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

Emeline Tabouret,Philippe Metellus,Thomas Graillon,Olivier Chinot,Celine Boucard,Laetitia Padovani,Isabelle Nanni,Dominique Figarella-Branger,Aurelie Tchoghandjian,L’Houcine Ouafik,Christine Delfino,Emilie Denicolai

doi:10.18632/oncotarget.3256

Abstract

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.

Highlights

Glioblastoma (GBM) is the most frequently occurring primary brain tumor among adults and is one of the most lethal tumors
All patients were treated with radiochemotherapy as first-line treatment
We did not identify a molecular angiogenic signature of recurrence, we observed a switch from VEGFR2-HIF1α to CXCL12CXCR4 expression at recurrence, and our results were largely consistent between RNA and protein expression

Summary

Introduction

Glioblastoma (GBM) is the most frequently occurring primary brain tumor among adults and is one of the most lethal tumors. Bevacizumab has been found to exhibit remarkable activity for patients with recurrent GBM, with response rates ranging from 30% to 50% [4, 5]. These results compare favorably with chemotherapy alone with regard to recurrence [6]. Bevacizumab was investigated in the first-line setting in two large randomized phase III trials (AVAglio [7] and RTOG 0825 [8]). In these trials, progression-free survival (PFS) was www.impactjournals.com/oncotarget

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