title: 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.
  
  
  CONCLUSIONS
  The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer.
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Ethan V
authors.initials: EV
authors.lastname: Abel
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jingjiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Hynes
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Filip
authors.initials: F
authors.lastname: Bednar
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Erica
authors.initials: E
authors.lastname: Proctor
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Lidong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Dziubinski
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America; Department Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America; Department Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000072056:Transcription Factor HES-1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D008024:Ligands; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human