gms | German Medical Science

Objective: Gliomas and meningiomas tend to share the same pro-proliferative and anti-apoptotic signaling, resulting in recurrent tumor growth. In both entities activating gene mutations are found in the receptor tyrosine kinase (RTK)/MAP kinase pathway. Therefore it is thought to be a target for targeted inhibition of further tumor growth. Nevertheless, aware of the different cellular origin of gliomas and meningiomas and their different growth kinetics, we were interested in differences in key molecule gene expression levels of the RTK/MAPK pathways in both tumor entities.

Method: RTK gene expression of VEGFR2, PDGFR, IGFR1, the oncogene PI3KCA and tumor suppressor PTEN, MAPK pathway key molecules Raf, Erk1 and Erk2 as well as of the relevant proteins of AKT/mTOR signaling AKT, mTORC1-2, EIF4E-BP and p70S6K were analyzed in 61 glioma specimens (WHO II-IV) and in 65 meningiomas (WHO I-III) using real-time PCR (qPCR) and consequently evaluated applying the comparative dd-Ct method against normal brain and dural tissue,respectively. Additionally we used western blot analysis to correlate the protein expression of p-mTOR, RICTOR, RAPTOR, p-AKT, ERK1/2, Raf, p70S6K and PTEN with our established gene expression levels.

Results: In gliomas gene expression of AKT (r=2.10-4.84), Raf (r=1.42-3.26), Erk1 (r=0.80-1.74), Erk2 (r=1.39-2.46) increased and of mTOR decreased (r=0.54-1.18) from WHO grade II to IV, whereas the RTK receptors PDGFR and VEGFR2 exhibited no significant alterations in their gene expression levels compared to normal brain tissue. In meningiomas overexpression of VEGFR2 (r=2.74-6.16), Raf (r=0.51-1.73) and Erk1 (r=1.12-2.34) was detected in WHO-I-III compared to dural tissue. In contrast PDGFR (r=0.47-0.18) and Erk2 (r=1.11-0.46) showed decreased gene expression levels in meningiomas. Related to these findings western blotting analysis showed contrary results. AKT, Raf and ERK protein levels raised in high-grade gliomas and decreased in high-grade meningiomas.

Conclusions: Analyzing mRNA of gliomas (WHO II-IV) and meningiomas (WHO I-III) by quantitative RT-PCR with regard to gene expression of key factors of the RTK/MAP kinase and AKT/mTOR pathway we detected significant different expression ratios between the WHO grades within each tumor entity on the one, but also intriguing differences between the neuroectodermal glial and mesodermal meningeal tumors on the other hand. MAP kinases in gliomas and RTK receptors, especially VEGFR2, in meningiomas seem to be alternative targets for an individualized tumor therapy.