Rubin Joshua B, Kung Andrew L, Klein Robyn S, Chan Jennifer A, Sun YanPing, Schmidt Karl, Kieran Mark W, Luster Andrew D, Segal Rosalind A
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13513-8. doi: 10.1073/pnas.2235846100. Epub 2003 Oct 31.
The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.
绝大多数成人脑肿瘤具有神经胶质细胞特征。儿童脑肿瘤则多种多样：许多具有神经元特征，而其他一些具有神经胶质细胞特征。在此我们表明，Gi蛋白偶联受体CXCR4的激活对于恶性神经元肿瘤和神经胶质细胞瘤的生长至关重要。全身给予CXCR4拮抗剂AMD 3100可通过增加细胞凋亡和减少肿瘤细胞增殖来抑制颅内胶质母细胞瘤和髓母细胞瘤异种移植物的生长。这反映了AMD 3100降低细胞外信号调节激酶1和2以及Akt激活的能力，所有这些都是CXCR4下游促进存活、增殖和迁移的信号通路。这些研究（i）证明CXCR4对多种脑恶性肿瘤的进展至关重要，（ii）为临床评估AMD 3100治疗成人和儿童恶性脑肿瘤提供了科学依据。
