Gregory M. Vercellotti, MD
Dr. Vercellotti indicated no relevant conflicts of interest.
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;120:694-705.
More than 100 years ago Goldmann1 described that a tumor is surrounded by new blood vessels, feeding it like the Lernaean Hydra in Greek mythology. Subsequently, it was hypothesized that tumors made factors to promote vessel growth. This seemed reasonable as cells need oxygen and nutrients to grow, and diffusion distances from the vasculature are limiting. Similar to Hercules cutting off each of the nine heads of the Hydra to kill it, Folkman’s2 concept that blocking angiogenesis could prevent cancer growth and metastases made sense. Newly discovered growth factors, receptors, and anti-angiogenic molecules have been identified over the past 40 years, and targeting angiogenesis is now an essential therapeutic strategy in the oncologist’s armamentarium. In 2009, the FDA approved bevacizumab, an anti-VEGF monoclonal antibody, for the treatment of glioblastoma multiforme (GBM); it decreased tumor size and prolonged survival, but despite treatment, tumors grew back. Just focusing on angiogenesis may not be adequate to prevent the recurrence of glioblastoma as suggested by Kioi et al from J. Martin Brown’s laboratory at Stanford. These authors showed that inhibiting vasculogenesis post-irradiation may be necessary to accomplish that end.
Human GBM cells transduced with a luciferase reporter gene were placed orthotopically into the brains of nude mice that had been transplanted with GFP-labeled bone marrow cells. Whole-brain irradiation was then delivered to cause the tumors to regress, and then the tumors were allowed to regrow. Bone marrow-derived cells (BMDCs) were shown to have influxed into the tumors. These cells were not endothelial cell progenitor cells (EPCs), but were CD11b+ myelomonocytes that expressed Tie-2 but not VEGF. Irradiation decreased CD31+ endothelial cells, decreased blood flow, and increased tumor hypoxia. HIF-1 was the key factor responsible for BMDC influx, as its inhibition abrogated BMDC influx post-irradiation. Furthermore, inhibition of HIF resulted in shrinkage of the tumor with no regrowth over time, suggesting that the BMDCs were proangiogenic. HIF-1 activated the chemokine SDF-1, which binds to its receptor CXCR4 on BMDCs. SDF levels rose after irradiation in the tumor, and phosphorylation of CXCR4 increased, suggesting an SDF/CXCR4 interaction. AMD3100 (plerixafor), an inhibitor of SDF-1interaction with CXCR4, prevented the blood flow in irradiated tumors and prevented tumor recurrence even more significantly than VEGF blockade. Finally, the authors showed that myelomonocytic cells were critical for tumor regrowth after irradiation. In 10 of 12 human GBM tumors examined, recurrent tumors had higher levels of CD11b+ cells compared to normal brain tissues.
This study suggests that a tumor can expand its vasculature as it grows by angiogenesis involving sprouting endothelial cells from nearby vessels or by vasculogenesis, which occurs by recruiting EPCs or BMDCs. A novel strategy to inhibit vasculogenesis after local tumor irradiation may help control tumor growth. The authors suggest that this strategy may allow lower radiation doses if only the endothelial cells and not the tumor cells need to be killed. Greenfield et al.3 commented on this paper, cautioning that resistant endothelial cells may still play a role in explaining the BMDCs seen in recurrent tumors. Furthermore, the potential targets to prevent angiogenesis and vasculogenesis are numerous. Thus, targeting blood vessels may require a Herculean effort to cut off the numerous heads of a tumor’s vascular Hydra.
- Goldmann, E. The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet. 1907;2:1236-1240.
- Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-1186.
- Greenfield JP, Cobb WS, Lyden D. Resisting arrest: a switch from angiogenesis to vasculogenesis in recurrent malignant gliomas. J Clin Invest. 2010;120:663-667.
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