ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers.
ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers.
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DOI：
10.3389/fonc.2012.00192
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发表时间：
2012
影响因子：
4.7
通讯作者：
Wellstein A
中科院分区：
文献类型：
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作者：
Wellstein A
细胞内间变性淋巴瘤激酶（ALK）片段显示出与胰岛素受体家族成员的惊人同源性，最初被鉴定为一种致癌融合蛋白，由淋巴瘤中的易位引起，最近在一系列癌症中被鉴定为一种致癌融合蛋白。基于这项初步工作，鉴定了约220 kDa的全长ALK跨膜受体。这种酪氨酸激酶受体及其配体，生长因子多效生长因子（PTN）和中期因子（MK）在神经系统和其他器官的发育过程中高度表达。这些基因中的每一个都与不同肿瘤类型的恶性进展有关，并且显示出改变培养的正常细胞和肿瘤细胞中的表型以及信号转导。除了在癌症中的作用外，ALK受体途径还被认为有助于神经系统发育、功能和修复，以及代谢稳态和组织再生的维持。癌症中的ALK受体活性可通过受体细胞内结构域的扩增、过表达、配体结合、突变以及受体酪氨酸磷酸酶PTPRz的活性上调。在这里，我们讨论配体控制ALK活性的证据，以及基因表达和功能研究的潜在预后和治疗意义。对来自不同癌症的18个已发表的基因表达数据集的分析表明，患者癌症组织中ALK、其较小的同系物LTK（白细胞酪氨酸激酶）以及配体PTN和MK的过表达与疾病的恶化过程和结果显著相关。该观察结果与临床前功能研究一起表明，该途径可能是有效的治疗靶点，可以使用小分子激酶抑制剂以及配体或受体抗体的互补靶向策略。
The intracellular anaplastic lymphoma kinase (ALK) fragment shows striking homology with members of the insulin receptor family and was initially identified as an oncogenic fusion protein resulting from a translocation in lymphoma and more recently in a range of cancers. The full-length ALK transmembrane receptor of ~220 kDa was identified based on this initial work. This tyrosine kinase receptor and its ligands, the growth factors pleiotrophin (PTN) and midkine (MK) are highly expressed during development of the nervous system and other organs. Each of these genes has been implicated in malignant progression of different tumor types and shown to alter phenotypes as well as signal transduction in cultured normal and tumor cells. Beyond its role in cancer, the ALK receptor pathway is thought to contribute to nervous system development, function, and repair, as well as metabolic homeostasis and the maintenance of tissue regeneration. ALK receptor activity in cancer can be up-regulated by amplification, overexpression, ligand binding, mutations in the intracellular domain of the receptor and by activity of the receptor tyrosine phosphatase PTPRz. Here we discuss the evidence for ligand control of ALK activity as well as the potential prognostic and therapeutic implications from gene expression and functional studies. An analysis of 18 published gene expression data sets from different cancers shows that overexpression of ALK, its smaller homolog LTK (leukocyte tyrosine kinase) and the ligands PTN and MK in cancer tissues from patients correlate significantly with worse course and outcome of the disease. This observation together with preclinical functional studies suggests that this pathway could be a valid therapeutic target for which complementary targeting strategies with small molecule kinase inhibitors as well as antibodies to ligands or the receptors may be used.