alter the significant prognostic impact of MMP-2 overexpression. In addition, we assessed the association between MMP-2 overexpression and clinicopathological features of gastric cancer. As indicated in Table 3, MMP-2 overexpression had a significant association with TNM stage (TIII/TIV vs TI/TII: OR 2.17, 95 % CI 1.64–2.87), the depth of invasion (T3/T4 vs T1/T2: OR 2.59, 95 % CI 1.63–4.12), lymph node metastasis (positive vs negative:
Discussion To our knowledge, it is the first time that a comprehensive and detailed meta-analysis has assessed the association between MMP-2 overexpression and OS and clinicopathological characteristics of gastric cancer. Our analysis combined the outcomes of 1603 gastric cancer patients from 10 individual studies, indicating that MMP-2 overexpression significantly predicted poor OS of gastric cancer patients (HR 1.92, 95 % CI 1.48–2.48). Subgroup analysis indicated that MMP-2 overexpression was also significantly associated with poor prognosis in Asian countries (HR 2.23, 95 % CI 1.57–3.17) and European countries (HR 1.43, 95 % CI 1.13–1.80). Furthermore, significant correlations were observed between MMP-2 overexpression and clinicopathological features including TNM stage, the depth of invasion, lymph node metastasis, and distant metastasis.
Study ID
HR (95% CI)
% Weight
Zhou (2010) Mrena (2006) Peng (2010) Dicken (2006) Chen (2013) Chen (2013) Allgayer (1998) Alakus (2008) Hwang (2010) Wang (2013) Overall (I−squared = 62.6%, p = 0.004)
2.48 (1.44, 4.26) 1.21 (0.90, 1.65) 1.06 (0.52, 2.18) 1.77 (1.09, 2.86) 2.37 (1.68, 3.33) 4.69 (2.67, 8.24) 1.67 (0.96, 2.91) 1.92 (1.20, 3.09) 1.60 (0.90, 2.84) 2.15 (1.07, 4.30) 1.92 (1.48, 2.48)
9.59 13.64 7.26 10.54 12.96 9.28 9.41 10.70 9.11 7.51 100.00
NOTE: Weights are from random effects analysis .121
1
Fig. 2 Meta-analysis of impact of MMP-2 overexpression on overall survival
13
8.24
J Cancer Res Clin Oncol (2014) 140:1003–1009
1007
Table 2 Meta-regression and subgroup analysis of the studies reporting the association of MMP-2 overexpression and overall survival of cancer Stratified analysis
Study location Asia Europe North America No. of patients >100
Original Article - Clinical Oncology
The prognostic role of matrix metalloproteinase 2 in gastric cancer: a systematic review with meta‑analysis Weisong Shen · Hongqing Xi · Bo Wei · Lin Chen
Received: 23 February 2014 / Accepted: 24 February 2014 / Published online: 8 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The prognostic role of matrix metalloproteinase 2 (MMP-2) in gastric cancer remains controversial. We systematically reviewed the evidence for assessment of MMP-2 expression in gastric cancer to elucidate this issue. Method Pubmed, Embase and Web of Science were searched to identify eligible studies to evaluate the association of MMP-2 expression and overall survival and clinicopathological features of gastric cancer. Results MMP-2 overexpression was significantly correlated with poor OS of gastric cancer patients (HR 1.92, 95 % CI 1.48–2.48). Subgroup analysis indicated that MMP-2 overexpression had an unfavorable impact on OS in Asian countries (HR 2.23, 95 % CI 1.57–3.17) and European countries (HR 1.43, 95 % CI 1.13–1.80). Furthermore, MMP-2 overexpression was significantly associated with TNM stage (TIII/TIV vs TI/TII: OR 2.17, 95 % CI 1.64–2.87), the depth of invasion (T3/T4 vs T1/T2: OR 2.59, 95 % CI 1.63–4.12), lymph node metastasis (positive vs negative: OR 2.21, 95 % CI 1.69–2.88), and distant metastasis (positive vs negative: OR 4.44, 95 % CI 1.24–15.94). Conclusion This meta-analysis indicated that MMP-2 overexpression might be a predictive factor for poor prognosis for gastric cancer. Keywords Gastric cancer · Matrix metalloproteinase 2 · Prognosis · Meta-analysis
W. Shen · H. Xi · B. Wei · L. Chen (*) Department of General Surgery, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853, China e-mail: [email protected]
Abbreviations MMP-2 Matrix metalloproteinase 2 HR Hazard ratio OR Odds ratio OS Overall survival
