Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach.
BACKGROUND
In this study, we planned to assess if adult stem cell-based suicide gene therapy can efficiently eliminate glioblastoma cells in vivo. We investigated the therapeutic potential of mouse Oct4(-) bone marrow multipotent adult progenitor cells (mOct4(-) BM-MAPCs) in a mouse glioblastoma model, guided by multimodal in vivo imaging methods to identify therapeutic windows.


METHODS
Magnetic resonance imaging (MRI) of animals, wherein 5 × 10(5) syngeneic enhanced green fluorescent protein-firefly luciferase-herpes simplex virus thymidine kinase (eGFP-fLuc-HSV-TK) expressing and superparamagnetic iron oxide nanoparticle labeled (1 % or 10 %) mOct4(-) BM-MAPCs were grafted in glioblastoma (GL261)-bearing animals, showed that labeled mOct4(-) BM-MAPCs were located in and in close proximity to the tumor. Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).


RESULTS
In the majority of GCV-treated, but not phosphate-buffered saline-treated animals, a significant difference was found in mOct4(-) BM-MAPC viability and tumor size at the end of treatment. Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.


CONCLUSIONS
Suicide gene therapy using mOct4(-) BM-MAPCs as cellular carriers was effective in reducing the tumor size in the majority of the GCV-treated animals leading to a longer progression-free survival compared to sham-operated animals. This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging. Noninvasive imaging is of particular interest for a rapid and efficient validation of stem cell-based therapeutic approaches for glioblastoma and hereby contributes to a better understanding and optimization of a promising therapeutic approach for glioblastoma patients.
Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. cindy.leten@gmail.com.|Molecular Small Animal Imaging Center, KU Leuven, 3000, Leuven, Belgium. cindy.leten@gmail.com.
Cindy
C
Leten
Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. trekker@imec.be.|Imec, Department of Life Science Technology, 3001, Leuven, Belgium. trekker@imec.be.
Jesse
J
Trekker
Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. tom.struys@uhasselt.be.|Biomedical Research Institute, Lab of Histology, Hasselt University, 3500, Hasselt, Belgium. tom.struys@uhasselt.be.
Tom
T
Struys
Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. tom.dresselaers@uzleuven.be.|Molecular Small Animal Imaging Center, KU Leuven, 3000, Leuven, Belgium. tom.dresselaers@uzleuven.be.
Tom
T
Dresselaers
Laboratory for Molecular Virology and Gene therapy, KU Leuven, 3000, Leuven, Belgium. Rik.Gijsbers@med.kuleuven.be.|Leuven Viral Vector Core, KU Leuven, 3000, Leuven, Belgium. Rik.Gijsbers@med.kuleuven.be.
Rik
R
Gijsbers
Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. Greetje.VandeVelde@med.kuleuven.be.|Molecular Small Animal Imaging Center, KU Leuven, 3000, Leuven, Belgium. Greetje.VandeVelde@med.kuleuven.be.
Greetje
G
Vande Velde
Biomedical Research Institute, Lab of Histology, Hasselt University, 3500, Hasselt, Belgium. ivo.lambrichts@uhasselt.be.
Ivo
I
Lambrichts
BioImaging Laboratory, University of Antwerp, Campus Drie Eiken, 2610, Antwerpen, Belgium. Annemie.VanDerLinden@ua.ac.be.
Annemie
A
Van Der Linden
Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000, Leuven, Belgium. Catherine.Verfaillie@med.kuleuven.be.
Catherine M
CM
Verfaillie
Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. Uwe.Himmelreich@med.kuleuven.be.|Molecular Small Animal Imaging Center, KU Leuven, 3000, Leuven, Belgium. Uwe.Himmelreich@med.kuleuven.be.
Uwe
U
Himmelreich
D000818:Animals; D024201:Bystander Effect; D002478:Cells, Cultured; D015316:Genetic Therapy; D005909:Glioblastoma / Q000628:therapy*; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology / Q000637:transplantation
D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse