title: The Vascular Notch Ligands Delta-Like Ligand 4 (DLL4) and Jagged1 (JAG1) Have Opposing Correlations with Microvascularization but a Uniform Prognostic Effect in Primary Glioblastoma: A Preliminary Study.
abstract: OBJECTIVE
  Delta-like ligand 4 (DLL4) and Jagged1 (JAG1), 2 vascular Notch ligands, are involved in the process of tumor angiogenesis. The present study investigates their relationship with microvascularization and the prognostic effect in primary glioblastoma.
  
  
  METHODS
  Tumor tissues from 61 glioblastomas were analyzed using immunohistochemistry for DLL4/JAG1 expression and microvascular formations. The correlations between DLL4/JAG1 and microvascularization were analyzed. The survival probabilities were computed using the Kaplan-Meier method. The Cox proportional hazards regression model was used for multivariate analysis of time to progression (TTP) and overall survival (OS).
  
  
  RESULTS
  The results showed increased DLL4 and JAG1 expression in glioblastoma tissues. Five types of basic microvascular formations, including microvascular sprouting, vascular cluster, vascular garland, glomeruloid vascular proliferation, and vasculogenic mimicry, were detected. Glioblastomas with the type I microvascular pattern (MVP) that displayed prominent microvascular sprouting and vascular clusters tended to have higher DLL4 expression, whereas those with the type II MVP that had numerous vascular garlands, glomeruloid vascular proliferations, and vasculogenic mimicries showed upregulated JAG1 expression. Univariate analysis documented that high DLL4 expression, high JAG1 expression, and type II (MVP) were statistically associated with reduced TTP and OS. Multivariate analysis confirmed high DLL4 expression, high JAG1 expression, and type II MVP as significant prognostic factors for both shorter TTP and OS, independent of age, Karnofsky performance scale, and other molecular markers (vascular endothelial growth factor, Ki67, and P53).
  
  
  CONCLUSIONS
  DLL4 and JAG1 may have opposing effects on tumor angiogenesis in glioblastoma. The Notch pathway may be a new target for antiangiogenic therapy in glioblastoma.
authors.affiliation: Tumor Invasion Microecological Laboratory, Fujian Medical University, Fuzhou, Fujian, China; Department of Neurosurgery, the Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xian-Xin
authors.initials: XX
authors.lastname: Qiu
authors.affiliation: Tumor Invasion Microecological Laboratory, Fujian Medical University, Fuzhou, Fujian, China; Intensive Care Unit, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Tumor Invasion Microecological Laboratory, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Chen-Hong
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Tumor Invasion Microecological Laboratory, Fujian Medical University, Fuzhou, Fujian, China; Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China. Electronic address: lzx1967@sina.com.
authors.forename: Zhi-Xiong
authors.initials: ZX
authors.lastname: Lin
authors.affiliation: Tumor Invasion Microecological Laboratory, Fujian Medical University, Fuzhou, Fujian, China; Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, China.
authors.forename: Bi-Juan
authors.initials: BJ
authors.lastname: Chen
authors.affiliation: Tumor Invasion Microecological Laboratory, Fujian Medical University, Fuzhou, Fujian, China; Department of Rehabilitation, Fujian Provincial Hospital, Fuzhou, Fujian, China.
authors.forename: Na
authors.initials: N
authors.lastname: You
authors.affiliation: Tumor Invasion Microecological Laboratory, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Xing-Fu
authors.initials: XF
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002681:China / Q000453:epidemiology; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D055806:Microvessels / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000401:mortality*; D010865:Pilot Projects; D015995:Prevalence; D011379:Prognosis; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013223:Statistics as Topic; D015996:Survival Rate; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins
keywords: Delta-like ligand 4; Glioblastoma; Jagged1; Microvascular pattern; Vascular endothelial growth factor