Departments of Neurological Surgery.
Psychiatry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60616, and.
J Neurosci. 2019 Mar 13;39(11):1982-1993. doi: 10.1523/JNEUROSCI.1589-18.2018. Epub 2019 Jan 16.
Glioblastoma (GBM) is one of the most aggressive and lethal tumor types. Evidence continues to accrue indicating that the complex relationship between GBM and the brain microenvironment contributes to this malignant phenotype. However, the interaction between GBM and neurotransmitters, signaling molecules involved in neuronal communication, remains incompletely understood. Here we examined, using human patient-derived xenograft lines, how the monoamine dopamine influences GBM cells. We demonstrate that GBM cells express dopamine receptor 2 (DRD2), with elevated expression in the glioma-initiating cell (GIC) population. Stimulation of DRD2 caused a neuron-like hyperpolarization exclusively in GICs. In addition, long-term activation of DRD2 heightened the sphere-forming capacity of GBM cells, as well as tumor engraftment efficiency in both male and female mice. Mechanistic investigation revealed that DRD2 signaling activates the hypoxia response and functionally alters metabolism. Finally, we found that GBM cells synthesize and secrete dopamine themselves, suggesting a potential autocrine mechanism. These results identify dopamine signaling as a potential therapeutic target in GBM and further highlight neurotransmitters as a key feature of the pro-tumor microenvironment. This work offers critical insight into the role of the neurotransmitter dopamine in the progression of GBM. We show that dopamine induces specific changes in the state of tumor cells, augmenting their growth and shifting them to a more stem-cell like state. Further, our data illustrate that dopamine can alter the metabolic behavior of GBM cells, increasing glycolysis. Finally, this work demonstrates that GBM cells, including tumor samples from patients, can synthesize and secrete dopamine, suggesting an autocrine signaling process underlying these results. These results describe a novel connection between neurotransmitters and brain cancer, further highlighting the critical influence of the brain milieu on GBM.
胶质母细胞瘤（GBM）是最具侵袭性和致命性的肿瘤类型之一。越来越多的证据表明，GBM 与大脑微环境之间的复杂关系促成了这种恶性表型。然而，GBM 与神经递质之间的相互作用，即参与神经元通讯的信号分子，仍不完全清楚。在这里，我们使用人源肿瘤异种移植系研究了单胺多巴胺如何影响 GBM 细胞。我们证明 GBM 细胞表达多巴胺受体 2（DRD2），在神经胶质瘤起始细胞（GIC）群体中表达上调。DRD2 的刺激仅在 GIC 中引起神经元样超极化。此外，DRD2 的长期激活提高了 GBM 细胞的球体形成能力，以及在雄性和雌性小鼠中的肿瘤植入效率。机制研究表明，DRD2 信号激活了缺氧反应，并在功能上改变了代谢。最后，我们发现 GBM 细胞自身合成和分泌多巴胺，提示存在潜在的自分泌机制。这些结果表明多巴胺信号是 GBM 的一个潜在治疗靶点，并进一步强调了神经递质是促肿瘤微环境的关键特征。这项工作为多巴胺在 GBM 进展中的作用提供了关键的见解。我们表明，多巴胺诱导肿瘤细胞状态的特定变化，增强其生长并将其转变为更类似于干细胞的状态。此外，我们的数据表明，多巴胺可以改变 GBM 细胞的代谢行为，增加糖酵解。最后，这项工作表明，GBM 细胞，包括来自患者的肿瘤样本，可以合成和分泌多巴胺，提示这些结果存在自分泌信号过程。这些结果描述了神经递质和脑癌之间的一种新联系，进一步强调了大脑环境对 GBM 的关键影响。
