Title Why do Glioblastomas relapse after anti-angiogenic treatment?
Sophie JAVERZAT
Laboratoire Angiogenèse et Microenvironnement des Cancers
1. Univ. Bordeaux, LAMC, UMR 1029, F-33400 Talence, France.
2. INSERM, LAMC, UMR 1029, F-33400 Talence, France.
Abstract (max 250 words):
Glioblastoma stands as the most common and lethal primary malignant brain tumor with more
than 2000 new cases diagnosed each year in France. The recurrence remains inexorable despite
multimodal therapy including surgery followed by radiation and temolozomide. Further treatment with
anti-angiogenics such as Bevacizumab, an anti-VEGF antibody, usually allows a transient remission.
However tumors systematically relapse within months and are from then on resistant to any known
additional therapy and display a highly invasive phenotype.
In mice xenografted with U87 glioblastoma cells and treated with Bevacizumab, we show that
relapsing tumors may in rare instances display CD31 positive tumor cells that can assemble into vascular
cords. This suggests that anti-angiogenics while causing hypoxia may exert a selection pressure on stemlike tumor cells driving them to transdifferentiate into endothelial-like cells. Because U87 cultures hold
only a few cells with stem properties, we have developed and characterized a new model of glioblastoma
using human tumor cells that are grown as neurospheres in culture hence retaining a large population of
cells with stem properties. We have characterized the growth of these cells in xenografted mice and are
currently challenging them with Bevacizumab. By combining this to another therapeutical antibody that
targets the IL6 pathway, we hope to lock switching of the treated tumors between the invasive and
angiogenic fate (Saidi et al; 2009) and therefore find a new way to control relapse.
We have previously identified new markers of angiogenesis with potential functional implication
(Javerzat et al., PlosOne 2009; Exertier et al. submitted manuscript). One of these colocalize with cells
tightly associated with tumor vessels in glioblastoma and may well be implicated in migration properties.
We currently investigate the implication of this new factor in glioblastoma that relapse and infiltrate
under anti-angiogenic treatment.
Anti-angiogenics stimulate endothelial transdifferentiation
References
Ahlame Saidi, Martin Hagedorn, Nathalie Allain, Chiara Verpelli, Carlo Sala, Lorenzo Bello, Andreas
Bikfalvi, Sophie Javerzat (2009) Combined targeting ofinterleukin6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness.
Int J Cancer 125: 5. 1054-1064
Javerzat, Franco, Herbert, Platonova, Peille, Pantesco, De
Vos, Assou, Bicknell, Bikfalvi, Hagedorn (2009) Correlating Global Gene Regulation toAngiogene
sis in the Developing Chick Extra-Embryonic Vascular System. PLoS One 4: 11. 11