Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature.
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.
Lavazza
Cristiana
C
Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milano, Italy.
Carlo-Stella
Carmelo
C
Giacomini
Arianna
A
Cleris
Loredana
L
Righi
Marco
M
Sia
Daniela
D
Di Nicola
Massimo
M
Magni
Michele
M
Longoni
Paolo
P
Milanesi
Marco
M
Francolini
Maura
M
Gloghini
Annunziata
A
Carbone
Antonino
A
Formelli
Franca
F
Gianni
Alessandro M
AM
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D017209:Apoptosis; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D017690:Cell Transplantation; D054377:Chemokine CXCL12 / Q000378:metabolism; D005818:Genetic Engineering; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D051379:Mice; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy; D011485:Protein Binding; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014018:Tissue Distribution; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018952:Antigens, CD34; D054377:Chemokine CXCL12; D053221:TNF-Related Apoptosis-Inducing Ligand; D019010:Vascular Cell Adhesion Molecule-1