Warrington Nicole M, Woerner B Mark, Daginakatte Girish C, Dasgupta Biplab, Perry Arie, Gutmann David H, Rubin Joshua B
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cancer Res. 2007 Sep 15;67(18):8588-95. doi: 10.1158/0008-5472.CAN-06-2220.
Astrocytoma (glioma) formation in neurofibromatosis type 1 (NF1) occurs preferentially along the optic pathway during the first decade of life. The molecular basis for this unique pattern of gliomagenesis is unknown. Previous studies in mouse Nf1 optic glioma models suggest that this patterning results from cooperative effects of Nf1 loss in glial cells and the action of factors derived from the surrounding Nf1+/- brain. Because CXCL12 is a stroma-derived growth factor for malignant brain tumors, we tested the hypothesis that CXCL12 functions in concert with Nf1 loss to facilitate NF1-associated glioma growth. Whereas CXCL12 promoted cell death in wild-type astrocytes, it increased Nf1-/- astrocyte survival. This increase in Nf1-/- astrocyte survival in response to CXCL12 was due to sustained suppression of intracellular cyclic AMP (cAMP) levels. Moreover, the ability of CXCL12 to suppress cAMP and increase Nf1-/- astrocyte survival was a consequence of mitogen-activated protein/extracellular signal-regulated kinase kinase-dependent inhibition of CXCL12 receptor (CXCR4) desensitization. In support of an instructive role for CXCL12 in facilitating optic glioma growth, we also show that CXCL12 expression along the optic pathway is higher in infant children and young mice and is associated with low levels of cAMP. CXCL12 expression declines in multiple brain regions with increasing age, correlating with the age-dependent decline in glioma growth in children with NF1. Collectively, these studies provide a mechanism for the unique pattern of NF1-associated glioma growth.
1型神经纤维瘤病（NF1）中的星形细胞瘤（胶质瘤）形成在生命的第一个十年中优先沿着视神经通路发生。这种独特的胶质瘤发生模式的分子基础尚不清楚。先前在小鼠Nf1视神经胶质瘤模型中的研究表明，这种模式是由神经胶质细胞中Nf1缺失的协同作用以及来自周围Nf1+/-脑的因子的作用导致的。由于CXCL12是恶性脑肿瘤的一种基质衍生生长因子，我们测试了CXCL12与Nf1缺失协同作用以促进NF1相关胶质瘤生长的假设。虽然CXCL12促进野生型星形胶质细胞的细胞死亡，但它增加了Nf1-/-星形胶质细胞的存活。Nf1-/-星形胶质细胞对CXCL12的存活增加是由于细胞内环磷酸腺苷（cAMP）水平的持续抑制。此外，CXCL12抑制cAMP并增加Nf1-/-星形胶质细胞存活的能力是丝裂原活化蛋白/细胞外信号调节激酶激酶依赖性抑制CXCL12受体（CXCR4）脱敏的结果。为了支持CXCL12在促进视神经胶质瘤生长中的指导作用，我们还表明，婴幼儿和幼鼠视神经通路中的CXCL12表达较高，并且与低水平的cAMP相关。随着年龄的增长，多个脑区的CXCL12表达下降，这与NF1儿童中胶质瘤生长的年龄依赖性下降相关。这些研究共同提供了NF1相关胶质瘤生长独特模式的机制。
