title: Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34(+) cells.
abstract: The proapoptotic death receptor 5 (DR5) expressed by tumor associated endothelial cells (TECs) mediates vascular disrupting effects of human CD34(+) cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL (+) cells) in mice. Indeed, lack of DR5 on TECs causes resistance to CD34-TRAIL (+) cells. By xenografting in nonobese diabetic/severe combined immunodeficient mice the TRAIL-resistant lymphoma cell line SU-DHL-4V, which generates tumors lacking endothelial DR5 expression, here we demonstrate for the first time that the Akt inhibitor perifosine induces in vivo DR5 expression on TECs, thereby overcoming tumor resistance to the vascular disruption activity of CD34-TRAIL (+) cells. In fact, CD34-TRAIL (+) cells combined with perifosine, but not CD34-TRAIL (+) cells alone, exerted marked antivascular effects and caused a threefold increase of hemorrhagic necrosis in SU-DHL-4V tumors. Consistent with lack of DR5 expression, CD34-TRAIL (+) cells failed to affect the growth of SU-DHL-4V tumors, but CD34-TRAIL (+) cells plus perifosine reduced tumor volumes by 60 % compared with controls. In view of future clinical studies using membrane-bound TRAIL, our results highlight a strategy to rescue patients with primary or acquired resistance due to the lack of DR5 expression in tumor vasculature.
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Giacomini
authors.forename: Marco
authors.initials: M
authors.lastname: Righi
authors.forename: Loredana
authors.initials: L
authors.lastname: Cleris
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Locatelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D017931:DNA Primers; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D010767:Phosphorylcholine; C105905:perifosine