Department of Neuropathology and Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University, Magdeburg, Germany.
Clin Cancer Res. 2013 Mar 1;19(5):1180-9. doi: 10.1158/1078-0432.CCR-12-1904. Epub 2013 Feb 13.
To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models.
Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls.
All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P < 0.01), which was paralleled by reduction of Ki67 mitotic index (P < 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors.
mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival.
评估脑膜瘤中 mTORC1（雷帕霉素哺乳动物靶标复合物 1）通路，并探索 mTORC1 作为脑膜瘤细胞系和小鼠模型中的治疗靶点。
使用组织微阵列（所有 WHO 分级的 53 例脑膜瘤）对 mTOR、Akt 的磷酸化多肽以及 mTORC1 靶标 4EBP1 和 p70S6K（mTORC1 活性的共识标志物）进行染色。通过 Western blot 和实时 PCR 在 25 个肿瘤中评估蛋白质和 mRNA 的表达。使用 Ben-Men-1（良性）、IOMM-Lee 和 KT21（恶性）细胞系以及 Merlin 阳性或阴性脑膜瘤细胞对，来评估 mTORC1 抑制剂在甲基噻唑基四唑和溴脱氧尿苷（BrdUrd）测定中的敏感性。通过治疗 8 只携带皮下 IOMM-Lee 异种移植物的裸鼠（vs. 7 只对照）或 8 只（5 只）颅内移植 IOMM-Lee（KT21）细胞的 8 只（5 只）未处理对照，来测试替西罗莫司（20mg/kg 每日）对肿瘤重量或 MRI 估计的肿瘤体积的影响。
所有脑膜瘤中 mTORC1 通路的所有成分均表达并激活，与 WHO 分级无关。替西罗司和依维莫司均表现出剂量依赖性的生长抑制，所有细胞系均有明显抑制作用。Merlin 缺失时略有减弱。在原位和皮下异种移植模型中，替西罗司治疗导致肿瘤生长减少约 70%（P<0.01），这与 Ki67 有丝分裂指数（P<0.05）和肿瘤内 mTORC1 活性（p70S6K 磷酸化）的降低相平行。
mTORC1 抑制剂可抑制小鼠模型中的脑膜瘤生长，尽管本研究未测量生存率。
