Abstract
Aberrant activation of the transcription factor GLI1, a central effector of the Hedgehog (HH) pathway, is associated with several malignancies, including pancreatic ductal adenocarcinoma (PDAC), one of most deadly human cancers. GLI1 has been described as an oncogene in PDAC, making it a promising target for drug therapy. Surprisingly, clinical trials targeting HH/GLI1 axis in advanced PDAC were unsuccessful, leaving investigators questioning the mechanism behind these failures. Recent evidence suggests the loss of GLI1 in the later stages of PDAC may actually accelerate disease. This indicates GLI1 may play a dual role in PDAC, acting as an oncogene in the early stages of disease and a tumor-suppressor in the late stages.
Highlights
The protein GLI1, originally isolated in 1987 due to high levels of amplification in malignant glioma (Kinzler et al, 1987), is a member of the GLI family of transcription factors
There is overwhelming evidence that GLI1 plays an important role in tumor initiation and progression of several kinds of malignancies, these results suggest the transcription factor may have a tumor protective role in the later stages of certain cancers
Based on work from Fendrich et al on HH signaling and acinar cell differentiation, it might even be provocatively proclaimed that increasing GLI1 levels could drive terminal differentiation and result in lower tumorigenicity (Fendrich et al, 2008). These studies demonstrating GLI1 may act as a tumor suppressor in the late stage of pancreatic ductal adenocarcinoma (PDAC) give insight into the disappointing results of clinical trials testing HH inhibitors in metastatic PDAC patients
Summary
The protein GLI1, originally isolated in 1987 due to high levels of amplification in malignant glioma (Kinzler et al, 1987), is a member of the GLI family of transcription factors. Increased IL-6 expression in the stromal compartment induces activation of STAT3 in the neighboring cancer cells, an essential molecular event for the progression of premalignant lesions in PDAC (Figure 1).
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