| 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
|
|
WOS Category
|
HEMATOLOGY
|
| Resource |
| DNA material |
hTRAIL/pMKITneo human TRAIL cDNA (RDB02934) |