Introduction Gastric cancer is one of the main malignant tumors. Despite the recent reduction in incidence, gastric cancer is still the second most frequent cause of cancer-related death worldwide (Ferlay et al. 2010). Most patients at the time of diagnosis are at advanced stage and have poor prognosis. It is, therefore, very important to identify prognostic factors for gastric cancer which can help us find a better treatment and preventive measures for extending the life of gastric cancer patients. Traditional clinicopathological characteristics, for example tumor size and stage, do not fully predict individual clinical outcome, and much better prognostic factors are needed (Zhao et al. 2010; Kim et al. 2011; Seshadri et al. 2011). To improve clinical care, biological prognostic markers are highly desirable and must be identified in gastric cancer. Several molecular markers, for example E-cadherin, epidermal growth factor (EGF), p53, and vascular endothelial growth factor (VEGF), have been proved to be associated with prognosis for gastric cancer patients (Xing et al. 2013; Yasui et al. 1988; Deveci and Deveci 2007; Fondevila et al. 2004). Among biomarkers, Matrix metalloproteinase (MMPs) expression has recently attracted increasing research attention. MMPs are a family of enzymes that are found in extracellular milieu of various tissues which play important roles in degrading extracellular matrix (ECM) and angiogenesis in tumor invasion and metastasis (Kubben
13
1004
et al. 2006). Over expression of MMPs can promote tumor cell detachments and metastasis which have been associated with malignancy with poor clinical outcome (McCawley and Matrisian 2000; Stetler-Stevenson 2001; Rundhaug 2005). Matrix metalloproteinase 2 (MMP-2) is correlated with poor prognosis in many cancer types including adrenocortical cancer, breast cancer, and thyroid malignancies (Kjellman et al. 1999; Dalberg et al. 2000). MMP-2 has been reported to be associated with tumor invasion and lymph node metastasis of gastric carcinoma by mediating the degradation of ECM components (Nomura et al. 1996; Sundblad and Ricci 1998; Monig et al. 2001; Takahashi et al. 2002). Several studies have described the relationship between MMP-2 expression and prognosis in gastric cancer (Zhou et al. 2010; Mrena et al. 2006; Peng et al. 2010; Dicken et al. 2006; Chen et al. 2013; Allgayer et al. 1998; Alakus et al. 2008; Hwang et al. 2010; Wang et al. 2013). However, the results were inconsistent. Meta-analysis is a popular and powerful tool which overcomes the limitation of small sample sizes by combining results from several individual studies to generate a best assessment (Nordmann et al. 2012). Therefore, we conducted the present meta-analysis to appraise the prognostic value of MMP-2 in gastric cancer.
Materials and methods Search strategy and selection criteria We conducted and reported this systematic review and meta-analysis following the PRISMA statement (Moher et al. 2009). Criteria for eligibility of a study included in this meta-analysis were to (1) evaluate the correlation between MMP-2 expression and overall survival (OS) of gastric cancer patients; (2) assess MMP-2 expression in the primary tumor tissues using immunohistochemistry (IHC); (3) provide sufficient information allowing for estimation of hazard ratios (HRs) and their 95 % confidence intervals (CIs); (4) be published as a full text in the English language. A literature search was performed in Pubmed, Embase, and Web of Science databases for clinical research published before November 2013 that assessed MMP-2 as a prognostic factor for survival of patients with primary gastric cancer using IHC. Article language was limited to English. The search used the following terms: gastric cancer, matrix metalloproteinase 2 or MMP-2 or MMP2, prognosis or prognostic, or survival. The references of all relevant articles were evaluated to find other related studies. All studies were carefully examined to avoid the inclusion of the duplicate data. Two reviewers (W.S.S. and H.Q.X) assessed the eligibility of the screened studies independently. Agreement was reached for the discrepancies by discussion.
