Pancreatic cancer cells resistant to chemoradiotherapy rich in "stem-cell-like" tumor cells

Dig Dis Sci. 2011 Mar;56(3):741-50. doi: 10.1007/s10620-010-1340-0. Epub 2010 Aug 4.

Abstract

Background: Tumor resistance to chemoradiation therapy is partly attributed to the presence of apoptosis-resistant cancer stem cells (CSCs). Chemoradiation therapy can enrich CSCs by killing apoptosis-susceptible cancer cells.

Aim: Our preliminary study showed chemoradiation-resistant pancreatic cancer cells to have some CSC characteristics, and to undergo epithelial-mesenchymal transition (EMT); we aimed to verify that study's implication that chemoradiation-resistant subpopulations are enriched with "stem-cell-like" tumor cells, which may be linked to EMT.

Methods: Four pancreatic cancer cell lines were cultured in gemcitabine with synchronous radiotherapy to obtain resistant subpopulations. Morphological changes were observed under microscope; migration and invasiveness were assessed by Transwell tests. Protein expression was determined by immunoblotting. Pancreatic CSC markers were studied using fluorescence-activated cell sorting analyses. Colony-formation tests, tumor sphere formation assays, and tumor xenografts in BALB/C nude mice were used to evaluate "stemness" in resistant cells.

Results: Resistant cells expressed more antiapoptotic protein Bcl-2, apoptosis-inhibitory protein survivin, and stem cell markers Oct4, ABCG2, CD24, and CD133, were more tumorigenic in vitro and in vivo, and showed phenotypic and molecular changes consistent with EMT, including upregulation of vimentin and downregulation of E-cadherin. They were also more invasive and migratory.

Conclusions: We found chemoradiation-resistant pancreatic cancer cells to be similar to CSCs and to undergo EMT, suggesting that chemoradiation resistance-induced EMT is linked to CSC generation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antigens, CD
  • CD24 Antigen / metabolism
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm*
  • Epithelial-Mesenchymal Transition
  • Glycoproteins
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology*
  • Neoplastic Stem Cells / radiation effects
  • Octamer Transcription Factor-3 / metabolism
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / radiotherapy
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Radiation Tolerance*
  • Survivin
  • Vimentin / metabolism

Substances

  • ABCG2 protein, human
  • AC133 Antigen
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antigens, CD
  • BIRC5 protein, human
  • CD24 Antigen
  • CD24 protein, human
  • Cadherins
  • Glycoproteins
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Survivin
  • Vimentin
  • Deoxycytidine
  • gemcitabine