Potential Role of Imatinib Mesylate (Gleevec, STI-571) in the Treatment of Vestibular Schwannoma
Potential Role of Imatinib Mesylate (Gleevec, STI-571) in the Treatment of Vestibular Schwannoma
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DOI：
10.1097/mao.0b013e3182009665
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发表时间：
2011-01-01
影响因子：
2.1
通讯作者：
Ongkeko, Weg M.
中科院分区：
文献类型：
--
作者：
Altuna, Xabier;Lopez, Jay Patrick;Ongkeko, Weg M.
假设：目的：探讨酪氨酸激酶血小板源性生长因子受体（PDGFR）和c-Kit在前庭神经鞘瘤（VS）中的表达，以及甲磺酸伊马替尼（Gleevec）在调节该肿瘤生长和细胞死亡中的作用。它们在影响细胞增殖、肿瘤发生、癌症侵袭、转移和细胞凋亡调节的许多过程中具有关键作用。这些激酶中的一些已被证明是过度表达和失调，在许多癌，肉瘤，和良性tumors.Methods：免疫组化染色，用于研究PDGFR和c-Kit在存档的听神经瘤组织中的表达。临床数据，包括肿瘤的大小，年龄，性别和症状与激酶的表达，而蛋白质印迹分析和免疫荧光进行证明的表达和定位的PDGFR和c-Kit在HEI 193，永生化VS细胞系。进行克隆形成存活测定以评估格列卫的增殖抑制。结果：在34例经福尔马林固定的VS肿瘤组织中，有23例（67.5%）表达PDGFR。C-kit阳性率为52.9%（18/34）。Western印迹分析表明c-Kit和PDGFR-Q在HEI 193和原代VS培养物中呈阳性表达。Western印迹分析显示5和10 μ M格列卫下调磷酸-c-kit和磷酸-PDGFR-Q。该细胞系的免疫荧光染色还揭示了PDGFR-A主要定位于细胞质中，而c-Kit既位于细胞核中又位于细胞质中。在与格列卫孵育96小时后，HEI 193的细胞周期分析表明，在5和10 μ M格列卫下，G1分别从61.6%增加到70.7%和74%，这是剂量依赖性的。集落形成实验表明，格列卫在HEI 193细胞系以及新鲜肿瘤来源的VS细胞培养物中具有剂量依赖性的生长抑制作用。结论：PDGFR-Q和c-Kit在VS组织中的表达可能是参与该肿瘤发展的新的分子靶点。格列卫对这些分子的直接抑制可能具有相关的治疗应用。
Hypothesis: To determine the expression of the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and c-Kit in vestibular schwannoma (VS) and to determine the potential role of imatinib mesylate (Gleevec) in regulating the growth and cell death of this tumor.Background: Protein tyrosine kinases are transmembrane tyrosine kinase receptors that transduce signals from inside and outside the cell and function as relay points for signaling pathways. They have a key role in numerous processes that affect cell proliferation, tumorigenesis, cancer invasion, metastasis, and modulation of apoptosis. A few of these kinases have been demonstrated to be overexpressed and dysregulated in many carcinomas, sarcomas, and benign tumors.Methods: Immunohistochemical staining was used to investigate the expression of PDGFR and c-Kit in archived acoustic neuroma tissue. Clinical data including size of tumors, age, sex, and symptoms were correlated with kinase expression, whereas Western blot analysis and immunofluorescence were performed to demonstrate the expression and localization of PDGFR and c-Kit in HEI193, an immortalized VS cell line. Clonogenic survival assays were performed to assess proliferation inhibition by Gleevec. Gleevec's effect on the cell cycle profile also was investigated via flow cytometry analysis.Results: Expression of PDGFR in the formalin-fixed VS tumor tissue was observed in 23 (67.5%) of the 34 samples. C-kit was expressed in 18 (52.9%) of the 34 samples. Western blot analysis demonstrates positive expression of c-Kit and PDGFR-Q in HEI193 and a primary VS culture. Western blot analysis showed downregulation of phospho-c-kit and phospho-PDGFR-Q with 5 and 10 uM Gleevec. Immunofluorescent staining of this cell line also reveals that PDGFR-A is localized primarily in the cytoplasm, whereas c-Kit is both nuclear and cytoplasmic. Cell cycle analysis of HEI193 96 hours after incubation with Gleevec indicates a dose-dependent increase in G1 from 61.6% to 70.7% and 74% at 5 and 10 uM of Gleevec, respectively. Colony formation assays demonstrate dose-dependent growth inhibition by Gleevec, in the HEI193 cell line as well as in a VS cell culture derived from a fresh tumor.Conclusion: The expression of PDGFR-Q and c-Kit in VS tissue may indicate novel molecular targets involved in the development of this tumor. Direct inhibition of these molecules by Gleevec may have relevant therapeutic applications.