13
J Cancer Res Clin Oncol (2014) 140:1003–1009
Data extraction and management Data were extracted independently by two investigators (W.S.S. and H.Q.X.) by means of a predefined form. Topics in this form were author’s name, year of publication, study location, number of patients, cutoff value, and tumor characteristics. Quality assessment and methodological assessment Quality assessment was performed in each of the acceptable studies in duplicate by independent reviewers (W.S.S., H.Q.X., and B.W.) using the Newcastle–Ottawa Quality Assessment Scale for cohort studies (Stang 2010). This scale is an eight-item instrument that allows for assessment of patient population and selection, study comparability, follow-up, and outcome of interest. The three investigators reported the quality stars of reviewed studies independently and reached a consensus value for each item. Methodological assessment for each of the included studies was also performed by three investigators (W.S.S., H.Q.X., and B.W.) and scored them according to the European Lung Cancer Working Party scale established by Steels et al. (Steels et al. 2001). The score assessed several aspects of methodology, grouped into four major classifications: the scientific design, the description of IHC methods, the generalizability of results, and the analysis of the study data. Each category had a maximal score of 10 points with an overall maximum theoretical score of 40 points. The final scores were expressed as percentages, with higher values reflecting a better methodological quality. Statistical analysis In this meta-analysis, univariate HR and 95 % CI were used to calculate the overall effect estimate. Some of the studies included provided HR and 95 % CI explicitly. If HR and 95 % CI were not directly reported in the included studies, we calculated the values in the original studies by using the methods illustrated by Parmar et al. (1998). Heterogeneity was assessed by use of Cochran Q and I2 statistics and considered significant at p 1 implied a worse survival for the group with overexpression of MMP-2 or the significant association between overexpression of MMP-2 and clinicopathological characteristics. We pooled HRs and ORs of the studies by using Stata 12.0 software (StatCorp, College Station, TX, USA). We also explored reasons for inter-study heterogeneity using
9
8
73
7
8
64.5
69.9
67.5
8
8
73.6
67.5
73.6
9
8
79.9
8
7
66.2
61
meta-regression analysis and subgroup analysis by study location, publication year, number of patients, and cutoff value. Sensitivity analysis was also conducted by omission of each single study to evaluate stability of the results. Publication bias was evaluated by use of Begg’s funnel plot and Egger’s linear regression test (Egger et al. 1997).
Result
T, the depth of invasion; N, lymph node status; M, distant metastasis; –, missing data and do not be analyzed in meta-analysis
25
– 22/18
85/104 – 103/86
21/19
107/82 81
China
40
China Hwang et al. (2010)
Wang et al. (2013)
189
35
25/15
–
50
25 –
– –
–
–
–
–
–
52.5
39.7 Germany
116
Germany Allgayer et al. (1998)
Alakus et al. (2008)
139
38
38 53/28
189/169 13/345
15/66
221/135
60/21
238/120
77/4
67.3
45.7 China
81
China Chen et al. (2013)
Chen et al. (2013)
358
40
33 –
26/11 8/29
–
27/10
–
–
– 74.6
54.1 37
Dicken et al. (2006)
114
China
Canada
Peng et al. (2010)
57
25 196/133
– –
83/236
122/78
183/145
148/52
216/113 73.6
73.9
Mrena et al. (2006)
200 China
Finland
Zhou et al. (2010)
329
Quality stars (NOS) M Positive/negative T T3T4/T1T2 MMP-2 expression (%) Number of patients Study location Study
Table 1 Major features of the included studies
1005
Study selection and characteristics
N Positive/negative
TNM stage TIII TIV/TI TII
Cutoff (%)
Methodological scores (%)
J Cancer Res Clin Oncol (2014) 140:1003–1009
A total of 154 reports were retrieved from a search of the above databases using search strategies as described. After exclusion of the reports that were out of the scope of our systematic review, 34 reports assessing prognostic value for survival of MMP-2 status in patients with gastric cancer were considered eligible for inclusion in the evaluation. By full-text review, 13 were excluded because the estimation of HRs in these reports was not allowed due to the insufficient data provided by the authors, 4 were excluded because the authors determined the MMP-2 status from other than tumor tissues, 3 were excluded because the reports were not published in English, and 5 were excluded because the authors assessed MMP-2 expression using a method other than IHC; especially, Chen’ report includes two studies (Chen et al. 2013). Therefore, 10 studies meeting the inclusion criteria were finally enrolled in this systematic review and meta-analysis. The characteristics of the 10 eligible studies