gms | German Medical Science

125. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

22. - 25.04.2008, Berlin

A novel targeted treatment to eliminate cancer stem cells in human pancreatic cancer

Meeting Abstract

  • S.L. Huber - Ludwig-Maximilians-Universität, Chirurgie
  • T.M. Müller - Ludwig-Maximilians-Universität, Chirurgie
  • P.C. Hermann - Ludwig-Maximilians-Universität, Chirurgie
  • T. Herrler - Ludwig-Maximilians-Universität, Chirurgie
  • J.M. Ellwart - Institut für of Molekulare Immunologie, Helmholtz Center for Environment and Health
  • C.J. Bruns - Ludwig-Maximilians-Universität, Chirurgie
  • corresponding author C. Heeschen - Ludwig-Maximilians-Universität, Chirurgie

Deutsche Gesellschaft für Chirurgie. 125. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 22.-25.04.2008. Düsseldorf: German Medical Science GMS Publishing House; 2008. Doc08dgch9229

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Veröffentlicht: 16. April 2008

© 2008 Huber et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen ( Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.



Introduction: Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. We have recently shown that human pancreatic cancer tissue contains cancer stem cells defined by CD133 expression which are exclusively tumorigenic and highly resistant to standard chemotherapy. The ultimate validation of the cancer stem cells hypothesis will depend on a demonstration that the successful targeting of the cancer stem cell population leads to better outcomes for patients with breast cancer. To first vigorously test the hypothesis in an experimental setting, we investigated novel treatment modalities to deplete the pool of cancer stem cells and subsequently eliminate the tumorigenic potential of the heterogeneous population of tumor cells.

Materials and methods: Bidirectional cellular communication is integral to both cancer progression and embryological development. In addition, aggressive cancer stem cells are phenotypically plastic, sharing many properties with embryonic cells. Owing to the similarities between these two types of cells and that Nodal is present in human metastatic tumors, but not in normal tissue, we investigated the role of Nodal signaling in human pancreatic cancer stem cells. Nodal, a member of the transforming growth factor ß family exerts its biological effects by signalling through its types I and II serine/threonine kinase receptor complex and intracellular Smad proteins. The type I receptors for Nodal are ALK 4 and ALK7.

Results: When pancreatic tumor spheres were treated with the ALK 4/5/7 inhibitor SB431542, a large proportion of human pancreatic tumor spheres dissociated and cells subsequently died suggesting that the clonogenic cancer stem cells had been significantly depleted. Consistent with this hypothesis, the stem-like fraction in pancreatic cancer marked by either CD133 staining or HOECHST staining (side population) was also significantly reduced by SB431542. In contrast, we found that gemcitabine treatment of pancreatic cancer cells dramatically increased the percentage of these stem-like cells, suggesting that this standard therapy preferentially targets more differentiated neoplastic cells. Most importantly, the combined treatment of the cells with SB431542 and gemcitabine reduced the number of cancer stem cells to undetectable levels. Ongoing experiments in athymic mice using pre-treated cells as well as in vivo treatment of established tumors will hopefully provide the final evidence that the tumor-initiating stem cell population critical for ongoing growth has indeed been removed.

Conclusion: Nodal inhibition promotes the differentiation of pancreatic cancer cells towards a more differentiated phenotype and, subsequently, allows their elimination by standard chemotherapy. These data suggest that Nodal signaling has a key role in pancreatic stem cell plasticity and tumorigenicity, thereby providing a previously unknown molecular target in human pancreatic cancer stem cells. Further investigations of this promising approach may eventually lead to the development of new therapeutic regimens to improve the devastating prognosis of patients with pancreatic cancer.