Hedgehog Pathway Proteins Glioma-Associated Oncogene-1 (GLI-1) and Smoothened (Smo) Expression in Colorectal Cancer (CRC)
Osama Elkadi, Dion Middleton, Mary Barrett, David M Jones, Christine E Sheehan, Jeffrey S Ross. Albany Medical College, Albany, NY
Background: The Hedgehog (Hh) signaling pathway is involved in the normal organ development during embryogenesis and been implicated in the development of numerous pediatric and adult malignancies. The recent approval of the hedgehog pathway inhibitor vismodegib for basal cell skin cancer has prompted keen interest in finding additional indications for this drug in other tumor types such as CRC.
Design: Formalin-fixed, paraffin embedded sections from 156 colorectal adenocarcinomas (CRCs) were immunostained by automated methods (Ventana Medical Systems, Inc, Tucson, AZ) with goat polyclonal GLI-1 and Smo antibodies (Santa Cruz Biotechnology, Inc, Santa Cruz, CA). Nuclear and cytoplasmic immunoreactivity for each protein was semiquantitatively assessed in the tumor for all cases. Scoring was based on staining intensity and distribution and results were correlated with morphologic and prognostic variables.
Results: Nuclear GLI-1 overexpression was noted in 42% tumors and correlated with early AJCC stage (51% of stage I/II and 33% stage III/IV; p=0.025), negative lymph node status (56% of node negative and 30% of node positive, p=0.001), and lengthened overall survival (Cox univariate, p=0.049). Cytoplasmic GLI-1 overexpression was noted in 64% tumors, but there were no significant correlations. Nuclear Smo overexpression was noted in 79% tumors and correlated with high tumor grade (88% of grade 3 vs 78% grade 2 vs 56% grade 1, p=0.017). Cytoplasmic Smo overexpression was noted in 43% tumors, but there were no significant correlations other than with nuclear Smo immunoreactivity (p=0.001) in the same case. On multivariate analysis, pathologic stage (p<0.0001) independently predicted overall survival.
Conclusions: Nuclear GLI-1 protein expression in CRC is associated with favorable prognostic variables, including early stage, negative node status, and lengthened overall survival; while increased nuclear Smo protein expression is associated with high tumor grade. We conclude that hedgehog pathway signaling may play a role in CRC development and progression warranting further study.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 94, Monday Morning