gms | German Medical Science

126. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

28.04. - 01.05.2009, München

Tumor stem cell targeted therapy with mTOR Inhibitor RAD001 and hedgehog signaling inhibitor Cyclopamine reverts chemoresistance towards 5-Fluorouracil in human pancreatic carcinoma cells

Meeting Abstract

  • corresponding author I. Ischenko - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • A. Renner - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • H. Seeliger - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • A. Kleespies - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • J.W. Ellwart - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • P. Camaj - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • M.E. Eichhorn - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • K-W. Jauch - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern
  • C.J. Bruns - Chirurgische Klinik und Poliklinik der Ludwig-Maximilians-Universität München Großhadern

Deutsche Gesellschaft für Chirurgie. 126. Kongress der Deutschen Gesellschaft für Chirurgie. München, 28.04.-01.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. Doc09dgch10976

DOI: 10.3205/09dgch098, URN: urn:nbn:de:0183-09dgch0980

Veröffentlicht: 23. April 2009

© 2009 Ischenko et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Introduction: In the present study, we aimed to identify and to eliminate putative cancer stem cells (CSC) within different human pancreatic cancer cell lines as well as within 5-Fluorouracil-resistant pancreatic cancer cell lines established in our laboratory.

Material and methods: Pancreatic CSC were identified and characterized by flow cytometry, using Hoechst 33342 dye staining. CSC from 5-FU-resistant cell lines were isolated by high-speed flow cell sorting (MoFlo) and the CSC self-renewal pathways were further analyzed by RT-PCR and Western blotting. Isolated CSC within 5-FU-resistant cell lines were exposed to the cancer stem cell targeted therapeutics (RAD001, Cyclopamine) and stained for Propidium iodide and BrdU. Furthermore, isolated CSC as well as non-tumorigenic cancer cells within 5-FU-resistant cell lines were orthotopically xenografted in nude mice and the efficacy of stem-cell-targeted therapy in combination with 5-FU was investigated.

Results: Flow cytometry analysis revealed a significantly high amount of CSC in all chemotherapy-resistant cell lines. Combined 5-Fluorouracil IC50 and cancer stem cell targeted therapy resulted in the reduction of tumor cell proliferation independently on 5-FU–chemoresistance status, as detected by Propidium iodide and BrdU staining. In vivo the combination of 5-FU with cancer stem cell targeted therapeutics RAD001 or Cyclopamine significantly decreased the tumorigenic potential of CSC derived from 5-FU-resistant cell lines and dramatically reduced primary pancreatic tumor volume and weight.

Conclusion: Our results demonstrate that chemotherapy-resistant cancer cells contain the increased CSC population (as compared to their parental sensitive cells) that is highly resistant to standard chemotherapy but not towards CSC-targeted therapy in vitro and in vivo. The further characterization of such cells might therefore lead to the development of new molecular and pharmaceutical therapeutics and better anti-cancer strategies.