Abstract
Higher grade meningiomas tend to recur. We aimed to evaluate protein levels of vascular endothelial growth factor (VEGF)-A with the VEGF-receptors 1-3 and the co-receptors Neuropilin (NRP)-1 and -2 in WHO grade II and III meningiomas to elucidate the rationale for targeted treatments. We investigated 232 specimens of 147 patients suffering from cranial meningioma, including recurrent tumors. Immunohistochemistry for VEGF-A, VEGFR-1-3, and NRP-1/-2 was performed on tissue micro arrays. We applied a semiquantitative score (staining intensity x frequency). VEGF-A, VEGFR-1-3, and NRP-1 were heterogeneously expressed. NRP-2 was mainly absent. We demonstrated a significant increase of VEGF-A levels on tumor cells in WHO grade III meningiomas (p = 0.0098). We found a positive correlation between expression levels of VEGF-A and VEGFR-1 on tumor cells and vessels (p < 0.0001). In addition, there was a positive correlation of VEGF-A and VEGFR-3 expression on tumor vessels (p = 0.0034). VEGFR-2 expression was positively associated with progression-free survival (p = 0.0340). VEGF-A on tumor cells was negatively correlated with overall survival (p = 0.0084). The VEGF-A-driven system of tumor angiogenesis might still present a suitable target for adjuvant therapy in malignant meningioma disease. However, its role in malignant tumor progression may not be as crucial as expected. The value of comprehensive testing of the ligand and all receptors prior to administration of anti-angiogenic therapy needs to be evaluated in clinical trials.
Highlights
Meningiomas are the most common brain tumors, mostly of benign nature (Louis et al 2016)
In patients undergoing primary surgery, we identified a significant increase of vascular endothelial growth factor (VEGF)-A on tumor cells in WHO grade III meningiomas compared to WHO grade II meningiomas
Comparing primary and recurrent tumors, there was a trend towards an increase of VEGF-A expression on tumor vessels in the third recurrence as compared to the primary situation (Fig. 3b), significance was lost after Bonferroni correction A trend towards an increase was observed for the receptor vascular endothelial growth factor receptor (VEGFR)-1 in the third recurrence compared to the primary situation (Fig. 3c), but once again significance was lost after the Bonferroni correction for multiple testing was applied
Summary
Meningiomas are the most common brain tumors, mostly of benign nature (Louis et al 2016). We previously reported a 70% recurrence rate within 5 years (Baumgarten et al 2016b). New methylation-based classifications claim to be even more precise than the WHO classification system (Sahm et al 2017; Nassiri et al 2019) but this analysis is only available for a very limited number of centers. Angiogenesis affects glial brain tumors (Plate et al 1992; Baumgarten et al 2016a) but the comprehensive impact is still not clear in higher grade meningiomas. Our previous study with a limited amount of patients and a short follow-up investigating vascular endothelial growth factor (VEGF) and its two receptors, vascular endothelial growth factor receptor (VEGFR) (flt1) and VEGFR-2 (flt-1/KDR), demonstrated heterogeneous
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