Functional significance of vascular endothelial growth factor receptor expression on human glioma cells

Vascular endothelial growth factor (VEGF) is one of the most important angiogenesis factors. In many tumors, VEGF plays a pivotal role for their vascularization and is necessary to supply the malignant tissue with oxygen and nutrients. However, VEGF receptors (VEGFR) have recently been detected also on some tumor cells, and autocrine mitogenic effects of VEGF have been suspected. Since glioma cells are known to produce large amounts of VEGF, we investigated VEGFR-expression and effects of VEGF on glioma cells. The three glioma cell lines and eight glioma cells cultivated from WHO grade IV gliomas investigated strongly expressed VEGF121 and VEGF165, but weakly either VEGFR-1 or -2, sometimes for both, as evidenced by reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry. Quantitative RT-PCR revealed a 1000- to 50-fold lower expression of VEGFR than in cultivated human umbilical vein endothelial cells. In two glioma cell lines analyzed, VEGF induced a weak tyrosine phosphorylation of the VEGFR, but downstream signal transduction effects on the mitogen-activated protein kinases p42/p44 or transcription factors like AP-1 or NFKB were within the background of the methods. In accordance, VEGF or the VEGFR agonists VEGF-D or placenta growth factor (P1GF) did not produce significant effects on glioma cell proliferation or VEGF production. We conclude that despite a low expression of VEGFR in some glioma cells functional effects are low and autocrine growth stimulatory effects within a glioma are minor.