Delivery of improved oncolytic adenoviruses by mesenchymal stromal cells for elimination of tumorigenic pancreatic cancer cells
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Adam Kaczorowski1, Katharina Hammer2, Li Liu1, Sabine Villhauer1, Clifford Nwaeburu1, Pei Fan1, Zhefu Zhao1, Jury Gladkich1, Wolfgang Groß1, Dirk M. Nettelbeck2, Ingrid Herr1
1Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
2Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
Ingrid Herr, e-mail: [email protected]
Keywords: TRAIL, virus therapy
Received: October 05, 2015 Accepted: January 15, 2016 Published: January 27, 2016
Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies and has poor therapeutic options. We evaluated improved oncolytic adenoviruses (OAds), in which the adenoviral gene E1B19K was deleted or a TRAIL transgene was inserted. Bone marrow mesenchymal stromal cells (MSCs) served as carriers for protected and tumor-specific virus transfers. The infection competence, tumor migration, and oncolysis were measured in cancer stem cell (CSC) models of primary and established tumor cells and in tumor xenografts. All OAds infected and lysed CSCs and prevented colony formation. MSCs migrated into PDA spheroids without impaired homing capacity. Xenotransplantation of non-infected PDA cells mixed with infected tumor cells strongly reduced the tumor volume and the expression of the proliferation marker Ki67 along with a necrotic morphology. Adenoviral capsid protein was detected in tumor xenograft tissue after intravenous injection of infected MSCs, but not in normal tissue, implying tumor-specific migration. Likewise, direct in vivo treatment correlated with a strongly reduced tumor volume, lower expression of Ki67 and CD24, and enhanced activity of caspase 3. These data demonstrate that the improved OAds induced efficient oncolysis with the OAd-TRAIL as most promising candidate for future clinical application.
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