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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 605-611

Abnormal vascular endothelial growth factor protein expression may be correlated with poor prognosis in diffuse large B-cell lymphoma: A meta-analysis


1 Department of Hematology, Harbin Medical University Cancer Hospital, Harbin 150000, P. R. China
2 Department of Radiology, Harbin Medical University Cancer Hospital, Harbin 150000, P. R. China

Date of Web Publication25-Jul-2016

Correspondence Address:
Ai-Chun Liu
Department of Hematology, Harbin Medical University Cancer Hospital, Haping Road No. 150, Nangang District, Harbin - 150000
P. R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.146086

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 > Abstract 


Objective: We conducted the present meta-analysis with relevant cohort studies to determine whether expression levels of vascular endothelial growth factor. (VEGF) could predict the prognosis of diffuse large B.cell lymphoma. (DLBCL).
Materials and Methods: The MEDLINE (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982--2013), Web of Science (1945-2013), and the Chinese Biomedical Database (1982-2013) were searched without any language restrictions. Meta-analysis was conducted using STATA software (Version 12.0, Stata Corporation, College Station, Texas USA). Hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI) were calculated.
Results: Eight clinical cohort studies, which recruited a total 670 DLBCL patients, were included in the meta-analysis. The results of this meta-analysis indicate that DLBCL patients with positive VEGF expression had a shorter overall survival than those with negative VEGF expression. (HR = 1.58, 95% CI = 0.80-2.36, P < 0.001). Ethnicity-stratified analysis illustrates that high expression levels of VEGF may be significantly correlated with poor DLBCL prognosis among both Caucasian and Asian populations. (Caucasian: HR = 1.73, 95% CI = 0.56-2.90, P = 0.004; Asian: HR = 1.45, 95% CI = 0.41-2.50, P = 0.006).
Conclusion: The major findings of our meta-analysis reveal that the aberrant expression of VEGF may correspond to shorter overall survival of patients with DLBCL, revealing that VEGF expression could be an unbiased prognostic determinant in the management of DLBCL patients.

Keywords: Diffuse large B-cell lymphoma, meta-analysis, vascular endothelial growth factor


How to cite this article:
Jiang L, Sun JH, Quan LN, Tian YY, Jia CM, Liu ZQ, Liu AC. Abnormal vascular endothelial growth factor protein expression may be correlated with poor prognosis in diffuse large B-cell lymphoma: A meta-analysis. J Can Res Ther 2016;12:605-11

How to cite this URL:
Jiang L, Sun JH, Quan LN, Tian YY, Jia CM, Liu ZQ, Liu AC. Abnormal vascular endothelial growth factor protein expression may be correlated with poor prognosis in diffuse large B-cell lymphoma: A meta-analysis. J Can Res Ther [serial online] 2016 [cited 2019 Sep 16];12:605-11. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/605/146086




 > Introduction Top


Diffuse large B-cell lymphoma (DLBCL), a type of the aggressive B-cell non-Hodgkin lymphoma (NHL), is the most common lymphoid malignancy in adults accounting for approximately 30% of all newly diagnosed NHL.[1],[2] An estimated 1417 new invasive cases of DLBCL/100,000 people are diagnosed each year.[3] In general, DLBCL occurs primarily in older populations, with an average age of diagnosis at around 70 years older, though it can strike children and young adults in rare cases.[4] A complex and multifactorial disease, DLBCL is known to result from interactions among immunological, genetic, and environmental factors.[5],[6] A large number of epidemiological studies have shown that risk factors including poor daily diet, immunosuppression such as that resulting from AIDS, iatrogenic etiologies in the setting of transplantation or autoimmune disease, and exposure to ultraviolet radiation, pesticides, and hair dyes, may all be implicated in DLBCL carcinogenesis.[6],[7] In recent times, evidence indicates that expression levels of certain cytokines may be related to the development and prognosis of DLBCL.[8],[9]

Vascular endothelial growth factor (VEGF), a signal protein produced by cells, acts as an endothelial cell-specific mitogen and vascular permeability inducer, and it is also considered a key mediator of vasculogenesis and angiogenesis.[10] As a potent multifunctional cytokine, VEGF has many important biological effects on vascular endothelium.[11] In general, VEGF controls normal endothelial proliferation, permeability, and survival, but it is also a main angiogenic mediator in tumors, and has thus been postulated to be involved in the pathogenesis of neoplasms.[12] During the past few decades, circulating VEGF levels have been investigated as a potential diagnostic marker for inflammation and malignant diseases.[13],[14] Large quantities of epidemiologic and experimental evidence have reported increased serum concentrations of free VEGF in various types of cancers; they also report the association of VEGF over-expression with poorer overall and poorer disease-free survival of patients with various solid tumors and hematological malignant neoplasms.[9],[15] In recent years, numerous studies have demonstrated that the pro-angiogenic cytokine VEGF may play an important role in the development and prognosis of DLBCL.[16],[17] To be specific, VEGF was found to be frequently expressed in DLBCL, and it has been demonstrated that elevated VEGF expression strongly correlates with increased angiogenesis, tumor invasion, and tumor resistance to apoptosis; therefore, it is plausible that DLBCL patients with positive VEGF expression may be at an increased risk of suffering poor clinical outcomes.[18],[19] Several studies support the notion that increased expression of VEGF is significantly correlated with invasiveness and poor overall survival in DLBCL patients,[16],[20] but contradictory results have also been reported.[16],[21] Given the conflicting evidence on this issue, we conducted a meta-analysis of all available cohort studies to determine the relationship between VEGF protein expression and DLBCL prognosis.


