gms | German Medical Science

Objective: Meningiomas are considered to be benign tumors with slow growth rates and in the majority of cases, complete surgical resection will be curative. However, a certain subset of meningiomas are biologically complex, show a high recurrence rate and a low susceptibility to adjuvant treatment. Invasion of the bone has been shown to be a risk factor for recurrence. We hypothesized that the molecular environment of the bone may induce a more aggressive biology in meningiomas leading to resistance towards adjuvant treatment. We have therefore treated meningioma cells in vitro with hydroxyurea (HU), a chemotherapeutic agent known to induce apoptotic cell death in meningiomas, in the presence or absence of bone specific growth factors (BSGF) such as insulin like growth factor (IGF) I&II, transforming growth factor (TGF) beta 1&2. We subsequently analyzed the toxicity, rate of apoptotic cell deaths and the molecular pathways causing the observed effects.

Methods: Meningioma cell culture was established from 21 tumors resected from 7 male (33.4%) and 14 female (66.6) patients, with a mean age of 62.7 years (range: 43–82 years). The purity of the cultures was defined by immunofluorescent staining for meningioma – specific markers and ultrastructural analysis using transmission electron microsopy. The cells were treated with HU at a concentration of 100 µmol/l, IGF I&II was added at a concentration of 100 ng/ml, TGF beta 1&2 at 10 ng/ml. Treatment with the phosphoinositide 3-kinase (PI3K) inhibitor Wortmannin was performed at 20 µmol/l. Cell toxicity and apoptotic cell death was analyzed by an aquous colorimetric assay and TUNEL labeling respectively. Akt phosphorylation was investigated by Western blotting utilizing pAkt specific antibodies

Results: HU treatment induced significant toxicity and a high rate of apoptotic cell death (p<0.001 vs. ctrl) in all meningioma cultures. However, the presence of BSGF's completely abolished this treatment effect. pAkt Western revealed a strong Akt phophorylation induced by BSGF's, indicating activation of Akt as the major antiapoptotic mechanism. Antagonizing the PI3K/pAkt pathway with Wortmannin completely restored the susceptibility of meningioma cells towards HU.

Conclusions: Our data indicate that the molecular bone microenvironment provides a protective niche to meningioma cells by activation of the PI3K/pAkt pathway leading to a resistance against adjuvant treatment