The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer.

Abstract

BACKGROUND:

Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized.

METHODS:

Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth.

RESULTS:

Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population.

CONCLUSION:

The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.

• Authors: Ethan V Abel, Edward J Kim, Jingjiang Wu, Mark Hynes, Filip Bednar, Erica Proctor, Lidong Wang, Michele L Dziubinski, Diane M Simeone
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e91983 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24647545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Homeodomain Proteins
• Ligands
• Protease Inhibitors
• RNA, Small Interfering
• Receptors, Notch
• Transcription Factor HES-1
• HES1 protein, human

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Disease Models, Animal
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Ligands
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Protease Inhibitors (pharmacology)
• RNA, Small Interfering (metabolism)
• Receptors, Notch (metabolism)
• Signal Transduction (drug effects)
• Spheroids, Cellular (drug effects, metabolism, pathology)
• Transcription Factor HES-1
• Tumor Cells, Cultured
• Up-Regulation (drug effects)
• Pancreatic Neoplasms