 > Materials and Methods Top


Literature search and selection criteria

The Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013), and the Chinese Biomedical Database (1982-2013) were searched without any language restrictions. The following keywords and MeSH terms were used in conjunction with a highly sensitive search strategy: (“DLBCL” or “lymphoma, large B-cell, diffuse” or “diffuse large cell lymphoma” or “diffuse histiocytic lymphoma” or “DLBCLs” or “DLCL”) and (“VEGF” or “vascular permeability factor” or “VPF”). A manual search on the basis of references identified in the returned articles was carried out to acquire other potential articles.

The following criteria were established for the eligibility of included studies: (1) The focus of any included study must concern the correlation between VEGF expression and DLBCL prognosis; (2) all included patients should be pathologically confirmed in diagnosis of DLBCL according to the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues;[22] (3) sufficient information with regard to expression levels of VEGF should be provided in included studies. Articles that did not meet all inclusion criteria were excluded. If several studies of the same subjects were published by authors, either the most recent or largest sample size publication was included.

Data extraction and methodological assessment

Two authors used a standardized form to extract the following data from included studies: Publication language, article publication year, first author's surname, geographical location, design of study, total number of cases, sample size, source of controls, sample type, method for protein detection, protein expression levels, overall survival.

Two observers assessed methodological quality separately with the use of the Newcastle–Ottawa Scale (NOS) criteria.[23] The NOS criteria comprised three aspects: (1) Subject selection: 0-4; (2) subject comparability: 0-2; (3) clinical outcome: 0-3. NOS scores range from 0 to 9; and a score ≥ 7 indicates good quality.

Statistical analysis

In order to apply rigorous statistical analysis, STATA statistical software (Version 12.0, Stata Corporation, College Station, TX, USA) was used to handle with statistical data. Hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI) were calculated to estimate the correlation of VEGF expression with DLBCL prognosis. The statistical significance of pooled HRs was evaluated with the Z test. Between-study heterogeneity was assessed by the Cochran's Q-statistic and I2 tests.[24] A P < 0.05 or I2 > 50% implies heterogeneity, in which case the random-effect model was employed; otherwise, the fixed-effects model was implemented. We also make use of subgroup analyses to explore sources of heterogeneity. A sensitivity analysis was implemented for the purpose of evaluating the influence of singular studies on overall results. The presence of publication bias was examined with Funnel plots and Egger's linear regression test.[25]


 > Results Top


Characteristics of included studies

A total of 77 articles relevant to the searched keywords were initially identified. The titles and abstracts of all the articles were reviewed, and 29 articles were excluded. Full texts and data integrity were then reviewed; another 35 articles were excluded failing to meet the inclusion criteria, and 3 studies were excluded due to lack of data integrity [Figure 1]. Eventually, 8 clinical cohort studies which recruited a total of 670 DLBCL patients were selected for statistical analysis.[16],[18],[20],[21],[26],[27],[28],[29] The eligible studies included in the current meta-analysis were published between 2007 and 2013. The distribution of the number of topic-related literatures in the electronic database during the last decade is shown in [Figure 2]. Overall, 4 studies were carried out among Asian populations, and the other four among Caucasian populations. Enzyme-linked immunosorbent assay, avidin-biotin-peroxidase complex, and EnVision methods were utilized to detect expression levels of VEGF. Peripheral blood samples and tumor tissues were carefully collected for VEGF protein detection. NOS scores of all included studies were ≥ 6. The baseline characteristics and methodological quality of eligible studies were recorded in [Table 1].
Figure 1: Flow chart showing the study selection procedure. Eight cohort studies were included in this meta-analysis

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Figure 2: The distribution of the number of topic-related literature in electronic databases over the last decade

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Table 1: Main characteristics and methodological quality of all eligible studies

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Quantitative data analysis

Since no heterogeneity was detected among studies (I2 = 0.00%, P = 0.858), the fixed effects model was conducted. The main findings of the current meta-analysis demonstrated that VEGF-positive patients had a shorter overall survival than VEGF-negative patients (HR = 1.58, 95%CI = 0.80-2.36, P < 0.001) [Figure 3].
Figure 3: Forest plots for the relationships between abnormal vascular endothelial growth factor protein expression and prognosis of patients with diffuse large B-cell lymphoma

