title: The antitumorigenic response of neural precursors depends on subventricular proliferation and age.
abstract: 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.
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin-Buch, Berlin, Germany.
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Walzlein
authors.forename: Michael
authors.initials: M
authors.lastname: Synowitz
authors.forename: Boris
authors.initials: B
authors.lastname: Engels
authors.forename: Darko S
authors.initials: DS
authors.lastname: Markovic
authors.forename: Konrad
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authors.lastname: Gabrusiewicz
authors.forename: Evgeni
authors.initials: E
authors.lastname: Nikolaev
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Bozena
authors.initials: B
authors.lastname: Kaminska
authors.forename: Gerd
authors.initials: G
authors.lastname: Kempermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.forename: Leszek
authors.initials: L
authors.lastname: Kaczmarek
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
authors.forename: Rainer
authors.initials: R
authors.lastname: Glass