Dual-targeted antitumor effects against brainstem glioma by intravenous delivery of tumor necrosis factor-related, apoptosis-inducing, ligand-engineered human mesenchymal stem cells.
OBJECTIVE
We sought to explore the dual-targeted antitumor effects of membrane-spanned, tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL)-engineered human mesenchymal stem cells (hMSCs) against brainstem gliomas.


METHODS
The migration capacity of hMSCs toward gliomas was studied by the Transwell system in vitro and by intravenous injection of hMSCs in glioma-bearing mice in vivo. MSCs were engineered with native full-length human TRAIL (hTRAIL) by a recombinant adeno-associated virus (rAAV) vector (rAAV-hTRAIL). The targeted antiglioma effect was analyzed by coculture of hTRAIL-engineered MSCs with glioma in vitro and by systematic delivery of hTRAIL-engineered MSCs to established human brainstem glioma xenografts.


RESULTS
We demonstrated systematically that transplanted MSCs migrated to a brainstem glioma with a high specificity. MSCs penetrated the vessels surrounding the tumor, then streamed in a chain pattern toward the glioma, eventually surrounding the tumor. Membrane-spanned, TRAIL-engineered MSCs not only expressed full-length TRAIL in MSC surface, but secreted some soluble TRAIL in medium. After being infected with rAAV-hTRAIL, hMSCs showed no increase in apoptosis. After coculture of hTRAIL-engineered MSCs and U87MG cells, the apoptosis of U87MG cells significantly increased more than soluble TRAIL-treated U87MG cells. Systematic delivery of hTRAIL-engineered MSCs to established human brainstem glioma xenografts resulted in the potent induction of apoptosis in gliomas, but not in normal brain and prolonged survival to 38.0 +/- 10.46 days compared with phosphate-buffered saline (16.0 +/- 0.66 days), soluble TRAIL (19.0 +/- 1.65 days), and hMSC-LacZ (14.0 +/- 0.59 days) treated groups.


CONCLUSIONS
Systematically transplanted MSCs migrated to gliomas with a high specificity. Systematic delivery of MSC-hTRAIL can prolong the survival of brainstem glioma-bearing mice, presumably through a dual-targeted effect of membrane-spanned, TRAIL-engineered MSCs in the tumor microenvironment. MSCs may be an effective vehicle for the targeted delivery of therapeutic agents to brainstem gliomas.
Yang
Bojie
B
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
Wu
Xing
X
Mao
Ying
Y
Bao
Weiming
W
Gao
Liang
L
Zhou
Ping
P
Xie
Rong
R
Zhou
Liangfu
L
Zhu
Jianhong
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms; D020295:Brain Stem Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D005818:Genetic Engineering / Q000379:methods; D005910:Glioma / Q000628:therapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D014409:Tumor Necrosis Factor-alpha