title: Delivery of improved oncolytic adenoviruses by mesenchymal stromal cells for elimination of tumorigenic pancreatic cancer cells.
abstract: 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.
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Kaczorowski
authors.affiliation: Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hammer
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Villhauer
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Clifford
authors.initials: C
authors.lastname: Nwaeburu
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Pei
authors.initials: P
authors.lastname: Fan
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Zhefu
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jury
authors.initials: J
authors.lastname: Gladkich
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Groß
authors.affiliation: Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
authors.affiliation: Surgical Research Section, Molecular OncoSurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D036022:Capsid Proteins / Q000302:isolation & purification; D021441:Carcinoma, Pancreatic Ductal / Q000628:therapy*; D053148:Caspase 3 / Q000378:metabolism; D002642:Chick Embryo; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000628:therapy*; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051927:CD24 Antigen; C497889:CD24 protein, human; D036022:Capsid Proteins; D019394:Ki-67 Antigen; D053148:Caspase 3
keywords: TRAIL; virus therapy
references.citation: Mol Ther. 2013 Jun;21(6):1212-23
references.pmid: 23546299
references.citation: Nat Biotechnol. 2000 Jul;18(7):723-7
references.pmid: 10888838
references.citation: Mol Ther. 2009 Oct;17(10):1667-76
references.pmid: 19690519
references.citation: Oncotarget. 2014 Mar 30;5(6):1621-34
references.pmid: 24742583
references.citation: Cytotherapy. 2005;7(6):509-19
references.pmid: 16306013
references.citation: Adv Virol. 2012;2012:805629
references.pmid: 22400027
references.citation: J Clin Oncol. 2007 Apr 10;25(11):1390-5
references.pmid: 17416859
references.citation: Gene Ther. 2011 Aug;18(8):765-77
references.pmid: 21412282
references.citation: Cancer Gene Ther. 2010 Jul;17(7):476-83
references.pmid: 20168350
references.citation: Oncoimmunology. 2014 Jun 01;3:e28694
references.pmid: 25097804
references.citation: Clin Cancer Res. 2010 Jan 15;16(2):541-53
references.pmid: 20068104
references.citation: Pancreatology. 2004;4(6):567-86
references.pmid: 15550766
references.citation: Cancer Gene Ther. 2008 Apr;15(4):231-40
references.pmid: 18202717
references.citation: J Transl Med. 2013 Jan 24;11:20
references.pmid: 23347343
references.citation: Oncolytic Virother. 2014 Feb;2014(3):21-33
references.pmid: 24834430
references.citation: Stem Cells. 2008 Mar;26(3):831-41
references.pmid: 18192232
references.citation: Hum Gene Ther. 2007 Jul;18(7):627-41
references.pmid: 17604566
references.citation: Clin Cancer Res. 2015 Mar 15;21(6):1406-18
references.pmid: 25391696
references.citation: Clin Cancer Res. 2013 May 15;19(10):2734-44
references.pmid: 23493351
references.citation: Gynecol Oncol. 2013 Sep;130(3):518-24
references.pmid: 23756180
references.citation: Mol Ther. 2007 Dec;15(12):2088-93
references.pmid: 17848962
references.citation: Cancer Gene Ther. 2006 Sep;13(9):830-44
references.pmid: 16439993
references.citation: Endocr Relat Cancer. 2013 Aug 23;20(5):R269-90
references.pmid: 23975882
references.citation: Mol Cancer. 2011 Nov 03;10:134
references.pmid: 22054049
references.citation: Br J Cancer. 2008 Aug 19;99(4):622-31
references.pmid: 18665180
references.citation: Nat Clin Pract Oncol. 2007 Feb;4(2):101-17
references.pmid: 17259931
references.citation: Mol Ther. 2010 Feb;18(2):243-50
references.pmid: 19935777
references.citation: Cancer Gene Ther. 2009 Jun;16(6):473-88
references.pmid: 19197323
references.citation: JOP. 2011 Mar 09;12(2):96-100
references.pmid: 21386629
references.citation: Cancer Gene Ther. 2010 Apr;17(4):289-97
references.pmid: 19876078
references.citation: Science. 2009 Jun 12;324(5933):1457-61
references.pmid: 19460966
references.citation: J Virol. 1987 Feb;61(2):426-35
references.pmid: 2949088
references.citation: J Surg Res. 2012 Jan;172(1):29-39
references.pmid: 21683373
references.citation: Hum Gene Ther. 2012 Jun;23(6):589-96
references.pmid: 22136065
references.citation: Int J Cancer. 2015 Oct 1;137(7):1775-83
references.pmid: 25821063
references.citation: Int J Cancer. 2015 Aug 15;137(4):978-90
references.pmid: 25604186
references.citation: Blood. 2014 Feb 27;123(9):1327-35
references.pmid: 24345754
references.citation: BMC Cancer. 2011 Jun 13;11:241
references.pmid: 21668953
references.citation: ALTEX. 2015;32(2):143-7
references.pmid: 25592390
references.citation: Oncotarget. 2015 Apr 30;6(12):9999-10015
references.pmid: 25846752
references.citation: Clin Cancer Res. 2002 Nov;8(11):3348-59
references.pmid: 12429621
references.citation: Int J Cancer. 2014 Aug 1;135(3):720-30
references.pmid: 24374597
references.citation: Stem Cells. 2011 Jun;29(6):883-7
references.pmid: 21509907
references.citation: Trends Mol Med. 2013 Nov;19(11):685-94
references.pmid: 24076237
references.citation: Exp Cell Res. 2009 Feb 1;315(3):498-507
references.pmid: 19084517
references.citation: PLoS One. 2009;4(4):e4992
references.pmid: 19352430
references.citation: Mol Ther. 2007 Sep;15(9):1607-15
references.pmid: 17579575
references.citation: Nature. 2006 Aug 17;442(7104):742-3
references.pmid: 16915262
references.citation: Anticancer Drugs. 2003 Sep;14(8):577-84
references.pmid: 14501378