Object: Vascular endothelial growth factor (VEGF) has been implicated in meningioma tumorigenesis and growth. The production of VEGF is regulated by hypoxia inducible factor-1alpha (HIF-1alpha), especially under conditions of hypoxia. In this study, the authors examine the expression of HIF-1alpha and VEGF in meningiomas, with a special emphasis on conditions of hypoxia, such as preoperative embolization, and on in vitro studies in cultured cells.
Methods: Meningiomas obtained in 142 patients were studied using immunohistochemical methods to detect HIF-1alpha and the results were correlated with the extent or lack of preoperative embolization and expression of VEGF. Primary meningioma cell cultures were established and cell culture experiments were performed using a hypoxia chamber to stimulate HIF-1alpha and VEGF production. Expression of HIF-1alpha in primary meningioma cell cultures was measured using immunoblot assays. The VEGF secretion was measured using enzyme-linked immunosorbent assay. Half of the meningiomas studied were positive for HIF-1alpha, with a strong correlation between complete embolization and HIF-1alpha expression. Most of the meningiomas studied expressed VEGF protein, and VEGF expression did not correlate with the degree of embolization. A strong correlation was found between VEGF and HIF-1alpha expression in immunohistochemical studies. Secretion of VEGF is increased by hypoxia and growth factor stimulation. In meningiomas, growth factors stimulate HIF-1alpha expression. The role of hypoxia is less clear.
Conclusions: The expression of HIF-1alpha is increased by complete preoperative embolization of meningiomas. The expression of HIF-1alpha also correlates with VEGF secretion in meningiomas. Growth factor and hypoxic stimulation both contribute to VEGF control, but which is most important (or whether both are equally important) will require further studies.