Expression Of CXCR4 In Osteosarcoma And Its Clinical Significance

Background:Osteosarcoma originates from primitive bone-forming mesenchymal cells, and is the most common bone malignancies in children and young adults. Despi te recent advances in the treatment, patients with osteosarcoma are often diagnosed at an advanced stage and have a poor prognosis. Thus, advances in the treatment of ost eosarcoma are still urgently needed and clinical factors for predicting prognosis need d eveloping. In order to improve the clinical outcomes for patients with poor prognosis, it is urgent to find new diagnostic and therapeutic approaches to identify high-riskpatie nts and block metastasis in this disease.Chemokine receptor CXCR4 on cancer cells is the most frequently constitutive, a nd cancer cells expressing CXCR4 may transfer into CXCL12 secreting tissues like ly mphatics.In osteosarcoma, published data demonstrated that the hypoxia-HIF-lα-CXCR4 pathway plays a crucial role during the migration of human osteosarcoma cells. Both i n vitro and in vivo results indicated CXCR4 become indicative of a new target in tu mor treatments. However, the precise roles of CXCR4 in grade and prognosis of osteo sarcoma are still unclear and debated.Purposes:To elucidate the practical significance of CXCR4 in clinical practice, w e introduced a meta-analysis to resolve the between-study heterogeneity, just for meta-analysis can avoid potential bias sources, such as study methods, population selected.H ere we extracted all data from published articles, and systematically evaluated the esse ntial implications of CXCR4 in lung metastasis and prognosis of osteosarcoma.Methods:①Search Strategy:A literature search was carried out using PubMed, Google Scholar, Medline, Cnki and Wanfang databases from Jan.1988 up to Nov.201 4. There were no restrictionsof sources and languages. Search terms were subjected to the following:"chemokine receptor CXCR4" or "CXCR4", "osteosarcoma [MeSH]", "expression", "prognosis", etc.All references in retrieved articles were scanned to identi fy other potentially availablereports.②Study Selection:Two reviewers independently sel ected eligible studies. Disagreement between the two reviewers was settled by discussi on with the third reviewer. Inclusion criteria were as follows:(1) the patients were co nfirmed with the diagnosis of osteosarcoma by department of pathology; (2) the main outcome of studies concentrated on age, gender, lung metastasis and overall survival; (3) CXCR4 expression model was identified by immunohistochemistry (IHC), Tissue C hip; (4) the HR value and 95%CI between CXCR4 expression and the survival status could be obtained from articles directly or calculated based on the figure and table gi ven in articles; (5) for the duplicate articles, only the most complete and/or the recent ly published one was included; for one study.③Data Extraction:The following data w ere collected by two reviewers independently using a purpose-designed form:name of the first author, publication year, country, histology, study methods, grade, patient num ber, mean ages, cut-off values of stained cells, positive percentage, and data type. Dis agreement between the two reviewers was settled by the third reviewer.④Quality Asse ssment:Quality assessment was conducted for eligible studies by independent reviewer s by reading and scoring each publication according to the quality scale for biologicall y prognostic factors established by the European Lung Cancer Working Party (ELCW P). This scale evaluates the scientific design, laboratory methodology, generalizability a nd results analysis. Each category could reach up to 10 points, so result maximum co uld reach up to 40 points. Both investigators compared their calculated scores and, if necessary, achieved a consensus score for each category during a meeting. The final s cores represent the percentage of the maximum of achievable scores, ranging from 0 t o 100%. Thus, higher values represent a better methodological quality.〥ata Synthesi s and Analysis:Differences were expressed as ORs with 95% CIs. Survival outcome data were synthesized using the time-to-event HR as the operational measure. As for t he studies where HR and 95% CI were not given directly, data in tables, text or/and figures of the original papers were extracted and then re-calculate the HR and 95%C I by using software SPSS 13.0, Engauge Digitizer version 4.1 and the methods introdu ced by Tierney et aland Parmar et al.To assess heterogeneity among the studies, we u sed the Chi-squared and Q test. If heterogeneity was significant (p<0.1), we used rand om effect model. Otherwise, we used fixed effect model. Funnel plots of Begger’s an d Egger’s test were used to investigate publication bias. Sensitivity analysis was perfor med to examine the stability of the pooled results.Generally, the effect of CXCR4 on pathological indicator and survival was considered as statistically significant if the corr esponding 95%CI for the pooled HR/OR did not overlap 1, or the pooled SMD did n ot overlap 0. All p values were two-sided, and p<0.05 was considered as statistically significant. Statistical calculations were performed using Stata version 11.0.Results: ①Sarch results and characteristics of studies:The articles retrieval was conducted as shown in Fig. Initially, a structured literature search generated 58 articles. Of the relevant studies,22 articles irrelevant to osteosarcoma were excluded by the tit le and abstract. And then, the rest of 36 articles underwent further identification, amo ng which 22 articles were excluded due to 12 for cell study,8 for animal study, and 2 for review. Eventually,14 articles met the criteria.②The general characteristics of 1 4 articles were summarized in Table 1. Generally, the total 865 patients or samples w ere included with the mean age of 20.9, of which the number of male was 441 cases. 10 articles were conducted in Chinese populations, the remaining 4 articles in Japan, USA, Switzerland and Brazil, respectively. The percentage of positive CXCR4 expressi on varies from 29.1% to 90.5%. HRs and 95% CIs were obtained from Kaplan-Meier curves merely in two articles. CXCR4 protein in osteosarcoma tissues was tested by t he method of IHC (13) and Tissue Chip (1). If the nucleus or cytoplasm was stained, CXCR4 expression can be referred to as positive. Regarding the cut-off value of posit ive expression, eight studies introduced the staining score according to the intensity an d percentage of stained cells, while other studies used the percentage alone. (3)In this meta-analysis, two articles evaluated the value of high CXCR4 expression inthree year s overall survival. CXCR4 expression was significantly associated with 3-year-OS (HR: 0.36,95% CI:0.14-0.96; p=0.042) in patients, indicating CXCR4 can effectively pred icted the prognosis and provide a useful tool for the early treatment.Conclusion:(1) CXCR4 expression in osteosarcoma can be recommended as an indicator of lung metastasis.(2) CXCR4 expression in osteosarcoma can predict three years overall survival.(3) CXCR4 expression in osteosarcoma can be relation with age.