ENDOTHELIAL-CELL IMPLANTATION AND SURVIVAL WITHIN EXPERIMENTAL GLIOMAS

The delivery of therapeutic genes to primary brain neoplasms opens new opportunities for treating these frequently fatal tumors. Efficient g ene delivery to tissues remains an important obstacle to therapy, and this problem has unique characteristics in brain tumors due to the blo od-brain and blood-tumor barriers. The presence of endothelial mitogen s and vessel proliferation within solid tumors suggests that genetical ly modified endothelial cells might efficiently transplant to brain tu mors. Rat brain endothelial cells immortalized with the adenovirus E1A gene and further modified to express the beta-galactosidase reporter were examined for their ability to survive implantation to experimenta l rat gliomas. Rats received 9L, F98, or C6 glioma cells in combinatio n with endothelial cells intracranially to caudate/putamen or subcutan eously to flank. Implanted endothelial cells were identified by beta-g alactosidase histochemistry or by polymerase chain reaction in all tum ors up to 35 days postimplantation, the latest time examined. Implante d endothelial cells appeared to cooperate in tumor vessel formation an d expressed the brain-specific endothelial glucose transporter type 1 as identified by immunohistochemistry. The proliferation of implanted endothelial cells was supported by their increased number within tumor s between postimplantation days 14 and 21 (P = 0.015) and by their exp ression of the proliferation antigen Ki67. These findings establish th at genetically modified endothelial cells can be stably engrafted to g rowing gliomas and suggest that endothelial cell implantation may prov ide a means of delivering therapeutic genes to brain neoplasms and oth er solid tumors. In addition, endothelial implantation to brain may be useful for defining mechanisms of brain-specific endothelial differen tiation.