Vascular endothelial growth factor signals through platelet-derived growth factor receptor β in meningiomas in vitro

Abstract

Background:Vascular endothelial growth factor (VEGF)-mediated angiogenesis mediates tumour growth and metastasis. Meningiomas are primarily benign, slow-growing, highly vascularised tumours. Aside from VEGF, there is little data on the function of major angiogenic proteins in meningiomas.Methods:The VEGFA, platelet-derived growth factor B (PDGFB), and their respective receptors – VEGF receptor 2 (KDR) and PDGF receptor β (PDGFRβ) – were quantified using real-time PCR and a TaqMan Protein Assay in meningiomas in vivo and in vitro. The effect of VEGFA and PDGFB on cell proliferation and the tyrosine phosphorylation of PDGFRβ were examined.Results:Most meningiomas displayed no KDR protein expression but elevated PDGFRβ levels. Exogenous VEGFA stimulation significantly increased cell proliferation. The PDGFRβ inhibition before stimulation with VEGFA abolished the proliferative stimuli. The VEGFA induced concentration-dependent PDGFRβ tyrosine phosphorylation comparable to PDGFB-induced PDGFRβ tyrosine phosphorylation. The PDGFRβ inhibitors gambogic acid, sunitinib, and tandutinib equally impaired the migration of meningioma cells. In addition, gambogic acid suppressed the VEGFA-induced PDGFRβ tyrosine phosphorylation.Conclusion:Collectively, our data suggest that VEGFA primarily regulates VEGF-mediated migration through PDGFRβ in meningiomas. The inhibitory effect of gambogic acid and tandutinib against meningioma growth in vitro suggests that selective PDGFRβ inhibitors, in combination with VEGF inhibitors, should be evaluated further as potential therapies for recurrent and malignant meningiomas.

Characteristics of the expression of KAI1/CD82 and PDGFRβ and their impact on glioma progression

“…Specific chemotactic signaling pathways are involved in the regulation of tumor cell motility [22]. In agreement with earlier data [14,16,21,31], we found the PDGFRβ expression more frequently in grade III and IV than in grade I and II gliomas. Some authors suggest that the autocrine and paracrine stimulation of PDGFRβ could play an essential role in glial tumorigenesis [4,31].…”

“…The correlation of PDGFRβ expression with the WHO high grade gliomas observed in the current study is partly linked to other data which suggest that this receptor is a crucial factor which regulates angiogenesis and might indirectly facilitate dissemination of tumor cells from primary tumor mass and invade normal brain tissue [21]. The role of PDGFRβ in invasion of tumor cells was revealed by inhibition of cell migration by suppression of PDGFRβ tyrosine phosphorylation [16].…”

Review of controversies in management of non-benign meningioma

“…It was shown to be efficacious against meningioma cell lines and against recurrent benign meningioma in vitro [79][80][81]82].…”

Recent developments in chemotherapy for meningiomas: a review

“…Several small-scale retrospective studies have been published, with mixed results, 42,49,55 and there is a need for larger Phase II trials. The VEGF has also been shown to crossactivate other growth factor pathways, 59 an observation that seems to be a recurring theme with new advances in understanding of cell signaling in meningiomas.…”