KA Robstad, JD Choate, MN Donovan, MA DiMaio, CE Sheehan and JS Ross
Department of Pathology, Albany Medical College, Albany, NY
Background: Notch signaling is believed to play a crucial role in cell differentiation, proliferation and survival. Dysregulation of Notch signaling has been reported in a wide variety of human malignancies including breast, cervical, CNS, lung, and pancreatic cancer as well as melanoma and certain leukemias. There is recent evidence that Notch signaling contributes to the natural progression of CRC. However, the prognostic significance of Notch-1 expression in CRC has not been previously investigated.
Design: Formalin-fixed, paraffin-embedded sections from 125 colorectal adenocarcinomas (CRCs) were immunostained by an automated method (Ventana Medical Systems; Tucson, AZ) using polyclonal Notch-1 antibody (sc-6014; Santa Cruz Biotechnology, Santa Cruz, CA). Cytoplasmic immunoreactivity was semiquantitatively evaluated based on both intensity and distribution and results were correlated with histologic and prognostic variables.
Result: Intense, diffuse overexpression of Notch-1 was observed in 45% (57/125) of CRC cases and correlated significantly with increasing AJCC stage (24% of stage I, 58% of stage II, 35% of stage III, and 66% of stage IV; p=0.041); histologic grade (11% of grade 1; 52% of grade 2, and 50% of grade 3; p=0.006), and overall survival (27% in those alive, 53% in those expired; p=0.011). On multivariate analysis, only pathologic stage was an independent predictor of overall survival.
Conclusion: Notch-1 overexpression is associated with tumor aggressiveness in CRC and significantly correlates with increasing tumor grade, pathologic stage and overall survival. Notch 1 overexpression may be a valuable prognostic indicator that can be used to plan therapy in CRC. Further study of Notch-1 expression in CRC management and targeted therapy development appears warranted.