Abstract
AbstractAdenovirus-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.
Highlights
IntroductionModified stem/progenitor cells represent an innovative approach for delivery of anticancer molecules.[1,2] Because of their homing properties, systemically injected stem/progenitor cells could infiltrate both primary and metastatic tumor sites, allowing tumor-specific targeting[3,4,5,6,7,8,9] and potentially overcoming limitations inherent to the pharmacokinetic profile of soluble drugs.[10,11,12]Soluble tumor necrosis factor (TNF)–related apoptosisinducing ligand (sTRAIL) is a proapoptotic member of the TNF superfamily of death receptor ligands
Treatment was started when tumors reached approximately 7 to 10 mm in diameter. Both CD34-TRAILϩ cells and sTRAIL significantly inhibited tumor growth by day 28, when tumor volumes were reduced by 38% (P Ͻ .05) and 31% (P Ͻ .05), respectively
We have previously demonstrated that intravenous injection of CD34-TRAILϩ cells in mice with systemic multiple myeloma exerts a marked antitumor activity, resulting in a significant increase of median survival.[29]
Summary
Modified stem/progenitor cells represent an innovative approach for delivery of anticancer molecules.[1,2] Because of their homing properties, systemically injected stem/progenitor cells could infiltrate both primary and metastatic tumor sites, allowing tumor-specific targeting[3,4,5,6,7,8,9] and potentially overcoming limitations inherent to the pharmacokinetic profile of soluble drugs.[10,11,12]Soluble tumor necrosis factor (TNF)–related apoptosisinducing ligand (sTRAIL) is a proapoptotic member of the TNF superfamily of death receptor ligands. Modified stem/progenitor cells represent an innovative approach for delivery of anticancer molecules.[1,2] Because of their homing properties, systemically injected stem/progenitor cells could infiltrate both primary and metastatic tumor sites, allowing tumor-specific targeting[3,4,5,6,7,8,9] and potentially overcoming limitations inherent to the pharmacokinetic profile of soluble drugs.[10,11,12]. Because of sTRAIL’s short half-life,[13,20,22] it seems unlikely that the recommended sTRAIL dose of 8 mg/kg body weight will allow prolonged exposure of tumor cells at high drug concentrations.[21]
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