Targeted Oncology

, Volume 10, Issue 2, pp 215–227

Side population cells of pancreatic cancer show characteristics of cancer stem cells responsible for resistance and metastasis

  • Hanno Niess
  • Peter Camaj
  • Andrea Renner
  • Ivan Ischenko
  • Yue Zhao
  • Stefan Krebs
  • Josef Mysliwietz
  • Carsten Jäckel
  • Peter J. Nelson
  • Helmut Blum
  • Karl-Walter Jauch
  • Joachim W. Ellwart
  • Christiane J. Bruns
Original Research

Abstract

Cancer stem cells (CSCs) have been proposed to underlie the initiation and maintenance of tumor growth and the development of chemoresistance in solid tumors. The identification and role of these important cells in pancreatic cancer remains controversial. Here, we isolate side population (SP) cells from the highly aggressive and metastatic human pancreatic cancer cell line L3.6pl and evaluate their potential role as models for CSCs. SP cells were isolated following Hoechst 33342 staining of L3.6pl cells. SP, non-SP, and unsorted L3.6pl cells were orthotopically xenografted into the pancreas of nude mice and tumor growth observed. RNA was analyzed by whole genome array and pathway mapping was performed. Drug resistant variants of L3.6pl were developed and examined for SP proportions and evaluated for surface expression of known CSC markers. A distinct SP with the ability to self-renew and differentiate into non-SP cells was isolated from L3.6pl (0.9 % ± 0.22). SP cells showed highly tumorigenic and metastatic characteristics after orthotopic injection. Transcriptomic analysis identified modulation of gene networks linked to tumorigenesis, differentiation, and metastasization in SP cells relative to non-SP cells. Wnt, NOTCH, and EGFR signaling pathways associated with tumor stem cells were altered in SP cells. When cultured with increasing concentrations of gemcitabine, the proportion of SP cells, ABCG2+, and CD24+ cells were significantly enriched, whereas 5-fluorouracil (5-FU) treatment lowered the percentage of SP cells. SP cells were distinct from cells positive for previously postulated pancreatic CSC markers. The Hoechst-induced side population in L3.6pl cells comprises a subset of tumor cells displaying aggressive growth and metastasization, increased gemcitabine-, but not 5-FU resistance. The cells may act as a partial model for CSC biology.

Keywords

Pancreatic cancer Cancer stem cells Tumor-initiating cells Side-population Chemotherapy resistance ABCG2 Pathway mapping Aldoketoreductase family 1 B10 

Supplementary material

11523_2014_323_MOESM1_ESM.pdf (697 kb)
ESM 1(PDF 696 kb)

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Hanno Niess
    • 1
  • Peter Camaj
    • 5
  • Andrea Renner
    • 1
  • Ivan Ischenko
    • 1
  • Yue Zhao
    • 5
  • Stefan Krebs
    • 2
  • Josef Mysliwietz
    • 3
  • Carsten Jäckel
    • 4
  • Peter J. Nelson
    • 4
  • Helmut Blum
    • 2
  • Karl-Walter Jauch
    • 1
  • Joachim W. Ellwart
    • 3
  • Christiane J. Bruns
    • 5
  1. 1.Department of SurgeryUniversity of MunichMunichGermany
  2. 2.Laboratory for Functional Genome AnalysisUniversity of MunichMunichGermany
  3. 3.Institute of Molecular ImmunologyHelmholtz Center for Environment and HealthMunichGermany
  4. 4.Medizinische Klinik und Poliklinik IVUniversity of MunichMunichGermany
  5. 5.Department of SurgeryOtto-von-Guericke-UniversityMagdeburgGermany

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