Gli-1 is a critical component of the Hedgehog (Hh) signalling pathway that is essential for morphogenesis and stem cell renewal and is dysregulated in many cancer types including basal cell carcinoma, medulloblastoma, prostate, pancreatic and breast cancers. Currently, no data are available on the role of Gli-1 expression in esophageal cancer progression. Here, we analyzed whether Gli-1 expression could predict disease progression and prognosis in esophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Gli-1 expression was evaluated in 69 patients with histologically confirmed esophageal squamous carcinomas (ESCC) undergoing preoperative CRT, by immunohistochemical staining. 25 out of 69 ESCC patients showed a pathological CR after CRT. Gli-1 expression was detected in the nucleus for 5 tumors as (+)-(++) (7.2%) and 2 as (±)(2.9%), and in the cytoplasm for 26 (37.7%), and was absent from the 12 remaining tumors (17.4%). Overall survival (OS) was significantly associated with lymph node metastasis (P<0.005), distant metastasis (P<0.0005) and CRT (P<0.0001) and further correlated with an absence of Gli-1 nuclear expression or no residual tumor (P=0.001). Patients with Gli-1-nuclear positive cancer showed significantly poorer prognosis than those without it (OS; Median Survival Time 386 vs 1742 months, 2-yr OS 16.7% vs 54.9%, P=0.001, Disease-Free Survival; MST 250 vs 1738 months, 2-yr DFS 0% vs 54.9%, P=0.009, log-rank test). In particular, even those with Gli-1 (±) expression after CRT died in a few months. Our study provides the first evidence that Hh pathway activation is a strong and independent predictor of early relapse and poor prognosis in ESCC after CRT. These results suggest that Hh signal activation may promote cancer regrowth and progression after CRT and that future research focused on cancer progenitor cells via Hh signalling cascade might improve treatment response resistant to traditional therapy, thereby prevent disease relapse, and enhance patient survival.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA