Increased c-Jun-NH2-Kinase Signaling in Neurofibromatosis-1 Heterozygous Microglia Drives Microglia Activation and Promotes Optic Glioma Proliferation
Increased c-Jun-NH2-Kinase Signaling in Neurofibromatosis-1 Heterozygous Microglia Drives Microglia Activation and Promotes Optic Glioma Proliferation
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DOI：
10.1158/0008-5472.can-08-2506
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Gutmann, David H.
中科院分区：
文献类型：
--
作者：
Daginakatte, Girish C.;Gianino, Scott M.;Gutmann, David H.
神经纤维瘤病-1（NF 1）是一种常见的肿瘤易感综合征，其中受影响的个体发展为良性和恶性肿瘤。我们实验室和其他实验室以前的研究表明，Nf 1基因工程小鼠（GEM）中良性肿瘤的形成需要一个宽松的肿瘤微环境。在中枢神经系统中，神经胶质细胞中的Nf 1缺失不足以形成胶质瘤，除非与脑中的Nf 1杂合性相结合。我们随后的研究确定了Nf 1 +/-小胶质细胞作为Nf 1 GEM中视神经胶质瘤生长的关键细胞决定因素。使用NF 1作为进一步表征小胶质细胞在胶质瘤生长中的作用的实验范例，我们首先在体外和体内研究了NF 1 +/-小胶质细胞的性质。Nf 1 +/-小胶质细胞表现出增殖和运动性增加，并表达与小胶质细胞活化相关的基因水平升高。我们进一步表明，Nf 1 +/-小胶质细胞具有高水平的活化c-Jun-NH 2-激酶（JNK），而Akt、丝裂原活化蛋白激酶（MAPK）或p38-MAPK活性没有任何显著变化。相比之下，Nf 1-/-星形胶质细胞不表现出增加的JNK激活。SP 600125对Nf 1 +/-小胶质细胞中JNK活性的抑制可改善增加的增殖和运动表型，并降低活化的小胶质细胞相关转录物的表达水平。此外，SP 600125治疗携带Nf 1视神经胶质瘤的GEM导致体内视神经胶质瘤增殖减少。总的来说，这些研究结果表明，Nf 1 +/-小胶质细胞代表了一个很好的模型系统，研究专门的小胶质细胞在脑肿瘤发生中的作用，并确定了一个独特的Nf 1失调途径，旨在消除促进脑肿瘤生长的微环境信号的治疗研究。[Cancer Res 2008;68（24）：10358-66]
Neurofibromatosis-1 (NF1) is a common tumor predisposition syndrome in which affected individuals develop benign and malignant tumors. Previous studies from our laboratory and others have shown that benign tumor formation in Nf1 genetically engineered mice (GEM) requires a permissive tumor microenvironment. In the central nervous system, Nf1 loss in glia is insufficient for glioma formation unless coupled with Nf1 heterozygosity in the brain. Our subsequent studies identified Nf1+/- microglia as a critical cellular determinant of optic glioma growth in Nf1 GEM. Using NF1 as an experimental paradigm to further characterize the role of microglia in glioma growth, we first examined the properties of Nf1+/- microglia in vitro and in vivo. Nf1+/- microglia exhibit increased proliferation and motility and express elevated levels of genes associated with microglia activation. We further show that Nf1+/- microglia harbor high levels of activated c-Jun-NH2-kinase (JNK) without any significant changes in Akt, mitogen-activated protein kinase (MAPK), or p38-MAPK activity. In contrast, Nf1-/- astrocytes do not exhibit increased JNK activation. SP600125 inhibition of JNK activity in Nf1+/- microglia results in amelioration of the increased proliferation and motility phenotypes and reduces the levels of expression of activated microglia-associated transcripts. Moreover, SP600125 treatment of Nf1 optic glioma-bearing GEM results in reduced optic glioma proliferation in vivo. Collectively, these findings suggest that Nf1+/- microglia represent a good model system to study the role of specialized microglia in brain tumorigenesis and identify a unique Nf1 deregulated pathway for therapeutic studies aimed at abrogating microenvironmental signals that promote brain tumor growth. [Cancer Res 2008;68(24):10358-66]