Brain Advance Access originally published online on June 9, 2005
Brain 2005 128(9):2200-2211; doi:10.1093/brain/awh563
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Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells
1 Laboratory of Molecular Neurooncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, 2 Department of Internal Medicine II (Hematology), University of Tübingen, Tübingen, Germany, 3 Department of Neurosurgery, University of Erlangen and 4 Institute of Neuropathology, University of Erlangen, Erlangen, Germany
Correspondence to: Wolfgang Wick, MD, Laboratory of Molecular Neurooncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany E-mail: wolfgang.wick{at}uni-tuebingen.de
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-ß) synthesis by the glioma cells strongly inhibits PC migration. We delineate a CXC chemokine ligand (CXCL) 12-dependent pathway of TGF-ß-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.
Key Words: CXCL12; hippocampal slice culture; metalloproteinase; TGF-ß
Abbreviations: CA1 = cornu ammonis 1; CA3 = cornu ammonis 3; CD117 = cluster of differentiation 117; CD34+PC = G-CSF mobilized peripheral blood CD34+ progenitor and stem cells; CFSE = carbofluorescein diacetate succinimidyl ester; CXCL12 = CXC chemokine ligand; CXCR4 = chemokine receptor 4; DG = dentate gyrus; EC = entorhinal cortex; FCS = fetal calf serum; G-CSF = granulocyte colony stimulating factor; HBSS = Hanks' balanced salt solution; lin– = lineage-depleted; MACS = magnetic activated cell sorting; MMP = matrix metalloproteinase; nu PC = bone marrow-derived murine lin–Sca1+ haematopoietic stem and progenitor and lin– stem and progenitor cells from athymic nude mice; PKB = protein kinase B; RO28-2653 = 5-biphenyl-4-yl-5-[4-(nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6; SC = stem cell; sca1 = stem cell antigen; SCF = stem cell factor; SDF = stromal cell-derived factor; SEM = standard error of the mean; SFM = serum-free medium; sKitL = soluble Kit ligand; TGF = transforming growth factor; VM/Dk PC = bone marrow-derived murine lin–Sca1+ haematopoietic stem and lin– stem and progenitor cells from immunocompetent VM/Dk mice
Received March 11, 2005. Revised May 3, 2005. Accepted May 17, 2005.
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