title: Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung.
abstract: OBJECTIVE
  Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non-small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC).
  
  
  METHODS
  We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC.
  
  
  RESULTS
  The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC.
  
  
  CONCLUSIONS
  Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC.
authors.affiliation: Center for Applied Medical Research (CIMA) and Clinica Universidad de Navarra (CUN), University of Navarra, Pamplona, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Pajares
authors.forename: Jackeline
authors.initials: J
authors.lastname: Agorreta
authors.forename: Marta
authors.initials: M
authors.lastname: Larrayoz
authors.forename: Aurélien
authors.initials: A
authors.lastname: Vesin
authors.forename: Teresa
authors.initials: T
authors.lastname: Ezponda
authors.forename: Isabel
authors.initials: I
authors.lastname: Zudaire
authors.forename: Wenceslao
authors.initials: W
authors.lastname: Torre
authors.forename: María D
authors.initials: MD
authors.lastname: Lozano
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.forename: Christian
authors.initials: C
authors.lastname: Brambilla
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Timsit
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015331:Cohort Studies; D018450:Disease Progression; D005060:Europe; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2