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Neural stem cells
display extensive tropism for pathology in adult brain: Evidence from
intracranial gliomas
Karen
S. Aboody,
Alice Brown,
Nikolai G. Rainov,
Kate A. Bower, Shaoxiong Liu, Wendy Yang,
Juan E. Small, Ulrich Herrlinger,
Vaclav Ourednik, Peter McL. Black, Xandra O.
Breakefield,
and Evan Y. Snyder
Departments
of Neurology, Pediatrics, and Neurosurgery, Children's Hospital [K.S.A., K.A.B.,
S.L., W.Y., J.E.S., V.O., E.Y.S.]; Molecular
Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital
[K.S.A., A.B., N.G.R., U.H., X.O.B.]; Brain Tumor Service, Department of Neurosurgery, Brigham and
Women's Hospital, Harvard Medical School, Boston, MA 02115 [P.M.B.]; Layton
Bioscience, Sunnyvale, CA 94086 [K.S.A.].
To whom reprint requests should be addressed. E-mail: Snyder@A1.TCH.Harvard.edu.[E.Y.S.].
Communicated
by Richard L. Sidman, Harvard Medical School, Southborough, MA, July 24, 2000
(received for review May 19, 2000)
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.
Copyright © 2000 by
the National Academy of Sciences
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