Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma

Abstract

Purpose: Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density. Experimental Design: Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated. Results: Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023). Conclusions: Shh and Gli1 are prognostic biomarkers for patients with resected PDAC. Clin Cancer Res; 21(5); 1215–24. ©2014 AACR.

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

“…6A). The increased expression of Gli1 has been reported to be clinically correlated with unfavorable overall prognosis in most solid malignancies (28,(30)(31)(32). We also determined whether Gli1 expression was associated with the clinical outcome of patients with osteosarcoma.…”

“…DGT inhibits osteosarcoma growth and metastasis through repression of the HH/Gli1 pathway The protein Gli1 functions as a downstream transcription factor of HH signaling and plays a pivotal role in cellular growth and metastasis of many types of tumors (27)(28)(29). However, the function of Gli1 in osteosarcoma remains unclear.…”

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

“…3,4 Over the last decade, a plethora of functions have been attributed to these components 3 giving rise to numerous reviews highlighting the growing interest in targeting this non-tumor compartment or its consequent impact on tumor development, maintenance or evolution. 5,6 Within this intra-tumor microenvironment compartment, non-cellular components such as extracellular matrix (ECM), to which both tumor cells and stroma contribute, are largely described and correlate with tumor aggressiveness and tumor cell abilities. 7,8 ECM proteins, such as hyaluronic acid, were shown to act as a barrier to perfusion because of compression of pancreatic tumor blood vessels limiting the amount of drug reaching the tumor cells.…”

GSH2 promoter methylation in pancreatic cancer analyzed by quantitative methylation-specific polymerase chain reaction

“…This may be due to the aberrant activation of Shh signaling commonly observed in pancreatic cancers (18). Furthermore, these data indicate that GSH2 promoter methylation may be used as a novel indicator of Shh activation, as well as a diagnostic tool for pancreatic cancer patients.…”