Authors
Kelleher, Fergal CAffiliation
Department of Medical Oncology, St Vincent's University Hospital, Dublin,, Ireland. fergalkelleher@hotmail.comIssue Date
2012-02-01T10:32:29ZMeSH
Adenocarcinoma/etiologyAnilides/therapeutic use
Animals
Clinical Trials as Topic
Hedgehog Proteins/antagonists & inhibitors/chemistry/*physiology
Humans
Neoplastic Stem Cells/drug effects/physiology
Pancreatic Neoplasms/drug therapy/*etiology
Pyridines/therapeutic use
Signal Transduction/*physiology
Metadata
Show full item recordCitation
Carcinogenesis. 2011 Apr;32(4):445-51. Epub 2010 Dec 24.Journal
CarcinogenesisDOI
10.1093/carcin/bgq280PubMed ID
21186299Abstract
OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.Language
engISSN
1460-2180 (Electronic)0143-3334 (Linking)
ae974a485f413a2113503eed53cd6c53
10.1093/carcin/bgq280
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