title: Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice.
abstract: Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b+ myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5152, USA.
authors.forename: Mitomu
authors.initials: M
authors.lastname: Kioi
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Schultz
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: Griffith R
authors.initials: GR
authors.lastname: Harsh
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000080027:Cyclams; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006571:Heterocyclic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D014916:Whole-Body Irradiation
chemical_list: D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D001596:Benzylamines; D039481:CD11b Antigen; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D051793:Hypoxia-Inducible Factor 1; C509295:ITGAM protein, human; D019718:Receptors, CXCR4; C088327:plerixafor