Endothelial cell transplantation for gene therapy in experimental gliomas.
OBJECTIVE
Malignant gliomas are prominent targets for cancer gene therapy approaches because of their poor prognosis despite all available therapies. Endothelial cells (ECs) are considered attractive vehicles for cell-based gene therapy because of their tropism to the tumor vasculature. In this study, we investigated the potential of ECs to incorporate into glioma vessels after intra-arterial or local application to establish whether ECs can be used as cellular vectors for gene therapy in gliomas.


METHODS
Immortalized rat brain endothelial cells (BECs) were modified to express either beta-galactosidase or green fluorescent protein (GFP). The ability of transduced BECs to integrate into tumor vessels after interstitial implantation was evaluated in C6 and 9L glioma models. The fate of GFP-BECs was investigated after selective intracarotid injection into C6 tumor-bearing animals.


RESULTS
The interstitially grafted BECs organized themselves into vascular-like structures and integrated into the tumor vasculature. Transgene expression was limited to 10 days after injection. After selective intra-arterial injection, numerous GFP-BECs were adherent to the vascular lumen at least 7 days after injection. These cells were evenly distributed within small vessels and capillaries of the injected hemisphere and did not home selectively to the tumor vessels.


CONCLUSIONS
Cell-based therapy approaches to brain tumor treatment using BECs as cellular vectors might be hampered by the rapid downregulation of transgene expression and by the fact that these cells do not home specifically to tumor vessels after intra-arterial injection. Nevertheless, locoregional administration of BECs might be an interesting approach for delivering molecules to brain tumors when short-term expression of transgene in the perivascular space is desirable.
Machein
Márcia Regina
MR
Department of Neurosurgery, University of Freiburg School of Medicine, Freiburg, Germany. machein@nz.ukl.uni-freiburg.de
Knoth
Rolf
R
Plate
Karl Heinz
KH
D000818:Animals; D001921:Brain / Q000098:blood supply*; D001932:Brain Neoplasms / Q000628:therapy*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology / Q000637:transplantation*; D005240:Feasibility Studies; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007269:Injections, Intra-Arterial; D049408:Luminescent Agents / Q000378:metabolism; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic; D014162:Transfection; D019076:Transgenes
D049408:Luminescent Agents; D049452:Green Fluorescent Proteins