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Pancreatology. 2014 Jan-Feb;14(1):48-53. doi: 10.1016/j.pan.2013.11.011. Epub 2013 Nov 28.

Notch pathway activation is associated with pancreatic cancer treatment failure.

Author information

  • 1Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, College of Medicine Yonsei University, South Korea.
  • 2Division 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.
  • 3Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, College of Medicine Yonsei University, South Korea. Electronic address: sensass@yuhs.ac.

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.

CONCLUSION:

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.

Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Cancer stem cell; Notch; Pancreatic cancer

PMID:
24555978
[PubMed - in process]
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