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dc.contributor.authorMohr, Andrea
dc.contributor.authorAlbarenque, Stella Maris
dc.contributor.authorDeedigan, Laura
dc.contributor.authorYu, Rui
dc.contributor.authorReidy, Mairead
dc.contributor.authorFulda, Simone
dc.contributor.authorZwacka, Ralf Michael
dc.date.accessioned2018-09-20T16:18:02Z
dc.date.available2018-09-20T16:18:02Z
dc.date.issued2010-11-01
dc.identifier.citationMohr, Andrea; Albarenque, Stella Maris; Deedigan, Laura; Yu, Rui; Reidy, Mairead; Fulda, Simone; Zwacka, Ralf Michael (2010). Targeting of xiap combined with systemic mesenchymal stem cell-mediated delivery of strail ligand inhibits metastatic growth of pancreatic carcinoma cells. STEM CELLS 28 (11), 2109-2120
dc.identifier.issn1066-5099
dc.identifier.urihttp://hdl.handle.net/10379/12927
dc.description.abstractDisseminating tumors are one of the gravest medical problems. Here, we combine the tumor-specific apoptosis-inducing activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with the ability of mesenchymal stem cells (MSCs) to infiltrate both tumor and lymphatic tissues to target primary tumors as well as disseminated cancer cells in a human pancreatic cancer mouse model. Furthermore, we targeted X-linked inhibitor of apoptosis protein (XIAP) by RNA interference (RNAi) inside the cancer cells to make use of the apoptosis sensitization as well the antimetastatic effect that is afforded by XIAP silencing. We generated MSCs, termed MSC.sTRAIL, that express and secrete a trimeric form of soluble TRAIL (sTRAIL). MSC.sTRAIL triggered limited apoptosis in human pancreatic carcinoma cells that were resistant to soluble recombinant TRAIL, which is most likely due to the enhanced effect of the direct, cell-mediated delivery of trimeric TRAIL. MSC.sTRAIL-mediated cell death was markedly increased by concomitant knockdown of XIAP by RNAi in the cancer cells. These findings were confirmed in xenograft models, in which tumors from the parental pancreatic carcinoma cells showed only growth retardation on treatment with MSC.sTRAIL, whereas tumors with silenced XIAP that were treated with MSC.sTRAIL went into remission. Moreover, animals with XIAP-negative xenografts treated with MSC.sTRAIL were almost free of lung metastasis, whereas animals treated with control MSCs showed substantial metastatic growth in the lungs. In summary, this is the first demonstration that a combined approach using systemic MSC-mediated delivery of sTRAIL together with XIAP inhibition suppresses metastatic growth of pancreatic carcinoma. STEM CELLS 2010;28:2109-2120
dc.publisherWiley-Blackwell
dc.relation.ispartofSTEM CELLS
dc.subjectmscs
dc.subjecttrail
dc.subjectxiap
dc.subjectpancreatic cancer
dc.subjectmetastasis
dc.subjecttrail-induced apoptosis
dc.subjectcolorectal-cancer cells
dc.subjectbone-marrow
dc.subjectgene-therapy
dc.subjectantitumor-activity
dc.subjecttrimeric trail
dc.subjectlung-cancer
dc.subjectin-vitro
dc.subjectantibody
dc.subjectsafety
dc.titleTargeting of xiap combined with systemic mesenchymal stem cell-mediated delivery of strail ligand inhibits metastatic growth of pancreatic carcinoma cells
dc.typeArticle
dc.identifier.doi10.1002/stem.533
dc.local.publishedsourcehttp://onlinelibrary.wiley.com/doi/10.1002/stem.533/pdf
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