Hedgehog signaling and therapeutics in pancreatic cancer.

Hdl Handle:
http://hdl.handle.net/10147/207599
Title:
Hedgehog signaling and therapeutics in pancreatic cancer.
Authors:
Kelleher, Fergal C
Affiliation:
Department of Medical Oncology, St Vincent's University Hospital, Dublin,, Ireland. fergalkelleher@hotmail.com
Citation:
Carcinogenesis. 2011 Apr;32(4):445-51. Epub 2010 Dec 24.
Journal:
Carcinogenesis
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207599
DOI:
10.1093/carcin/bgq280
PubMed ID:
21186299
Abstract:
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:
eng
MeSH:
Adenocarcinoma/etiology; Anilides/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
ISSN:
1460-2180 (Electronic); 0143-3334 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorKelleher, Fergal Cen_GB
dc.date.accessioned2012-02-01T10:32:29Z-
dc.date.available2012-02-01T10:32:29Z-
dc.date.issued2012-02-01T10:32:29Z-
dc.identifier.citationCarcinogenesis. 2011 Apr;32(4):445-51. Epub 2010 Dec 24.en_GB
dc.identifier.issn1460-2180 (Electronic)en_GB
dc.identifier.issn0143-3334 (Linking)en_GB
dc.identifier.pmid21186299en_GB
dc.identifier.doi10.1093/carcin/bgq280en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207599-
dc.description.abstractOBJECTIVE: 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.en_GB
dc.language.isoengen_GB
dc.subject.meshAdenocarcinoma/etiologyen_GB
dc.subject.meshAnilides/therapeutic useen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshClinical Trials as Topicen_GB
dc.subject.meshHedgehog Proteins/antagonists & inhibitors/chemistry/*physiologyen_GB
dc.subject.meshHumansen_GB
dc.subject.meshNeoplastic Stem Cells/drug effects/physiologyen_GB
dc.subject.meshPancreatic Neoplasms/drug therapy/*etiologyen_GB
dc.subject.meshPyridines/therapeutic useen_GB
dc.subject.meshSignal Transduction/*physiologyen_GB
dc.titleHedgehog signaling and therapeutics in pancreatic cancer.en_GB
dc.contributor.departmentDepartment of Medical Oncology, St Vincent's University Hospital, Dublin,, Ireland. fergalkelleher@hotmail.comen_GB
dc.identifier.journalCarcinogenesisen_GB
dc.description.provinceLeinster-

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