title: Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway.
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.
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.|APHM, Timone Hospital, Department of Neuro-Oncology, Marseille 13005, France.
authors: Emeline
authors: E
authors: Tabouret
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.
authors: Aurelie
authors: A
authors: Tchoghandjian
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.
authors: Emilie
authors: E
authors: Denicolai
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.
authors: Christine
authors: C
authors: Delfino
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.|APHM, Timone Hospital, Department of Neuro-Surgery, Marseille 13005, France.
authors: Philippe
authors: P
authors: Metellus
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.|APHM, Timone Hospital, Department of Neuro-Surgery, Marseille 13005, France.
authors: Thomas
authors: T
authors: Graillon
authors: APHM, Timone Hospital, Department of Neuro-Oncology, Marseille 13005, France.
authors: Celine
authors: C
authors: Boucard
authors: APHM, North Hospital, Transfer Laboratory, Marseille 13015, France.
authors: Isabelle
authors: I
authors: Nanni
authors: APHM, Timone Hospital, Department of Radiotherapy, Marseille 13005, France.
authors: Laetitia
authors: L
authors: Padovani
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.|APHM, North Hospital, Transfer Laboratory, Marseille 13015, France.
authors: L'Houcine
authors: L
authors: Ouafik
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.|APHM, Timone Hospital, Department of Anatomopathology, Marseille 13005, France.
authors: Dominique
authors: D
authors: Figarella-Branger
authors: Aix-Marseille Univ, CRO2, UMR 911, Marseille 13284, France.|APHM, Timone Hospital, Department of Neuro-Oncology, Marseille 13005, France.
authors: Olivier
authors: O
authors: Chinot
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001596:Benzylamines; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D000080027:Cyclams; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005909:Glioblastoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction; D000077204:Temozolomide; D013997:Time Factors; D046509:Tissue Culture Techniques; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; C497442:HIF1A protein, human; D006571:Heterocyclic Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4; D003606:Dacarbazine; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C088327:plerixafor; D000077204:Temozolomide
keywords: angiogenesis; glioblastoma; paired; switch