Associations Between Vascular Notch Ligands Delta-like 4(DLL4), Jagged1 And Peritumoral Brain Edema(PTBE), Prognosis In Primary Glioblastoma.

Glioblastoma is a highly aggressive brain tumor characterized by massive neovascularization, necrosis, and intense resistance to therapy. Deregulated Notch signaling has been implicated in the formationand progression of different malignancies. The present study attempted to investigate the expression of vascular Notch ligands delta-like 4(DLL4) and Jagged1 in primary glioblasotma, their associations with vascular and clinical parameters, and their prognostic value in patients with primary glioblastoma.Part 1. Expression patterns and levels of vascular Notch ligands Delta‐like 4(DLL4) and Jagged1 in primary glioblastoma.Objective: Glioblastoma is a highly aggressive brain tumor. Aberrant Notch pathway has been implicated in the formation and progression of glioblastoma. The present study attempted to characterize the expression of two vascular Notch ligands DLL4 and Jagged1 in primary glioblastoma.Methods and results: Tumor tissues from 82 patients with primary glioblastoma were analyzed using immunohistochemistry for DLL4 and Jagged1 expression. The results showed that elevated DLL4 expression was primarily distributed in the cytoplasm of tumor vascular endothelial cells and rarely detected in tumor cells. In addition, immunohistochemistry results showed markedly increased Jagged1 expression in both endothelial cells and tumor cells within glioblastoma tissues compared to adjacent non-neoplastic brain tissues.Conclusion: Notch signaling is active during glioblastoma angiogenesis, and may confer new strategy for the therapy of glioblastoma.Part 2. The relationships between vascular Notch ligands DLL4/Jagged1 and clinical features in primary glioblastoma.Objective: Several clinical features have been implicated to significantly influence the prognosis of patients with glioblastoma. The present study elucidated a possible link between Notch signaling components expression and important clinical parameters. Methods and results: A total of 82 glioblastoma patients were enrolled to evaluate the relationship between DLL4/Jagged1 expression and clinical parameters. Both elevated DLL4 and Jagged1 expression was closely associated of expression with KPS and symptom duration, 2 adverse factors influencing patient survival.Conclusion: DLL4 and Jagged1 expression were associated with tumor progression, indicating that these two ligands may be involved in the carcinogenesis and progression of glioblastoma.Part 3. Correlations of Notch ligands DLL4 and Jagged1 expression with peritumoral brain edema(PTBE) in primary glioblastoma. Objective: DLL4 and Jagged1 are involved in a variety of tumor initiation and progression, particularly in the process of tumor angiogenesis. The present aimed to investigate the correlation of DLL4 and Jagged1 with PTBE in Glioblastoma.Methods and results: Tumor tissues from 82 glioblastoma patients were analyzed using immunohistochemistry for DLL4 and Jagged1 expression. Peritumoral brain edema(PTBE) on preoperative magnetic resonance imaging of these patients and the relationship with DLL4 expression were evaluated. DLL4 expression was positively related with PTBE(Spearman’s test: r=0.845, P<0.001). A multiple linear regression model was constructed to confirm that the positive index of DLL4 was associated with an increase in maximum extent of PTBE(P<0.001). However, the study failed to find the significant relationship between Jagged1 and PTBE.Conclusion: DLL4 is correlated with PTBE and may be a new target to develop a potential strategy for controlling PTBE and improving patient outcome in glioblastoma.Part 4. Effect of Notch ligands DLL4 and Jagged1 on the prognosis of patients with primary gliobalstomaObjective: Notch pathway is involved in Glioblastoma progression, however, the clinical and prognostic significance of DLL4 and Jagged1 in glioblastoma have not been fully elucidated.Methods and results: The effect on prognosis was assessed using the Kaplan–Meier survival and the Cox proportional hazard model. Univariate analysis indicated significant correlation of high DLL4 expression with shorter time to progression(TTP)(P<0.001) and overall survival(OS)(P<0.001). High Jagged1 expression in tumor cells(TC) and endothelialcells(EC) were both statistically associated with reduced time to progression(TTP)(P<0.001 for TC, P=0.001 for EC) and overall survival(OS)(P<0.001 for TC, P = 0.003 for EC) in primary glioblastoma. The median TTP(P<0.001) and OS(P = 0.001) were higher in patients with dual-low Jagged1 expression in TC and EC compared to those in patients with non-dual Jagged1 expression and dual high expression. Multivariate analysis confirmed high DLL4 expression as an unfavorable prognostic indicator for TTP(P<0.001) and OS(P<0.001), independent of age, gender, symptom duration, resection degree, and PTBE. In addition, high Jagged1 expression in both tumor cells and endothelial cells was independent unfavorable prognostic factors TTP(P<0.001 for TC, P<0.001 for TC) and OS(P<0.001 for TC, P<0.001 for TC) in primary glioblastoma patients.Conclusion: Notch signaling plays an important role in the progress of glioblastoma. DLL4 and Jagged1 expression may be used as independent prognosis factors in patients with glioblastoma.