Hutterer Markus, Knyazev Pjotr, Abate Ariane, Reschke Markus, Maier Hans, Stefanova Nadia, Knyazeva Tatjana, Barbieri Verena, Reindl Markus, Muigg Armin, Kostron Herwig, Stockhammer Guenther, Ullrich Axel
Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Clin Cancer Res. 2008 Jan 1;14(1):130-8. doi: 10.1158/1078-0432.CCR-07-0862.
The receptor tyrosine kinase Axl has recently been identified as a critical element in the invasive properties of glioma cell lines. However, the effect of Axl and its ligand growth arrest--specific gene 6 (Gas6) in human gliomas is still unknown.
Axl and Gas6 expression was studied in 42 fresh-frozen and 79 paraffin-embedded glioma specimens by means of reverse transcription-PCR and immunohistochemistry. The prognostic value of Axl and Gas6 expression was evaluated using a population-based tissue microarray derived from a cohort of 55 glioblastoma multiforme (GBM) patients.
Axl and Gas6 were detectable in gliomas of malignancy grades WHO 2 to 4. Moderate to high Axl mRNA expression was found in 61%, Axl protein in 55%, Gas6 mRNA in 81%, and Gas6 protein in 74% of GBM samples, respectively. GBM patients with high Axl expression and Axl/Gas6 coexpression showed a significantly shorter time to tumor progression and an association with poorer overall survival. Comparative immunohistochemical studies showed that Axl staining was most pronounced in glioma cells of pseudopalisades and reactive astrocytes. Additionally, Axl/Gas6 coexpression was observed in glioma cells and tumor vessels. In contrast, Axl staining was not detectable in nonneoplastic brain tissue and Gas6 was strongly expressed in neurons.
In human gliomas, Axl and Gas6 are frequently overexpressed in both glioma and vascular cells and predict poor prognosis in GBM patients. Our results indicate that specific targeting of the Axl/Gas6 signaling pathway may represent a potential new approach for glioma treatment.
受体酪氨酸激酶Axl最近被确定为胶质瘤细胞系侵袭特性中的关键因素。然而，Axl及其配体生长停滞特异性基因6（Gas6）在人类胶质瘤中的作用仍不清楚。
通过逆转录PCR和免疫组织化学方法，对42例新鲜冷冻和79例石蜡包埋的胶质瘤标本进行Axl和Gas6表达研究。使用来自55例多形性胶质母细胞瘤（GBM）患者队列的基于人群的组织芯片评估Axl和Gas6表达的预后价值。
在世界卫生组织2至4级恶性胶质瘤中可检测到Axl和Gas6。在GBM样本中，分别有61%的样本Axl mRNA表达为中度至高度，55%的样本Axl蛋白表达为中度至高度，81%的样本Gas6 mRNA表达为中度至高度，74%的样本Gas6蛋白表达为中度至高度。Axl高表达和Axl/Gas6共表达的GBM患者肿瘤进展时间明显缩短，且与较差的总生存期相关。比较免疫组织化学研究表明，Axl染色在假栅栏状胶质瘤细胞和反应性星形胶质细胞中最为明显。此外，在胶质瘤细胞和肿瘤血管中观察到Axl/Gas6共表达。相比之下，在非肿瘤性脑组织中未检测到Axl染色，而Gas6在神经元中强烈表达。
在人类胶质瘤中，Axl和Gas6在胶质瘤细胞和血管细胞中均频繁过度表达，并预示GBM患者预后不良。我们的结果表明，特异性靶向Axl/Gas6信号通路可能代表一种潜在的胶质瘤治疗新方法。
