title: The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study.
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.
authors.affiliation: The First Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, 350005, China.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China.
authors.forename: Xian-Xin
authors.initials: XX
authors.lastname: Qiu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Tang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
authors.forename: Jian-Huang
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
authors.forename: Guo-Shi
authors.initials: GS
authors.lastname: Lin
authors.affiliation: Department of Pathology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
authors.forename: Xing-Fu
authors.initials: XF
authors.lastname: Wang
authors.affiliation: The First Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, 350005, China. lzx1967@sina.com.|Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China. lzx1967@sina.com.
authors.forename: Zhi-Xiong
authors.initials: ZX
authors.lastname: Lin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051881:Receptor, Notch1 / Q000096:biosynthesis; D051883:Receptor, Notch2 / Q000096:biosynthesis; D000071656:Receptor, Notch3 / Q000096:biosynthesis; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000096:biosynthesis*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein; C078493:HES1 protein, human
keywords: Angiogenesis; DLL4-Notch signaling; Microvessel density; Primary glioblastoma; Vascular endothelial growth factor