HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2008-0307v1 26/11/2945    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Walzlein, J.-H. Articles by Glass, R. Search for Related Content PubMed PubMed Citation Articles by Walzlein, J.-H. Articles by Glass, R.

TISSUE-SPECIFIC STEM CELLS

The Antitumorigenic Response of Neural Precursors Depends on Subventricular Proliferation and Age

^aCellular Neuroscience and
^cMolecular Cell Biology and Gene Therapy, Max Delbrück Center for Molecular Medicine, Berlin, Germany;
^bDepartment for Neurosurgery, Charité University Hospital Berlin, Berlin, Germany;
^dDepartment for Neurosurgery, Helios Klinikum, Berlin, Germany;
^eLaboratory of Transcription Regulation, Department of Cell Biology, and
^fDepartment of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland;
^gLaboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Suita, Osaka, Japan;
^hDeutsche Forschungsgemeinschaft Center for Regenerative Therapies Dresden, Cluster of Excellence/Technical University Dresden, Dresden, Germany

Key Words. Central nervous system neoplasms • Tissue maintenance • Stem and precursor cells of the central nervous system • Tumor microenvironment

Correspondence: Correspondence: Helmut Kettenmann, Ph.D., Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin-Buch (MDC), Robert Rössle Strasse 10, 13125 Berlin, Germany. Telephone: 49-30-9406-3325; Fax: 49-30-9406-3819; e-mail: kettenmann{at}mdc-berlin.de; or Rainer Glass, Ph.D., Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin-Buch (MDC), Robert Rössle Strasse 10, 13125 Berlin, Germany. Telephone: 49-30-9406-3325; Fax: 49-30-9406-3819; e-mail: rainer.glass{at}mdc-berlin.de

Received on March 25, 2008; accepted for publication on August 16, 2008.

First published online in STEM CELLS EXPRESS  August 28, 2008.

Glioblastomas, the most aggressive primary brain tumors, occur almost exclusively in adult patients. Neural precursor cells (NPCs) are antitumorigenic in mice, as they can migrate to glioblastomas and induce tumor cell death. Here, we show that the antitumor effect of NPCs is age-dependently controlled by cell proliferation in the subventricular zone (SVZ) and that NPCs accumulating at a glioblastoma are diverted from their normal migratory path to the olfactory bulb. Experimentally induced cortical glioblastomas resulted in decreased subventricular proliferation in adult (postnatal day 90) but not in young (postnatal day 30) mice. Adult mice supplied fewer NPCs to glioblastomas and had larger tumors than young mice. Apart from the difference in proliferation, there was neither a change in cell number and death rate in the SVZ nor a change in angiogenesis and immune cell density in the tumors. The ability to kill glioblastomas was similar in NPCs isolated from young and adult mice. The proliferative response of NPCs to glioblastomas depended on the expression of D-type cyclins. In young mice, NPCs express the cyclins D1 and D2, but the expression of cyclin D1 is lost during aging, and in adult NPCs only cyclin D2 remains. In young and adult cyclin D2-deficient mice we observed a reduced supply of NPCs to glioblastomas and the generation of larger tumors compared with wild-type mice. We conclude that cyclin D1 and D2 are nonredundant for the antitumor response of subventricular NPCs. Loss of a single D-type cyclin results in a smaller pool of proliferating NPCs, lower number of NPCs migrating to the tumor, and reduced antitumor activity.

Disclosure of potential conflicts of interest is found at the end of this article.