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 independent 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% CI, 1.2-4.1 [P<.001]). In SCC, low stromal Delta-like ligand 4 expression was an independent indicator of poor prognosis (HR, 3.3; 95% CI, 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.
Donnem
Tom
T
Institute of Clinical Medicine, University of Tromso, Tromso, Norway. tom.donnem@uit.no
Andersen
Sigve
S
Al-Shibli
Khalid
K
Al-Saad
Samer
S
Busund
Lill-Tove
LT
Bremnes
Roy M
RM
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
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; D008024:Ligands; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D042461:Vascular Endothelial Growth Factor A