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: Mitomu Kioi, Hannes Vogel, Geoffrey Schultz, Robert M Hoffman, Griffith R Harsh, J Martin Brown
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 3 Pg. 694-705 (Mar 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 20179352 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antibodies, Neutralizing
• Antineoplastic Agents
• Benzylamines
• CD11b Antigen
• CXCR4 protein, human
• CXCR4 protein, mouse
• Chemokine CXCL12
• Cxcl12 protein, mouse
• Cyclams
• Heterocyclic Compounds
• Hypoxia-Inducible Factor 1
• ITGAM protein, human
• Receptors, CXCR4
• plerixafor

Topics

• Animals
• Anti-HIV Agents
• Antibodies, Neutralizing
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzylamines
• Bone Marrow Cells (metabolism, pathology)
• Brain Neoplasms (metabolism, pathology, therapy)
• CD11b Antigen (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects, radiation effects)
• Chemokine CXCL12 (antagonists & inhibitors, metabolism)
• Cyclams
• Glioblastoma (metabolism, pathology, therapy)
• Heterocyclic Compounds (pharmacology, therapeutic use)
• Humans
• Hypoxia-Inducible Factor 1 (metabolism)
• Mice
• Mice, Nude
• Monocytes (metabolism, pathology)
• Neoplasm Recurrence, Local (metabolism, pathology, therapy)
• Neoplasm Transplantation
• Neovascularization, Pathologic (metabolism, pathology, therapy)
• Receptors, CXCR4 (antagonists & inhibitors, metabolism)
• Transplantation, Heterologous
• Whole-Body Irradiation