Department of General Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Clin Cancer Res. 2011 Apr 15;17(8):2237-49. doi: 10.1158/1078-0432.CCR-10-1689. Epub 2011 Mar 3.
The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.
Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.
Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R-signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.
We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials.
胸腺癌（TEM）的潜在分子机制尚未完全阐明。因此，目前缺乏有效的靶向治疗方法，患者预后仍然较差，尤其是晚期 TEM 患者。我们旨在研究与这种研究不足的癌症相关的促肿瘤发生机制。
最近建立的源自胸腺癌的细胞系被用作模型系统。通过 MTT 分析和流式细胞术分析细胞活力、细胞周期和细胞凋亡来研究特定热休克蛋白 90（Hsp90）抑制剂的抗肿瘤活性。Western blot 用于研究 Hsp90 客户的改变表达。使用针对选定 Hsp90 客户的药理学抑制剂以及 RNAi 来独立测试每个客户的相关性。进行组织微阵列分析，将体外发现与从患者来源的样本中获得的观察结果相匹配。
Hsp90 抑制显著降低胸腺癌细胞的细胞活力，诱导细胞周期停滞和细胞凋亡，并阻止侵袭性。Hsp90 抑制触发多种致癌客户的降解，例如胰岛素样生长因子 1 受体（IGF-1R）、CDK4 和 PI3K/Akt 和 RAF/Erk 信号的失活。从机制上讲，IGF/IGF-1R 信号轴有助于建立胸癌细胞的抗凋亡表型。最后，IGF-1R 在晚期 TEM 中过度表达。
我们已经揭示了 TEM 中的一种新的促肿瘤发生机制，即 HSP90 赋予 IGF-1R 的过度表达，赋予恶性胸上皮细胞逃避凋亡的能力。我们的数据表明，同时阻断多个癌症特征的 Hsp90 抑制代表了 TEM 的一种治疗策略，可能值得在临床试验中进行评估。
