title: Expression of vascular Notch ligands Delta-like 4 and Jagged-1 in glioblastoma.
abstract: OBJECTIVE
  The coordinated expression of the Notch ligands Delta-like 4 (Dll4) and Jagged (Jag)1 is believed to define appropriate endothelial sensitivity to vascular endothelial growth factor (VEGF). Preclinical data suggest that Dll4-Notch signalling may confer resistance to anti-VEGF therapy with bevacizumab, and Jag1 may antagonize Dll4-Notch. The aims of this study were to characterize the expression of Dll4 and Jag1 in primary glioblastomas.
  
  
  RESULTS
  Immunohistochemistry was performed on 40 glioblastomas and normal brain using validated antibodies against Dll4 and Jag1. In-situ hybridization for Dll4 was performed on serial sections and compared with protein expression. Dll4 expression was localized to the cytoplasm and membrane of endothelial cells in all glioblastomas; it was weak or absent in normal brain. Jag1 expression was observed in the cytoplasm and membrane of glomeruloid and non-glomeruloid endothelial cells from 76% and 67% of glioblastomas, respectively. However, endothelial Jag1 expression was less intense and less prevalent than Dll4. There was no association between Dll4 and Jag1 expression.
  
  
  CONCLUSIONS
  In summary, Dll4 and Jag1 are expressed in glioblastoma vasculature. These data may define subsets of glioblastoma that might be sensitive (Dll4(+) /Jag1(+) ) or resistant (Dll4(+) /Jag1(-) ) to bevacizumab. Our data also suggest that anti-Dll4 therapy should be evaluated experimentally in glioblastoma.
authors.affiliation: Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK. adrianjubb@gmail.com
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Lisa
authors.initials: L
authors.lastname: Browning
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Graham
authors.initials: G
authors.lastname: Steers
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D004273:DNA, Neoplasm / Q000032:analysis; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D000072099:Serrate-Jagged Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D004273:DNA, Neoplasm; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins