The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study.

• 发表时间: Mar 2016
• 来源期刊: Tumour Biol
• DOI: 10.1007/s13277-015-4202-8
• PMID: 26472724
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 医学
• 作者列表: Zhang JF,Chen Y,Qiu XX,Tang WL,Zhang JD,Huang JH,Lin GS,Wang XF,Lin ZX

关键词: Angiogenesis; DLL4-Notch signaling; Microvessel density; Primary glioblastoma; Vascular endothelial growth factor

Mesh: Adolescent; Adult; Aged; Female; Glioblastoma / blood supply metabolism pathology; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins / biosynthesis; Male; Membrane Proteins / biosynthesis; Middle Aged; Neovascularization, Pathologic / metabolism; Proto-Oncogene Proteins / biosynthesis; Receptor, Notch1 / biosynthesis; Receptor, Notch2 / biosynthesis; Receptor, Notch3 / biosynthesis; Receptor, Notch4; Receptors, Notch / biosynthesis; Signal Transduction; Transcription Factor HES-1 / biosynthesis; Vascular Endothelial Growth Factor A / biosynthesis; Young Adult

Abstract

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.