Occurrence of Fibrotic Tumor Vessels in Grade I Meningiomas Is Strongly Associated with Vessel Density, Expression of VEGF, PlGF, IGFBP-3 and Tumor Recurrence

SIMPLE SUMMARY: Meningiomas are one of the most common intracranial tumors and although up to 80% of meningiomas are classified as WHO grade I (benign), recurrence rates of up to 20% have been described. Surgical resection is the first-line therapy for meningiomas, but is not always possible depending on the location of the tumor. Therefore, the detection of predictive biomarkers and potential therapeutic targets is important for the postoperative care of meningioma patients. The analysis of tumor samples from a group of 297 meningioma patients demonstrated that histologically detected fibrotic tumor vessels (FTV) correlated with an increased risk of patient recurrence and with characteristic changes in radiological imaging. In addition, FTV were associated with increased vessel density and expression of VEGF, PlGF and IGFBP-3, which could serve as potential therapeutic markers. ABSTRACT: Angiogenesis is a key feature during oncogenesis and remains a potential target of antiangiogenic therapy. While commonly described in high-grade lesions, vascularization and its correlation with prognosis in grade I meningiomas is largely unexplored. In the histological classification, not only the number but also the composition of blood vessels seems to be important. Therefore, tumor vessel density and fibrosis were correlated with clinical and imaging variables and prognosis in 295 patients with intracranial grade I meningioma. Expression of pro-angiogenic proteins within the meningiomas was investigated by proteome analyses and further validated by immunohistochemical staining. Fibrotic tumor vessels (FTV) were detected in 48% of all tumors and strongly correlated with vessel density, but not with the histopathological tumor subtype. Occurrence of FTV was correlated with a 2-fold increased risk of recurrence in both univariate and multivariate analyses. Explorative proteome analyses revealed upregulation of VEGF (vascular endothelial growth factor), PlGF (placental growth factor), and IGFBP-3 (insulin-like growth factor-binding protein-3) in tumors displaying FTV. Immunohistochemical analyses confirmed strong correlations between tumor vessel fibrosis and expression of VEGF, PlGF, and IGFBP-3. Presence of FTV was strongly associated with disruption of the arachnoid layer on preoperative MRI in univariate and multivariate analyses. In summary, the occurrence of fibrotic tumor vessels in grade I meningiomas is strongly associated with vessel density, disruption of the arachnoid layer, expression of VEGF, PlGF, IGFBP-3 and tumor recurrence.