Kothmaier H, Quehenberger F, Halbwedl I, Morbini P, Demirag F, Zeren H, Comin C E, Murer B, Cagle P T, Attanoos R, Gibbs A R, Galateau-Salle F, Popper H H
Institute of Pathology, Statistics and Documentation, Medical University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria.
Thorax. 2008 Apr;63(4):345-51. doi: 10.1136/thx.2007.085241. Epub 2007 Dec 17.
Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival <3 years; STS) and long term survivors (survival >3 years; LTS) of MPM.
37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology.
Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS.
We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.
恶性胸膜间皮瘤（MPM）是一种与石棉相关的肿瘤，难以早期发现并有效治疗。石棉会引发基因修饰和细胞信号转导事件，从而使MPM对细胞凋亡和化疗产生抗性。只有少数患者（约10%）能存活超过3年。我们研究的目的是评估MPM短期存活者（存活时间<3年；STS）和长期存活者（存活时间>3年；LTS）在信号通路方面可能存在的差异。
通过组织微阵列（TMA）技术研究了37种检测参与细胞信号通路、促进增殖、抗凋亡、血管生成及其他细胞活动的蛋白质的抗体。
表皮生长因子受体（EGFR）在LTS中表达更强，而血小板衍生生长因子受体（PDGFR）信号在STS中更为丰富。TIE2/Tek是一种参与血管生成的酪氨酸激酶受体，其表达通过PDGFR受到不同调节，因此在STS中更为重要。在STS中，信号转导和转录激活因子1（STAT1）-生存素及相关分子上调了抗凋亡作用，但在LTS中未出现这种情况。我们的研究为MPM信号通路的调节机制提供了新见解，这些机制在LTS和STS中对肿瘤生长的促进作用有所不同。
我们已经证明，通过TMA、免疫组织化学和统计方法的有力结合，可以进行小规模蛋白质组学研究，以识别可能成为治疗干预相关靶点的蛋白质。
