Translational Emphasis: Hypoxia and Vasculo genesis in Glioma Recurrence


doi: 10.1227/01.neu.0000375278.07027.42
Science Times

The invariable recurrence of glioblastoma multiforme (GBM) is a frontier where therapeutic advances can be made. It is now considered important not only to treat GBM with surgery, chemotherapy and radiation, but also to consider any potential combinatorial approaches that target the refractory, residual cells thought to create recurrence. The role of increased vasculogenesis and hypoxia have been previously suggested, and now have been experimentally shown to be a fundamental component for the successful proliferation of post-treatment residual glioma cells.

Kioi et al (Kioi M, Vogel H, Schultz G, et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010;120(3):694–705) recently show through intracranial human GBM xenograft model (using U251 human GBM cells) that irradiation induces recruitment of CD11b+ cells 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 with a HIF1 inhibitor compound, NSC-134754, reduced tumor levels of CD11b+ which prevents tumor recurrence. Utilizing the already approved Food and Drug Administration clinical drug AMD3100 (Figure 4 from Kioi et al), the group was able inhibit glioma recurrence by inhibiting the vasculogenesis through inhibition of stromal cell-derived factor 1/ C-X-C chemokine receptor 4 (SDF-1/CXCR4) interaction, a HIF1 downstream pathway that might control BMDC recruitment.

Hypoxia is a well-known regulatory factor for angiogenesis and development of stem cell biology, with HIF-1 playing major role in the recruitment of stem cells and tumors. The tumor vasculature can arise from sprouting and proliferation of endothelial cells from local vessels or by colonization of circulating endothelial cells, primarily from the bone marrow (BM). By exploiting vasculogenesis inhibition, the effective reduction of tumor recurrence offers a promising translational approach to expand the current treatment strategy to also include agents that would improve time to recurrence for patients. With the current push by the National Institute of Health (NIH) to focus on patient oriented investigation with an increased emphasis on innovation, exploring opportunities to employ clinically available drugs within a new paradigm is an inventive approach to translational science.



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