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Brain Advance Access published online on June 9, 2005
Brain, doi:10.1093/brain/awh563
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received March 11, 2005
Revised May 3, 2005
Accepted May 17, 2005

Article

Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells

Ghazaleh Tabatabai 1, Oliver Bähr 1, Robert Möhle 2, Ilker Y. Eyüpoglu 3, Andreas M. Boehmler 2, Jörg Wischhusen 1, Johannes Rieger 1, Ingmar Blümcke 4, Michael Weller 1, and Wolfgang Wick 1*

1 Laboratory of Molecular Neurooncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
2 Department of Internal Medicine II (Hematology), University of Tübingen, Tübingen, Germany
3 Department of Neurosurgery, University of Erlangen, Erlangen, Germany
4 Institute of Neuropathology, University of Erlangen, Erlangen, Germany

* To whom correspondence should be addressed.
Wolfgang Wick, E-mail: wolfgang.wick{at}uni-tuebingen.de


  Abstract

Stem and progenitor cells (PCs) of various lineages have become attractive vehicles to improve therapeutic gene delivery to cancers, notably glioblastoma. Here we report that adult human and murine haematopoietic PCs display a tropism for intracerebral gliomas but not for normal brain tissue in mice. Organotypic hippocampal slice culture and spheroid confrontation assays confirm a directed PC migration towards glioma cells ex vivo and in vitro. RNA interference-mediated disruption of transforming growth factor beta (TGF-{beta}) synthesis by the glioma cells strongly inhibits PC migration. We delineate a CXC chemokine ligand (CXCL) 12-dependent pathway of TGF-{beta}-induced PC migration that is facilitated by MMP-9-mediated stem cell factor cleavage in vitro. Moreover, neutralizing antibodies to CXCL12 strongly reduce PC homing to experimental gliomas in vivo. Thus, we define here the molecular mechanism underlying the glioma tropism of the probably most easily accessible PC population suitable for cancer therapy, that is, adult haematopoietic PC.

Keywords: CXCL12; hippocampal slice culture; metalloproteinase; TGF-{beta}.
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