Brain Advance Access originally published online on July 10, 2006
Brain 2006 129(9):2426-2435; doi:10.1093/brain/awl173
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Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-ß-dependent HIF-1
-mediated induction of CXCL12
1 Laboratory of Molecular Neuro-Oncology, 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
Correspondence to: Wolfgang Wick, MD, Laboratory of Molecular Neuro-Oncology, 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
Previously we defined a pathway of transforming growth factor beta (TGF-ß) and stromal cell-derived factor-1/CXC chemokine ligand 12 (SDF-1
/CXCL12) dependent migration of adult haematopoietic stem and progenitor cells (HPC) towards glioma cells in vitro and their homing to experimental gliomas in vivo. Hypoxia is a critical aspect of the microenvironment of gliomas and irradiation is an essential part of the standard therapy. To evaluate the therapeutic potential of HPC as vectors for a cell-based therapy of gliomas, we investigated the impact of hypoxia and irradiation on the attraction of HPC by glioma cells. Temozolomide (TMZ) treatment and hyperthermia served as controls. Supernatants of irradiated or hypoxic LNT-229 glioma cells promote HPC migration in vitro. Reporter assays reveal that the CXCL12 promoter activity is enhanced in LNT-229 cells at 24 h after irradiation at 8 Gy or after exposure to 1% oxygen for 12 h. The irradiation- and hypoxia-induced release of CXCL12 depends on hypoxia inducible factor-1 alpha (HIF-1), but not on p53. Induction of transcriptional activity of HIF-1 by hypoxia or irradiation requires an intact TGF-ß signalling cascade. This delineates a novel stress signalling cascade in glioma cells involving TGF-ß, HIF-1 and CXCL12. Stress stimuli can be irradiation, hypoxia or TMZ, but not hyperthermia. Cerebral irradiation of nude mice at 21 days after intracerebral implantation of LNT-229 glioma induces tumour satellite formation and enhances the glioma tropism of HPC to the tumour bulk and even to these satellites in vivo. These data suggest that the use of HPC as cellular vectors in the treatment of glioblastoma may well be combined with irradiation or other anti-angiogenic therapies that induce tumour hypoxia.
Key Words:
Haematopoietic progenitor cells; glioma; irradiation; non-lethal hypoxia; CXCL12; HIF-1; TGF-ß
Abbreviations: CXCL12, CXC chemokine ligand; DAPI, 4',6'-diamidino-2-phenylindole dihydrochloride; ELISA, enzyme-linked immunosorbent assay; HIF, hypoxia-inducible factor; HPC, haematopoietic progenitor and stem cells; MMP, matrix metalloproteinase; sKitL, soluble Kit ligand; SCF, stem cell factor; SDF, stromal cell-derived factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor
Received January 25, 2006. Revised April 22, 2006. Accepted June 2, 2006.
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