Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California-San Diego and the VA San Diego Healthcare System, San Diego, California, USA.
Otol Neurotol. 2011 Feb;32(2):308-14. doi: 10.1097/MAO.0b013e318206fc3d.
Vestibular schwannomas (VSs) are slow-growing benign tumors but, on rare occasion, can invade adjacent cranial nerves, causing significant morbidity, especially in association with neurofibromatosis 2 (NF2). We aimed to determine the role of the growth factors EGF, bFGF, and the hormone, Epo, in promoting such invasive behavior in VS, as well as their mechanisms of action.
Immunohistochemical staining showed expression of EGFR, bFGF, Epo, EpoR in archived VS tissue. Western blots and immunofluorescence showed expression of EGFR, EpoR and FGF in HEI-193, an immortalized cell line derived from human NF2-related VS. Matrigel invasion assays were used to study the effect of Epo, FGF and bFGF on invasive behavior in HEI-193. Western blotting showed levels of phospho-Akt and phospho-Erk in HEI-193 upon addition of growth factors plus PI3K or MEK inhibitors. Quantitative RT-PCR was performed to determine the expression of MMP2 and MMP9 after treatment with growth factors.
EGFR, bFGF, Epo and EpoR were expressed in VS tissue and HEI193. Addition of EGF and bFGF increased cellular invasion by 10 and 3.5-fold, respectively. Epo had minimal effect on invasion. Results indicated that Erk is involved in bFGF but not EGF-induced invasion, while Akt is involved in both pathways. EGF treatment moderately induced MMP9, but is unlikely to account for the observed invasion.
Activation of EGFR and FGFR may promote invasive behavior in VS through ERK and Akt signaling pathways. Further investigation will be necessary to elucidate their potential as useful targets in the treatment of VS.
前庭神经鞘瘤（VSs）是生长缓慢的良性肿瘤，但在极少数情况下，可侵犯邻近颅神经，导致显著的发病率，尤其是与神经纤维瘤病 2 型（NF2）相关时。我们旨在确定表皮生长因子（EGF）、碱性成纤维细胞生长因子（bFGF）和激素 Epo 在促进 VS 这种侵袭行为中的作用，以及它们的作用机制。
免疫组织化学染色显示 EGFR、bFGF、Epo、EpoR 在存档的 VS 组织中的表达。Western blot 和免疫荧光显示 EGFR、EpoR 和 FGF 在源自人类 NF2 相关 VS 的永生化细胞系 HEI-193 中的表达。Matrigel 侵袭实验用于研究 Epo、FGF 和 bFGF 对 HEI-193 侵袭行为的影响。Western blot 显示在添加生长因子加 PI3K 或 MEK 抑制剂后，HEI-193 中磷酸化 Akt 和磷酸化 Erk 的水平。进行定量 RT-PCR 以确定在生长因子处理后 MMP2 和 MMP9 的表达。
EGFR、bFGF、Epo 和 EpoR 在 VS 组织和 HEI193 中表达。添加 EGF 和 bFGF 可分别使细胞侵袭增加 10 倍和 3.5 倍。Epo 对侵袭的影响最小。结果表明，Erk 参与 bFGF 但不参与 EGF 诱导的侵袭，而 Akt 参与两条途径。EGF 处理适度诱导 MMP9，但不太可能解释观察到的侵袭。
EGFR 和 FGFR 的激活可能通过 ERK 和 Akt 信号通路促进 VS 的侵袭行为。进一步的研究将有必要阐明它们作为 VS 治疗有用靶点的潜力。
