Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1.
Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1.
复制标题
DOI：
10.1158/0008-5472.can-09-3769
复制
发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Rubin JB
中科院分区：
文献类型：
--
作者：
Warrington NM;Gianino SM;Jackson E;Goldhoff P;Garbow JR;Piwnica-Worms D;Gutmann DH;Rubin JB
目前的肿瘤发生模型包括慢性炎症和衰老对肿瘤形成模式的贡献。这些致癌途径，涉及白细胞和成纤维细胞是不容易适用于脑肿瘤（神经胶质瘤），和其他机制必须考虑微环境对中枢神经系统肿瘤发生的影响。我们实验室以前的研究采用神经纤维瘤病-1（NF 1）基因工程小鼠（GEM）模型来了解胶质瘤形成对幼儿视通路的空间限制。基于我们的初步研究结果，我们假设脑内cAMP水平的区域特异性差异解释了NF 1胶质瘤形成的模式。为了提供证据表明低水平的cAMP促进神经胶质瘤形成的NF 1，我们产生了减少的cAMP的病灶，在神经胶质瘤很少形成的NF 1儿童的大脑区域。通过在Nf 1 GEM菌株的皮质中强制表达磷酸二酯酶4A 1（PDE 4A 1）实现局灶性cAMP减少。异位PDE 4A 1表达产生具有人NF 1相关胶质瘤特征的高细胞病变。相反，在Nf 1 GEM体内，PDE 4抑制剂Rolipram的cAMP药理学升高显著抑制视神经胶质瘤生长和肿瘤大小。总之，这些结果表明，在易感Nf 1小鼠品系中低水平的cAMP足以促进胶质瘤的发生，并证明了实施基于cAMP的基质靶向治疗胶质瘤的合理性。
Current models of oncogenesis incorporate the contributions that chronic inflammation and aging make to the patterns of tumor formation. These oncogenic pathways, involving leukocytes and fibroblasts are not readily applicable to brain tumors (glioma), and other mechanisms must account for microenvironmental influences on central nervous system tumorigenesis. Previous studies from our laboratories have employed Neurofibromatosis-1 (NF1) genetically-engineered mouse (GEM) models to understand the spatial restriction of glioma formation to the optic pathway of young children. Based on our initial findings, we hypothesize that brain region-specific differences in cAMP levels account for the pattern of NF1 gliomagenesis. To provide evidence that low levels of cAMP promote glioma formation in NF1, we generated foci of decreased cAMP, in brain regions where gliomas rarely form in children with NF1. Focal cAMP reduction was achieved by forced expression of phosphodiesterase 4A1 (PDE4A1) in the cortex of Nf1 GEM strains. Ectopic PDE4A1 expression produced hypercellular lesions with features of human NF1-associated glioma. Conversely, pharmacologic elevation of cAMP with the PDE4 inhibitor Rolipram dramatically inhibited optic glioma growth and tumor size in Nf1 GEM in vivo. Together, these results indicate that low levels of cAMP in a susceptible Nf1 mouse strain are sufficient to promote gliomagenesis, and justify the implementation of cAMP-based stroma-targeted therapies for glioma.