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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-HIV Agents
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Antibodies, Neutralizing
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Benzylamines
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Brain Neoplasms / therapy*
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CD11b Antigen / metabolism
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / radiation effects
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Chemokine CXCL12 / antagonists & inhibitors
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Chemokine CXCL12 / metabolism
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Cyclams
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Glioblastoma / therapy*
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Heterocyclic Compounds / pharmacology*
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Heterocyclic Compounds / therapeutic use
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Humans
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Hypoxia-Inducible Factor 1 / metabolism
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Mice
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Mice, Nude
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Monocytes / metabolism
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Monocytes / pathology
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Neoplasm Recurrence, Local / metabolism
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Neoplasm Recurrence, Local / pathology
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Neoplasm Recurrence, Local / therapy*
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Neoplasm Transplantation
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / therapy*
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Receptors, CXCR4 / antagonists & inhibitors
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Receptors, CXCR4 / metabolism
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Transplantation, Heterologous
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Whole-Body Irradiation*
Substances
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Anti-HIV Agents
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Antibodies, Neutralizing
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Antineoplastic Agents
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Benzylamines
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CD11b Antigen
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CXCR4 protein, human
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CXCR4 protein, mouse
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Chemokine CXCL12
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Cxcl12 protein, mouse
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Cyclams
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Heterocyclic Compounds
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Hypoxia-Inducible Factor 1
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ITGAM protein, human
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Receptors, CXCR4
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plerixafor