Delta-like ligand-4 (DLL4)-Notch signaling is known to play a pivotal role in the regulation of
tumor angiogenesis. We had previously found that DLL4 was overexpressed, while
Notch1 receptor, which binds to DLL4 during angiogenesis, was absent in the majority of human primary
glioblastomas. Thus, DLL4-Notch signaling pathway in the regulation of
tumor angiogenesis in primary
glioblastoma remains unknown.
Tumor tissues from 70 patients with primary
glioblastoma were analyzed by immunohistochemistry for expression of components of DLL4-Notch signaling,
vascular endothelial growth factor (
VEGF), and microvessel density (MVD). Immunohistochemistry results showed that the positive staining of DLL4 and Notch4 was primarily distributed in
tumor vascular endothelial cells but rarely detected in
tumor cells. However,
VEGF, hairy/enhancer of split-1 (HES1; a target gene of Notch signaling), and Notch1-3 expression was seen in both
tumor vascular endothelial cells and
tumor cells. Univariate analysis showed that the expression levels of
VEGF and DLL4, HES1, and Notch4 in
tumor endothelial cells were significantly associated with MVD in primary
glioblastoma (P < 0.001). Binary logistic regression analysis showed that high expression levels of DLL4, HES1, and Notch4 in
tumor endothelial cells were associated with a decrease of MVD in primary
glioblastoma, while MVD increased with elevated
VEGF expression in contrast. In addition, DLL4, Notch4, and HES1 expression were positively correlated in
tumor vascular endothelial cells (P < 0.05). We conclude that the vascular DLL4-Notch4 signaling and
VEGF signaling complementing each other plays an important role in the progression of
tumor angiogenesis in primary
glioblastoma. Graphical abstract A, positive staining of DLL4 in human kidney; B, positive staining of
VEGF in human
breast cancer; C, positive staining of CD34 in human
lung cancer; D, positive staining of HES1 in human
breast cancer; E-H, positive staining of Notch1-4: E-F in human
lung cancer; G-H in human kidney.