Studies on the role of platelet-derived growth factor (PDGF) in human meningiomas

Abstract

Over-expression of platelet-derived growth factor is critically involved in the development of a number of tumor types. Expression of PDGF and its receptors PDGFR-α and PDGFR-β has also been shown in previous studies in human meningiomas. We have investigated the expression, functional role and some aspects of mechanism of action of PDGF isoforms (PDGF-AA, PDGF-AB, PDGF-BB) and PDGF-receptors in tissue and primary cell cultures of 25 human meningiomas. Immunohistochemical studies of the meningiomas showed that most tumors expressed PDGF-β-receptors, whereas PDGF-α-receptors could be found in only a few tumors. In studies in meningioma cell cultures, PDGF isoforms had a heterogeneous effect on cell proliferation and only in few cases a significant stimulation was observed. PDGF-AA, PDGF-AB or PDGF-BB also variably influenced the mRNA synthesis and secretion of vascular endothelial growth factors VEGF121 and VEGF165 and mostly inhibited VEGF secretion. This was somewhat surprising since we observed, that PDGF isoforms activated the PI3 kinase/mTOR signaling pathway and enhanced the production of a downstream target of mTOR, hypoxia-inducible factor-1α, which is a transcription factor strongly inducing VEGF production. Due to the poor tumorigenic effects of PDGF isoforms, Gleevec, a PDGF receptor tyrosine kinase inhibitor had only poor anti-tumorigenic effects in meningioma cell cultures. In contrast, the mTOR inhibitor RAD001 and the plant compound curcumin strongly suppressed the proliferation of meningioma cells indicating that these substances are promising tools for the development of pharmacological treatment concepts of meningiomas.