title: Activation of multiple growth factor signalling pathways is frequent in meningiomas.
abstract: A minority of meningiomas are difficult to treat with surgery or radiotherapy, and chemotherapeutic alternatives are limited. This study aims to better understand pathways that are active in meningiomas, in order to direct future treatment strategies. We investigated the expression and activation of multiple growth factor receptors, their ligands and downstream signalling pathways in 30 meningiomas using immunohistochemistry. Expression was correlated with chromosome 22q loss. Membrane expression of VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR)β was seen in 83% of tumors, Axl in 70%, EGFR in 50% and insulin-like growth factor receptor in 47%. Expression was similar in low- and high-grade tumors, but membrane EGFR expression was not seen in tumors showing chromosome 22q loss (P < 0.05). Expression of ligands (IGF, NRG, VEGF, Gas 6), and signalling proteins (Mek, Erk, Jnk, Akt) and pS6RP, was widespread. Western blot confirmed widespread Axl expression and supported selective expression of EGFR in NF2-intact meningiomas. The majority of meningiomas express and show activation of multiple growth factor receptors and their signalling pathways, irrespective of tumor grade. In addition to previously reported receptors, Axl offers a new therapeutic target. The findings also suggest that anti-EGFR based therapies may be less effective in meningiomas with 22q loss.
authors.affiliation: Department of Cellular and Anatomical Pathology, Derriford Hospital, Plymouth, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Hilton
authors.affiliation: Department of Cellular and Anatomical Pathology, Derriford Hospital, Plymouth, UK.
authors.forename: Aditya
authors.initials: A
authors.lastname: Shivane
authors.affiliation: Department of Cellular and Anatomical Pathology, Derriford Hospital, Plymouth, UK.
authors.forename: Leanne
authors.initials: L
authors.lastname: Kirk
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine & Dentistry, Plymouth, UK.
authors.forename: Kayleigh
authors.initials: K
authors.lastname: Bassiri
authors.affiliation: Plymouth University Peninsula Schools of Medicine & Dentistry, Plymouth, UK.
authors.forename: Doyo G
authors.initials: DG
authors.lastname: Enki
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine & Dentistry, Plymouth, UK.
authors.forename: C Oliver
authors.initials: CO
authors.lastname: Hanemann
mesh_terms: D002892:Chromosomes, Human, Pair 22; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008577:Meningeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008579:Meningioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: NF2 gene; growth factor; meningioma; merlin; protein kinase