Details

Autor(en) / Beteiligte

• Lavazza, Cristiana
• Carlo-Stella, Carmelo
• Giacomini, Arianna
• Cleris, Loredana
• Righi, Marco
• Sia, Daniela
• Di Nicola, Massimo
• Magni, Michele
• Longoni, Paolo
• Milanesi, Marco
• Francolini, Maura
• Gloghini, Annunziata
• Carbone, Antonino
• Formelli, Franca
• Gianni, Alessandro M.

Titel

Human CD34+ cells engineered to express membrane-bound tumor necrosis factor–related apoptosis-inducing ligand target both tumor cells and tumor vasculature

Ist Teil von

• Blood, 2010-03, Vol.115 (11), p.2231-2240

Ort / Verlag

Washington, DC: Elsevier Inc

Erscheinungsjahr

2010

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 105 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.