Prognostic Impact of Notch Ligands and Receptors in Nonsmall Cell Lung Cancer Coexpression of Notch-1 and Vascular Endothelial Growth Factor-A Predicts Poor Survival

BACKGROUND Notch signaling plays a key role in embryonic vascular development and angiogenesis The authors aimed to study the prognostic role of the angiogenesis-related Notch ligands and receptors and investigate the prognostic impact of the coexpression of vascular endothelial growth factor A (VEGF A) and Notch signaling METHODS Tumor tissue samples from 335 resected patients with stage I to IIIA nonsmall cell lung cancer (NSCLC) were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and tumor-related stroma from each specimen Immunohistochemistry was used to evaluate the expression of the molecular markers Notch-1 Notch-4 Delta-like ligand 4 (DLL4) and Jagged-1 RESULTS There were 191 squamous cell carcinomas (SCCs) 113 adenocarcinomas (ACs) and 31 large cell carcinomas In AC low tumor cell Delta like ligand 4 expression was an in! dependent negative prognostic factor (hazard ratio [HR] 2 9 95% confidence interval [CI] 1 4 6 3 [P = 006]) whereas high tumor cell Notch-1 expression was an independent negative prognostic factor (HR 2 2 95% Cl 1 2 41 1 [P<001]) In SCC low stromal Delta-like ligand 4 expression was an independent indicator of poor prognosis (HR 3 3 95% Cl 1 8-6 1 [P<001]) The coexpression of Notch-1 and VEGF-A had a significant prognostic impact (P<001) For Notch-1 and VEGF A low/low (n=142) versus high/high (n=35) expression resulted in 5-year survival rates of 69% and 32% respectively CONCLUSIONS Delta-like ligand 4 and Notch-1 are independent prognostic factors in NSCLC but have diverse impacts in SCC and AC The coexpression of tumor cell Notch-1/VEGF-A has a major impact on survival Cancer 2010,116 5676-85 (C) 2010 American Cancer Society