Clinicopathological and Prognostic Significance of CD44s and CD44v6 Expression in Patients with Glioma: A Systematic Review and Meta-analysis

Abstract Background: Cancer stem cell surface marker CD44 has been revealed to promote tumor growth, progression, and metastasis in gliomas. Although the prognostic and clinicopathological value of CD44 standard form (CD44s) and its variant isoform CD44v6 expression in glioma patients has been evaluated in several independent studies, their results remained controversial. Therefore, we performed this meta-analysis to investigate the prognostic and clinicopathological association of CD44s/CD44v6 expression with glioma patients.Methods: A comprehensive literature search was performed in the electronic databases PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wangfang Data. The statistical analysis was conducted using Stata 15.0 and Review Manager 5.3.Results: A total of 43 studies with 2817 glioma patients were included in this meta-analysis. Pooled results indicated that positive expression of CD44s was significantly associated with poorer overall survival (OS, univariate analysis, HR =1.63, 95% CI= [1.16–2.29], P=0.005; multivariate analysis, HR=2.14, 95%CI= [1.21, 3.78], P=0.009), and reduced progression-free survival (PFS) in the univariate analysis (HR=2.09, 95% CI= [1.59, 2.75], P<0.00001), but not with PFS in the multivariate analysis (P>0.05) or tumor recurrence (P>0.05). CD44 expression was significantly upregulated in glioma tissues when compared with non-tumorous brain tissues (CD44s, OR=31.31, 95% CI= [15.22, 64.43], P<0.00001; CD44v6, OR=13.18, 95% CI= [5.51, 31.51], P<0.00001). In particular, CD44 expression was preferentially expressed in high-grade gliomas (grade III-IV vs. grade I-II, CD44s, OR=4.67, 95% CI= [3.18, 6.87], P<0.00001; CD44v6, OR=2.06, 95% CI= [1.21, 3.51], P=0.008). CD44s expression was lower in brain metastases than that in primary gliomas (OR=0.25, 95% CI= [0.10, 0.60], P=0.002), however, higher expression of CD44v6 was detected in brain metastases when compared with primary gliomas (OR=49.44, 95% CI= [13.06, 187.22], P<0.00001).Conclusions:This meta-analysis revealed the prognostic value of CD44s expression and clinicopathological significance of CD44s/CD44v6 expression in gliomas. Increased CD44s expression can predict worse prognosis of glioma patients. Particularly, CD44s is an independent prognostic factor for poor OS of glioma patients. Both CD44s and CD44v6 were glioma patients predominantly expressed in glioma tissues, especially in high-grade gliomas. Additionally, CD44v6 is a potential diagnostic biomarker for differentiating brain metastases from primary gliomas in individual cases. Therapeutic strategies targeting CD44 in gliomas should be further explored in the future.