title: Notch pathway activation is associated with pancreatic cancer treatment failure.
abstract: BACKGROUND
  Pancreatic cancer is resistant to conventional treatment. The aim of the study was to confirm the hypothesis that changes in cancer stem cells (CSCs) and developmental pathway after treatment was responsible for treatment failure in pancreatic cancer.
  
  
  METHODS
  After recovery from a gemcitabine treatment, the percentage of pancreatic cancer CSCs and Notch pathway in BxPC3 and HPAC pancreatic cancer cell lines were analyzed by FACS (CD24 and CD44) and western blot (Notch1, Hes1, β-catenin, and pAKT). The effect of DAPT, a gamma-secretase inhibitor, was similarly investigated. The association between immunohistochemical expression of Hes1 and survival was analyzed.
  
  
  RESULTS
  The percentage of CD24(+)CD44(+) cells was higher in gemcitabine-treated BxPC3 and HPAC cells than at pre-treatment. CD24(+)CD44(+) cells sorted from the gemcitabine-treated cell lines showed higher migration and invasion ability than CD24(-)CD44(-) or CD24(-)CD44(+) cells from the same cell lines. Western blot analysis showed an increased expression of Notch1 and Hes1 in gemcitabine-treated cell lines. The overall survival of pancreatic cancer patients with strong expression of Hes1 was shorter than that in patients with no or weak expression (11.1 vs. 21.6 months, P = 0.036). Treatment with DAPT reversed the increase in Hes1, β-catenin, and pAKT expression and the proportion of CD24(+)CD44(+) cells in gemcitabine-treated cell lines. The treatment also decreased migration and invasion ability.
  
  
  CONCLUSIONS
  Our data suggested that an increase in CSCs and activation of the Notch pathway might contribute to the failure of treatment in pancreatic cancer. Notch pathway can be a potential target to overcome treatment failure.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, College of Medicine Yonsei University, South Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, College of Medicine Yonsei University, South Korea; Brain Korea 21 Project for Medical Science, Seoul, South Korea.
authors.forename: Si Young
authors.initials: SY
authors.lastname: Song
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, College of Medicine Yonsei University, South Korea. Electronic address: sensass@yuhs.ac.
authors.forename: Jeong Youp
authors.initials: JY
authors.lastname: Park
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D051880:Receptors, Notch / Q000502:physiology*; D000072056:Transcription Factor HES-1; D017211:Treatment Failure; D000093542:Gemcitabine
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D003841:Deoxycytidine; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D000093542:Gemcitabine; C078493:HES1 protein, human
keywords: Cancer stem cell; Notch; Pancreatic cancer