ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice
ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice
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DOI：
10.1158/0008-5472.can-06-1193
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Housman, David
中科院分区：
文献类型：
--
作者：
Charest, Al;Wilker, Erik W.;Housman, David
多形性胶质母细胞瘤是最常见和最致命的原发性脑癌。由于目前的治疗方法无效，这种晚期胶质瘤的诊断预后很差。受体酪氨酸激酶(RTK)在多形性胶质母细胞瘤中的异常表达提示它们在中枢神经系统肿瘤的发生和维持中起作用。事实上，孤儿RTK ROS的异位表达在人类脑癌中是一种常见的事件，但这种表达的病理意义尚不确定。在这里，我们展示了一种与胶质母细胞瘤相关的、配体无关的ROS重排产物(FIG-ROS)与肿瘤抑制基因位点Ink4a；Arf的缺失合作，从而在小鼠中产生胶质母细胞瘤。我们发现，这种由FIG-ROS介导的体内肿瘤形成与肿瘤和肿瘤衍生细胞系中含酪氨酸磷酸酶SH2结构域的磷酸酶-2(SHP-2)和雷帕霉素信号轴的磷脂酰肌醇3-激酶/Akt/哺乳动物靶点的激活平行。我们已经建立了一个与人类疾病中观察到的主要遗传事件相一致的成人多形性胶质母细胞瘤发病的完全穿透性临床前模型。这些发现为ROS和SHP-2功能在实体肿瘤生物学中的作用提供了新的和重要的见解，并为靶向治疗方法的临床前测试奠定了基础。
Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain-containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches.