Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice
Mitomu Kioi, … , Griffith R. Harsh, J. Martin Brown
Mitomu Kioi, … , Griffith R. Harsh, J. Martin Brown
Published February 22, 2010
Citation Information: J Clin Invest. 2010;120(3):694-705. https://doi.org/10.1172/JCI40283.
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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

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Figure 6

Model of the main contributions of BMDCs; and cytokines that promote restoration of tumor vasculature after irradiation.

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Model of the main contributions of BMDCs; and cytokines that promote res...
(A) Prior to irradiation, tumor growth is governed largely by local angiogenesis. When local angiogenesis is inhibited by irradiation, growth of the tumor vasculature (essential for recurrence of the tumor) can only occur from circulating cells, of which BMDCs are an essential component. (B) After irradiation, the tumor becomes more hypoxic, and HIF-1 is increased as the tumor attempts to regrow. This induces SDF-1 and promotes the mobilization of CD11b+ monocytes from the BM and retention of these BMDCs into the tumor. SDF-1 is the key factor for the influx of BMDCs, as AMD3100, an inhibitor of CXCR4/SDF-1, and antibodies against CXCR4 block the recruitment and/or tumor retention of the BMDCs, inhibit restoration of the tumor vasculature, and prevent tumor recurrence. The various inhibitors and the points in the cycle at which they act are shown in boxes. Mϕ, macrophages.