Karen S. Aboody1, Alyssa Brown1, Nikolai G. Rainov1, Kate A. Bower1, Shaoxiong Liu1, Wendy Yang1, Juan E. Small1, Ulrich Herrlinger1, Václav Ourednik1, Peter McL. Black1, Xandra O. Breakefield1, Evan Y. Snyder1
1Departments of Neurology, Pediatrics, and Neurosurgery,
Children's Hospital; Molecular Neurogenetics Unit,
Department of Neurology, Massachusetts General Hospital; and
Brain Tumor Service, Department of Neurosurgery, Brigham
and Women's Hospital, Harvard Medical School, Boston, MA 02115;
and Layton Bioscience, Sunnyvale, CA 94086
Tóm tắt
One of the impediments to the treatment of brain tumors (e.g.,
gliomas) has been the degree to which they expand, infiltrate
surrounding tissue, and migrate widely into normal brain, usually
rendering them “elusive” to effective resection, irradiation,
chemotherapy, or gene therapy. We demonstrate that neural stem cells
(NSCs), when implanted into experimental intracranial gliomas
in
vivo
in adult rodents, distribute themselves quickly and
extensively throughout the tumor bed and migrate uniquely in
juxtaposition to widely expanding and aggressively advancing tumor
cells, while continuing to stably express a foreign gene. The NSCs
“surround” the invading tumor border while “chasing down”
infiltrating tumor cells. When implanted intracranially at distant
sites from the tumor (e.g., into normal tissue, into the contralateral
hemisphere, or into the cerebral ventricles), the donor cells migrate
through normal tissue targeting the tumor cells (including human
glioblastomas). When implanted outside the CNS intravascularly, NSCs
will target an intracranial tumor. NSCs can deliver a therapeutically
relevant molecule—cytosine deaminase—such that quantifiable reduction
in tumor burden results. These data suggest the adjunctive use of
inherently migratory NSCs as a delivery vehicle for targeting
therapeutic genes and vectors to refractory, migratory, invasive brain
tumors. More broadly, they suggest that NSC migration can be extensive,
even in the adult brain and along nonstereotypical routes, if pathology
(as modeled here by tumor) is present.
