Targeting Tumor Stroma Using Engineered Mesenchymal Stem Cells Reduces the Growth of Pancreatic Carcinoma

作者：C Zischek, Hanno Nieß, Ivan Ischenko, Claudius Conrad, Ralf Huss, Karl-Walter Jauch, Peter J. Nelson, Christiane J. Bruns · 发表于：Annals of Surgery · 年份：2009 · DOI：10.1097/sla.0b013e3181bd62d0 · 被引用次数：159 · 研究领域：Mesenchymal stem cell research、Cancer Cells and Metastasis、Biological Research and Disease Studies

In Brief Objective: To analyze the efficacy of engineered mesenchymal stem cell based therapy directed towards pancreatic tumor stroma. Summary Background Data: Mesenchymal stem cells (MSC) are actively recruited to tumor stroma where they enhance tumor growth and metastases. Upregulation of chemotactic cytokine (CCL5) by MSCs within the tumor stroma has been shown to play a central role in this process. Murine MSCs were engineered to express reporter genes or therapeutic genes under control of the CCL5 promoter and adoptively transferred into mice with growing pancreatic tumors. The effect on tumor growth and metastases was then evaluated. Methods: MSCs isolated from bone marrow of C57/Bl6 p53−/− mice were stably transfected with red fluorescent protein (RFP), enhanced green fluorescent protein (eGFP), or herpes simplex virus (HSV) thymidine kinase (Tk) gene driven by the RANTES promoter. MSCs were intravenously applied once per week over 3 weeks to mice carrying an orthotopic, syngeneic pancreatic Panc02 tumor. Results: eGFP and RFP signals driven by the CCL5 promoter were detected by fluorescence in treated pancreatic tumor samples. The HSV-Tk therapy group treated intraperitoneal with the prodrug ganciclovir 5 to 7 days after stem cell application lead to a 50% reduction of primary pancreatic tumor growth (P < 0.0003, student t test) and reduced liver metastases (0% vs. 60%). Conclusion: The active homing of MSCs into primary pancreatic tumor stroma and activation of the ...