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Ethnicity-stratified analysis indicated that abnormal VEGF protein expression was significantly related to poor prognosis in DLBCL patients among both Caucasians and Asians (Caucasians: HR = 1.73, 95% CI = 0.56-2.90, P = 0.004; Asians: HR = 1.45, 95%CI = 0.41-2.50, P = 0.006; respectively) [Figure 4]. Subgroup analyses based on source of sample and genotyping method were also performed. The results showed significant associations between VEGF-positive expression and poor DLBCL patient prognoses in the majority of the subgroups.
Figure 4: Subgroup analyses based on ethnicity, source of sample, and detection method for the relationships between abnormal vascular endothelial growth factor protein expression and prognosis of patients with diffuse large B-cell lymphoma

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A sensitivity analysis indicated that the removal of any single study could not affect the overall pooled ORs HR [Figure 5]. There was no significant evidence for asymmetry in the funnel plots [Figure 5]. No evidence of publication bias was presented by Egger's test (t = −0.37, P = 0.721).
Figure 5: Sensitivity analysis of the summary odds ratio coefficients and funnel plot of publication biases on the relationships between abnormal vascular endothelial growth factor protein expression and prognosis of patients with diffuse large B-cell lymphoma

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 > Discussion Top


With the success of anti-VEGF in colon and rectal carcinoma as well as other solid tumors, much attention has turned toward the possibility of employing VEGF inhibitors in lymphoma therapy.[20] However, little is known about the functional role of VEGF expression in lymphoma, not to mention in DLBCL. It is well established that angiogenesis plays an important role in the development, invasion, and metastasis of several solid tumor types, and hematologic malignancies.[31],[32] The function of VEGF signaling is not at all limited to the vasculature, and in addition to its angiogenic and vascular permeabilizing properties, VEGF also has a direct role in hematolymphoid cell development.[33] Specifically, VEGF and its receptors, VEGFR1 and VEGFR2, have been shown to be expressed in the cell lines derived from various hematolymphoid malignancies, and they were also observed to be coordinately expressed in primary human DLBCL specimens.[30] Both VEGFR1 and VEGFR are capable of stimulating the proliferation of tumor cells. In the development of vasculature, VEGFR2-mediated signaling is the predominant growth signal, and VEGFR1, perhaps by sequestering excess VEGF ligand, appears to largely act as a brake on VEGFR2 activation.[20],[34] In general, in lymphoma cells, an autocrine loop involving VEGF and its receptors can not only induce blood and lymph vessel in situ generation, but also promote the growth and metastasis of tumor cells.[20] We, therefore, hypothesized that expression of VEGF in the lymphoma cells may be related with the prognosis of DLBCL. Lech-Maranda et al. has provided supporting evidence consistent with the notion that VEGF plays a crucial role in mediating angiogenesis and stimulating the growth and survival of malignant cells, further supporting the prognostic value of elevated VEGF levels in patients with DLBCL, and revealing that lymph-angiogenesis is critical in clinical outcome.[28]

In the current meta-analysis, we systematically assessed the prognostic value of VEGF in the management of DLBCL. The main findings of our meta-analysis showed that DLBCL patients with positive expression of VEGF exhibited lower overall survival than those with negative VEGF expression, demonstrating that VEGF expression may predict the prognosis of patients with DLBCL.

Furthermore, our ethnicity-stratified subgroup analyses illustrated that increased expression of VEGF might be strongly connected with a poor prognosis of DLBCL among both Caucasian and Asian populations, revealing that there seems to be no ethnic difference in the effects of VEGF protein on the progression of DLBCL. Therefore, we speculate that VEGF may act as a potential unbiased prognostic factor for DLBCL.

Although our meta-analysis was a practical way to generate a more powerful estimate of true effect-size with less random error than individual studies, it did come with some potential limitations. Firstly, given the small number of included studies, our results may not have included all the data from all trials to evaluate the relationship of VEGF expression with DLBCL prognosis. Nevertheless, our meta-analysis managed to overcome limits of size or scope in individual studies to acquire more reliable and more general information on the correlation of VEGF expression and the prognosis of DLBCL by systematically aggregating results from each study. A second potential limitation of our meta-analysis is the fact that the meta-analysis is a retrospective study, which may induce potential publication bias and reduce reliability of results. Another potential limitation is that our meta-analysis was unable to acquire original data from the included studies. Even with the above limitations, this is the first example of a meta-analysis on the association of VEGF expression with the prognosis of DLBCL. And, importantly, our meta-analysis had clear selection criteria in its literature search strategy. In order to achieve strong objectivity, all the research methods were carried out on strict inclusion and exclusion criteria. Our meta-analysis, undertaken according to these rigorous statistical analyses, can provide a more accurate and comprehensive conclusion.

In brief, the present meta-analysis indicates that abnormal expression of VEGF may be significantly associated with poor prognosis in DLBCL patients. Thus, abnormal VEGF expression may serve as a potential prognostic factor for DLBCL. However, given that our meta-analysis possessed several limitations, further studies with more integral data and larger sample-sizes are needed to achieve a more insightful statistical analysis with general applicability.


 > Acknowledgments Top


This study was supported by Research Projects of Traditional Chinese Medicine in Heilongjiang Province (No: ZHY12-W034). We would like to acknowledge the reviewers for their helpful comments on this paper.

 
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