Basic—Liver, Pancreas, and Biliary TractCombined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer
Section snippets
Human Pancreatic Cancer Cell Line
The highly metastatic human pancreatic cancer cell line L3.6pl was maintained as previously described.5 CSC spheres were cultured in Dulbecco's modified Eagle medium/F12 supplemented with B27 (Gibco, Karlsruhe, Germany) and FGF-2 (PeproTech EC, London, England).
Primary Human Pancreatic Cancer Cells
Human pancreatic tumors were obtained with written informed consent from all patients. Tissue fragments were minced and enzymatically digested with collagenase (Stem Cell Technologies, Vancouver, British Columbia, Canada) for 90 minutes
In Vitro Evaluation of Anti-CSC Agents
First we screened for potentially effective substances for targeted elimination of CD133+ pancreatic CSCs by means of flow cytometry following 48 hours of therapy.5 Consistent with previous reports, we observed a marked enrichment of CD133+ cells following gemcitabine therapy (Figure 1A).5 Because a gemcitabine concentration of 100 ng/mL was the lowest concentration capable of achieving a strong relative enrichment for CD133+ cells through depletion of CD133− cells and similar dosages have been
Discussion
Considering the still devastating prognosis of patients with pancreatic cancer,1 the development of novel therapeutic strategies is a prerequisite to eventually achieve better outcomes. Previous studies including our own were the first to show that pancreatic cancers contain a rare population of undifferentiated cells that are characterized by expression of CD133 or CD44/CD24,5, 14 are exclusively tumorigenic, and are highly resistant to chemotherapy.5, 9 Treatment of pancreatic cancer with the
Acknowledgments
The authors thank Ana Castillo, Sonia Alcalá, Aurora Garcia, Martin Luckner, Virginia Granda, and Karin Nispel for their excellent technical assistance. This report includes data generated during the doctoral thesis of M.-T.M. at the Medical School of the Ludwig-Maximilian-University Munich (manuscript in preparation).
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Conflicts of interest The authors disclose the following: Ludwig-Maximilian-University has filed a patent application for the use of the described treatment modality for epithelial cancer. The authors (M.-T.M., P.C.H., S.H., and C.H.) are inventors of this patent and may receive royalties from licensees. The remaining authors disclose no conflicts.
Funding Supported by the Dr Mildred Scheel Foundation (108168 to C.H.), Friedrich-Baur Foundation, ERC Advanced Investigator Grant (Pa-CSC 233460), and Ludwig-Maximilian University (research grant to M.-T.M.).