Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway
Metrics: PDF 1943 views | HTML 2490 views | ?
Emeline Tabouret1,2, Aurelie Tchoghandjian1, Emilie Denicolai1, Christine Delfino1, Philippe Metellus1,3, Thomas Graillon1,3, Celine Boucard2, Isabelle Nanni4, Laetitia Padovani5, L’Houcine Ouafik1,4, Dominique Figarella-Branger1,6, Olivier Chinot1,2
1Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France
2APHM, Timone Hospital, Department of Neuro-Oncology, Marseille 13005, France
3APHM, Timone Hospital, Department of Neuro-Surgery, Marseille 13005, France
4APHM, North Hospital, Transfer Laboratory, Marseille 13015, France
5APHM, Timone Hospital, Department of Radiotherapy, Marseille 13005, France
6APHM, Timone Hospital, Department of Anatomopathology, Marseille 13005, France
Olivier Chinot, e-mail: [email protected]
Keywords: Angiogenesis, glioblastoma, paired, switch
Received: December 14, 2014 Accepted: January 29, 2015 Published: March 25, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.