title: High DLL4 expression in tumour-associated vessels predicts for favorable radiotherapy outcome in locally advanced squamous cell head-neck cancer (HNSCC).
abstract: BACKGROUND
  Expression of the DLL4 (a notch pathway ligand) by tumor-associated endothelium is a postulated marker of vascular maturity and functionality. As vascular functionality is an important parameter defining chemotherapy and oxygen intra-tumoral distribution, we investigated the role of DLL4 expression in tumour vasculature in the efficacy of radio-chemotherapy for HNSCC patients.
  
  
  METHODS
  Sixty-five biopsy specimens from HNSCC patients with inoperable disease were immunohistochemically examined using anti-CD31 (pan-endothelial cell marker) and anti-DLL4 antibodies and the vascular density (VD) was recorded. Patients were treated with platinum based hypofractionated accelerated conformal radiotherapy. The median follow-up period was 24 months (4-80 months).
  
  
  RESULTS
  Using the 33rd and 66th percentiles cases were grouped in three categories of low, medium and high CD31+ or DLL4+ VD. The percentage of vessels expressing DLL4 (DLL4-ratio) ranged from 17 to 100 % (mean 71 %), showing substantial variation among cases. In accordance with previous published studies, a biphasic pattern of association of CD31+ VD with poor outcome was noted. Cases with a medium VD had a significantly better local relapse free survival (LRFS) compared to cases of high VD (p = 0.0005, HR 0.15) and of low VD (p = 0.02, HR 0.28). High DLL4/CD31 ratio defined improved LRFS in both these subgroups of poor prognosis.
  
  
  CONCLUSIONS
  The expression of DLL4 is associated with reduced radio-resistance, presumably by reducing hypoxia and improving chemotherapy accessibility. Using the combination of CD31 and DLL4 staining, a classification is suggested so that HNSCCs are categorized in sub-groups to be targeted by different anti-angiogenic and hypoxia targeting agents.
authors.affiliation: Department of Radiotherapy/Oncology, Democritus University of Thrace, PO BOX 12, 68100, Alexandroupolis, Greece. targ@her.forthnet.gr
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: Efthimios
authors.initials: E
authors.lastname: Sivridis
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Gatter
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism* / Q000532:radiotherapy; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins