Notch Signaling in Non Small Cell Lung Cancers (NSCLC) Is Associated with Squamous Differentiation and Favorable Clinical Outcome
L Li, CE Sheehan, JS Ross. Albany Medical College, Albany, NY
Background: Notch protein signaling via a complex network of transmembrane receptors, ligands and effectors plays a major role in the development, differentiation and growth control of human respiratory epithelia. Clinical outcome studies of Notch expression in NSCLC have not been previously performed.
Design: Formalin-fixed, paraffin embedded sections from 134 NSCLC, including 47 squamous cell carcinomas (SCC), 50 adenocarcinomas (AC), and 30 bronchioloalveolar carcinomas (BAC) were immunostained by automated methods (Ventana, Tucson, AZ) with polyclonal antibodies to Notch1, Notch2, Notch3 and Notch4 (Santa Cruz Biotech., Santa Cruz, CA). Cytoplasmic (C) and nuclear (N) immunoreactivity of each protein was semiquantitatively assessed for all cases. Scoring was based on staining intensity (weak, moderate, intense) and percentage of positive cells (focal <= 10%, regional 11-50%, diffuse >50%). Results were correlated with clinicopathologic variables.
Results: C+N Notch1 overexpression was greatest in SCC (38%) vs AC (16%) and BAC [16%] (p<0.0001). NSCLC N Notch1 overexpression correlated with lengthened survival overall [p=0.02] and low grade [p=0.05] and low stage [p=0.03] in SCC. C+N Notch2 overexpression correlated with low stage [p=0.038] in SCC and small tumor size [p=0.005] within AC. NSCLC C Notch 2 overexpression correlated with low stage (p=0.05); SCC tumor type (p=0.05), low stage in SCC (p=0.038) and small tumor size in AC (p=0.02). NSCLC C Notch3 overexpression correlated with lengthened survival (p=0.002), survival in SCC (p=0.016) and BAC (p=0.036), and tumor size in AC (p=0.007). NSCLC C+N Notch4 immunoreactivity was greatest in SCC [33%] vs AC [8%] and BAC [16%] (p=0.008) and correlated with small tumor size (p=0.02) overall and in SCC (p=0.016) and AC (p=0.05); with male gender (p=0.05) in SCC and lengthened survival within the BAC (p=0.016). N Notch4 overexpression correlated with SCC tumor type (p<0.0001), small tumor size (p=0.05), male gender (p=0.04) overall and in the SCC. Notch1 coexpression was significant with Notch3 (p=0.011) and Notch4 (p<0.0001), as well as Notch3 with Notch4 (p=0.002). On multivariate analysis, stage was the only independent predictor of survival.
Conclusions: NSCLC Notch protein expression is variable and associated with squamous differentiation, early pathologic stage and lengthened survival. The potential oncogenic roles for Notch proteins in NSCLC as prognostic factors and targets of therapy warrant further study.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 243, Tuesday Afternoon