Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway

Emeline Tabouret (1, 2) , Aurelie Tchoghandjian (1) , Emilie Denicolai (1) , Christine Delfino (1) , Philippe Metellus (3, 1) , Thomas Graillon (1, 3) , Celine Boucard (2) , Isabelle Nanni (4) , Laetitia Padovani (5) , L'Houcine Ouafik (1, 4) , Dominique Figarella-Branger (1, 6) , Olivier Chinot (1, 2)

1 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
2 Service de Neuro-oncologie
3 Service de Neurochirurgie
4 Laboratoire de Transfert en Oncologie Biologique
5 Service de radiothérapie
6 Service d'anatomie et cytologie pathologique humaine

Angiogenesis is one of the key features of glioblastoma (GBM). Our objective was to explore the potential changes of angiogenic factors in GBM between initial diagnosis and recurrence after radiotherapy-temozolomide (RT/TMZ). Paired frozen tumors from both initial and recurrent surgery were available for 29 patients. Screening of genes expressions related to angiogenesis was performed using RT-PCR arrays on 10 first patients. Next, RNA expressions of the selected genes were analyzed on all samples. Protein expression was examined by immunohistochemistry. The anti-tumor effect of AMD3100 (anti-CXCR4) was tested in GBM explants. In the screening step, the initial-recurrence expression changes contributed to a selection of seven genes (VEGFA, VEGFR2, VEGFR1, CXCL12, CXCR4, uPA HIF1α). By quantitative RT-PCR, RNA expressions of CXCR4 (p = 0.029) and CXCL12 (p = 0.107) were increased while expressions of HIF1α (p = 0.009) and VEGFR2 (p = 0.081) were decreased at recurrence. Similarly, CXCL12 protein expression tended to increase (p = 0.096) while VEGFR2 staining was decreased (p = 0.004) at recurrence. An increase of anti-tumoral effect was observed with the combination of AMD3100 and RT/TMZ versus RT/TMZ alone in GB explants. Recurrence of GB after chemo-radiation could be associated with a switch of angiogenic pattern from VEGFR2-HIF1α to CXCL12-CXCR4 pathway, leading to new perspectives in angiogenic treatment.

Mots clés: glioblastoma; paired; switch; angiogenesis

Domaines: Cancer

Emeline Tabouret, Aurelie Tchoghandjian, Emilie Denicolai, Christine Delfino, Philippe Metellus, et al.. Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway. Oncotarget, 2015, 13, 6, pp.11664-11675. ⟨10.18632/oncotarget.3256⟩. ⟨hal-01437863⟩