Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene.
Adult stem cells are promising cellular vehicles for therapy of malignant gliomas as they have the ability to migrate into these tumors and even track infiltrating tumor cells. However, their clinical use is limited by a low passaging capacity that impedes large-scale production. In the present study, a bone marrow-derived, highly proliferative subpopulation of mesenchymal stem cells (MSCs)-here termed bone marrow-derived tumor-infiltrating cells (BM-TICs)-was genetically modified for the treatment of malignant glioma. Upon injection into the tumor or the vicinity of the tumor, BM-TICs infiltrated solid parts as well as the border of rat 9L glioma. After intra-tumoral injection, BM-TICs expressing the thymidine kinase of herpes simplex virus (HSV-tk) and enhanced green fluorescent protein (BM-TIC-tk-GFP) were detected by non-invasive positron emission tomography (PET) using the tracer 9-[4-[(18)F]fluoro-3-hydroxymethyl)butyl]guanine ([(18)F]FHBG). A therapeutic effect was demonstrated in vitro and in vivo by BM-TICs expressing HSV-tk through bystander-mediated glioma cell killing. Therapeutic efficacy was monitored by PET as well as by magnetic resonance imaging (MRI) and strongly correlated with histological analysis. In conclusion, BM-TICs expressing a suicide gene were highly effective in the treatment of malignant glioma in a rat model and therefore hold great potential for the therapy of malignant brain tumors in humans.
Miletic
Hrvoje
H
Abteilung für Neuropathologie, Universität zu Köln, Köln, Germany. h.miletic@uni-koeln.de
Fischer
Yvonne
Y
Litwak
Sara
S
Giroglou
Tsanan
T
Waerzeggers
Yannic
Y
Winkeler
Alexandra
A
Li
Huongfeng
H
Himmelreich
Uwe
U
Lange
Claudia
C
Stenzel
Werner
W
Deckert
Martina
M
Neumann
Harald
H
Jacobs
Andreas H
AH
von Laer
Dorothee
D
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D024201:Bystander Effect / Q000235:genetics*; D002460:Cell Line; D002465:Cell Movement; D017629:Gap Junctions / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D049268:Positron-Emission Tomography; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism
D013937:Thymidine Kinase