RRC ID 11945
Author Lavazza C, Carlo-Stella C, Giacomini A, Cleris L, Righi M, Sia D, Di Nicola M, Magni M, Longoni P, Milanesi M, Francolini M, Gloghini A, Carbone A, Formelli F, Gianni AM.
Title Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature.
Journal Blood
Abstract Adenovirus-transduced CD34+ cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL+ cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL+ cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45+ cells per 10(5) tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL+ cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL+ cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL+ cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL+ cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL+ cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling+ endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL+ cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.
Volume 115(11)
Pages 2231-40
Published 2010-3-18
DOI 10.1182/blood-2009-08-239632
PII S0006-4971(20)56633-0
PMID 20075160
MeSH Animals Antigens, CD34 / metabolism* Apoptosis Blood Vessels / metabolism Blood Vessels / pathology Cell Line, Tumor Cell Membrane / metabolism* Cell Transplantation Chemokine CXCL12 / metabolism Genetic Engineering* Hemorrhage / pathology Humans Mice Necrosis Neoplasms / blood supply* Neoplasms / genetics Neoplasms / pathology Neoplasms / therapy* Neovascularization, Pathologic / pathology Neovascularization, Pathologic / therapy Protein Binding TNF-Related Apoptosis-Inducing Ligand / metabolism* Tissue Distribution Vascular Cell Adhesion Molecule-1 / metabolism Xenograft Model Antitumor Assays
IF 17.794
Times Cited 28
DNA material hTRAIL/pMKITneo human TRAIL cDNA (RDB02934)