Expression of the Hedgehog Family of Proteins in Prostatic Adenocarcinomas (PACS): Hedgehog Signaling Is Associated with High Grade, Advanced Stage and Biochemical Disease Recurrence.
Bhaskar VS Kallakury, Gregory M Sheehan, Christine E Sheehan, Hugh AG Fisher, Ronald P Kaufman, Tipu Nazeer, Jeffrey S Ross. Georgetown Univ Hospital, Washington, DC; Albany Medical College, NY
Background: The hedgehog signaling pathway plays an important role in cell proliferation, differentiation, stem cell maintenance and tissue regeneration. This pathway is also implicated in carcinogenesis and in promoting tumor cell growth of several cancers including those arising from skin, liver, brain, pancreas, breast, colon, soft tissue and bladder. The role of HH pathway in prostate carcinogenesis is contradictory; a mouse model study shows no evidence of its involvement in tumor development while a human tissue study demonstrates expression of HH ligands at different stages of prostate cancer development. In this study, we report the prognostic significance of HH signaling in human PACs.
Design: Formalin-fixed, paraffin embedded sections from 138 PACs were immunostained by automated methods (Ventana) with goat polyclonal Shh, Dhh, Smo, and GLI-1 and rabbit polyclonal patched (Santa Cruz) antibodies. Cytoplasmic and/or nuclear immunoreactivity was scored for intensity and percentage of positive cells in both tumor and adjacent benign epithelium. Cases were assessed as tumor = benign (T = B), tumor > benign (T > B) and tumor < benign (T < B). Results were correlated with clinicopathologic variables.
Results: Tumor immunoreactivity was predominantly cytoplasmic for all proteins. Cytoplasmic protein expression was noted as: Shh [T = B 62%, T > B 38%, T < B 0%]; Dhh [T = B 73%, T > B 24%, T < B 3%]; patched [T = B 34%, T > B 66%]; GLI-1 [T = B 72%, T > B 27%, T < B 1%], and Smo [T = B 84%, T > B 10%, T < B 6%]. Increased Shh and GLI-1 expression each correlated with high grade [p < 0.0001; p = 0.004], advanced stage [p = 0.007; p = 0.005], and biochemical disease recurrence [p = 0.046, p = 0.038], respectively. Increased Dhh expression correlated with high grade [p < 0.0001] and biochemical disease recurrence [p = 0.044]. Increased patched expression correlated with high grade [p < 0.0001] and advanced stage [p = 0.006]. Increased Smo expression correlated with advanced stage [p = 0.042]. On multivariate analysis, increased Shh expression (p = 0.029) independently predicted biochemical disease recurrence.
Conclusions: The hedgehog signaling pathway appears to play an important role in prostate carcinogenesis with increased expression of this family of proteins correlating with adverse prognostic variables, warranting further studies of this pathway as a therapeutic target in the management of patients with prostate cancer.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 1:00 PM
Poster Session II # 160, Monday Afternoon