The delta-like ligand 4-notch signaling inhibits tumor angiogenesis but promotes tumor growth in primary glioblastoma: An immunohistochemical study

Abstract

Background: Delta-like ligand 4 (DLL4) is a key Notch ligand implicated in tumor angiogenesis. However, previous studies have shown that the DLL4-Notch signaling inhibits tumor angiogenesis but promotes tumor progression in primary glioblastoma. The underlying mechanism remains unknown. Methods: Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for the expression of DLL4, microvessel density (MVD), and Ki67 labeling index. The degree of tumor contrast enhancement (DTCE) on preoperative magnetic resonance imaging was also evaluated. The effect on prognosis was assessed based on Kaplan–Meier survival and Cox proportional hazard models. Results: Results showed that the DTCE was negatively correlated with DLL4 but positively correlated with MVD (r = −0.260, 0.593, P < 0.05). The Ki67 labeling index was shown to be positively correlated with both DLL4 and MVD (r = 0.346, 0.346, P < 0.05). Univariate analysis indicated a significant correlation of high DLL4 and Ki67 labeling index expression with shorter progression-free survival (PFS) and overall survival (OS) (P < 0.05). Multivariate analysis confirmed high DLL4 and MVD expression as unfavorable prognostic indicators for PFS and OS (P < 0.05), and the hazard ratio of DLL4 was higher than MVD for both PFS and OS (P < 0.05). Conclusion: We conclude that the DLL4-Notch signaling improves tumor vascular function and contributes to the survival of malignant cells, resulting in less MVD but more tumor progression in primary glioblastoma.

Keywords

• Angiogenesis
• delta-like ligand 4-notch signaling
• microvessel density
• primary glioblastoma
• prognosis