are summarized in Table 1. Six studies evaluated patients from China, two from Germany, one from Finland, one from Canada. The ten studies comprised 1,603 patients, with sample sizes ranging from 37 to 358 patients. Three of these studies enrolled less than 100 patients and 7 studies included more than 100 patients (Table 1). Study results report and meta‑analysis As indicated in Table 1, 6 of 10 studies revealed that MMP-2 overexpression was a poor prognostic factor for survival of patients and 4 of 10 studies reported that MMP-2 overexpression did not have an unfavorable impact on survival (Fig. 1). Figure 2 demonstrates a forest plot of the individual HRs and results from the meta-analysis. Overall, MMP-2 overexpression in the primary tumor had significant association with an enhanced mortality risk of gastric cancer patients in the random-effects model (combined HR 1.92, 95 % CI 1.48–2.48), despite the exhibition of heterogeneity among studies (I2 62.6 %, p = 0.004). For the exploration of the source of heterogeneity, meta-regression analysis and subgroup analysis was conducted by study location,
13
1006
J Cancer Res Clin Oncol (2014) 140:1003–1009
OR 2.30, 95 % CI 1.77–2.97), and distant metastasis (positive vs negative: OR 4.44, 95 % CI 1.24–15.94). Moreover, diffuse-type gastric cancer had a significant MMP-2 overexpression as compared to intestinal-type (OR 1.50, 95 % CI 1.13–1.99) according to Lauren classification. The meta-analysis of TNM stage and lauren classification with MMP-2 overexpression did not exhibit inter-study heterogeneity (I2 15–23 %), whereas the analysis of other clinicopathological parameters exhibited heterogeneity (I2 54–79 %). The assessment of publication bias showed that the Egger’s tests (p = 0.464) and Begg’s tests (p = 0.721) were not significant (p > 0.05) for studies included in analysis of OS. The funnel plots for publication bias also demonstrated a certain degree of symmetry (Fig. 3). Sensitivity analysis also indicated that omitting any single study did not affect the pooled HR significantly.
Fig. 1 Flow chart of included studies
publication year, number of patients, and cutoff value. The results showed that study location had significant association with the heterogeneity (p = 0.008), while other factors did not (Table 2). Moreover, subgroup analysis indicated a significant relation between MMP-2 overexpression, and OS was also exhibited in Asian countries (HR 2.23, 95 % CI 1.57–3.17) and European countries (HR 1.43, 95 % CI 1.13–1.80). Moreover, subgroup analysis on other factors comprising publication year, number of patients, and cutoff value did not alter the significant prognostic impact of MMP-2 overexpression. In addition, we assessed the association between MMP-2 overexpression and clinicopathological features of gastric cancer. As indicated in Table 3, MMP-2 overexpression had a significant association with TNM stage (TIII/TIV vs TI/TII: OR 2.17, 95 % CI 1.64–2.87), the depth of invasion (T3/T4 vs T1/T2: OR 2.59, 95 % CI 1.63–4.12), lymph node metastasis (positive vs negative:
Discussion To our knowledge, it is the first time that a comprehensive and detailed meta-analysis has assessed the association between MMP-2 overexpression and OS and clinicopathological characteristics of gastric cancer. Our analysis combined the outcomes of 1603 gastric cancer patients from 10 individual studies, indicating that MMP-2 overexpression significantly predicted poor OS of gastric cancer patients (HR 1.92, 95 % CI 1.48–2.48). Subgroup analysis indicated that MMP-2 overexpression was also significantly associated with poor prognosis in Asian countries (HR 2.23, 95 % CI 1.57–3.17) and European countries (HR 1.43, 95 % CI 1.13–1.80). Furthermore, significant correlations were observed between MMP-2 overexpression and clinicopathological features including TNM stage, the depth of invasion, lymph node metastasis, and distant metastasis.
Study ID
HR (95% CI)
% Weight
Zhou (2010) Mrena (2006) Peng (2010) Dicken (2006) Chen (2013) Chen (2013) Allgayer (1998) Alakus (2008) Hwang (2010) Wang (2013) Overall (I−squared = 62.6%, p = 0.004)
2.48 (1.44, 4.26) 1.21 (0.90, 1.65) 1.06 (0.52, 2.18) 1.77 (1.09, 2.86) 2.37 (1.68, 3.33) 4.69 (2.67, 8.24) 1.67 (0.96, 2.91) 1.92 (1.20, 3.09) 1.60 (0.90, 2.84) 2.15 (1.07, 4.30) 1.92 (1.48, 2.48)
9.59 13.64 7.26 10.54 12.96 9.28 9.41 10.70 9.11 7.51 100.00
NOTE: Weights are from random effects analysis .121
1
Fig. 2 Meta-analysis of impact of MMP-2 overexpression on overall survival
13
8.24
J Cancer Res Clin Oncol (2014) 140:1003–1009
1007
Table 2 Meta-regression and subgroup analysis of the studies reporting the association of MMP-2 overexpression and overall survival of cancer Stratified analysis
Study location Asia Europe North America No. of patients >100
