1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. [3].
Nat Neurosci. 2014 Jan;17(1):46-55. doi: 10.1038/nn.3597. Epub 2013 Dec 8.
Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.
脑肿瘤起始细胞 (BTICs) 有助于神经胶质瘤的发生和复发。我们研究了丰富存在于神经胶质瘤中的小胶质细胞和巨噬细胞是否会改变 BTIC 的生长。我们发现，源自非神经胶质瘤的人类供体的小胶质细胞通过诱导控制细胞周期停滞和分化的基因表达，显著减轻了来自神经胶质瘤患者的 BTIC 在培养中的球体形成能力。这种减少球体的作用可以被巨噬细胞模拟，但不能被神经元或星形胶质细胞模拟。通过药物筛选，我们验证了两性霉素 B (AmpB) 作为单核细胞样细胞的激活剂，并发现 AmpB 增强了小胶质细胞对 BTIC 球体的减少作用。在携带颅内鼠源或患者源性 BTIC 的小鼠中，每日给予非毒性剂量的 AmpB 可显著延长生存期。值得注意的是，来自神经胶质瘤患者的小胶质细胞和单核细胞在减少自体 BTIC 的球体形成能力方面效率低下，但 AmpB 可以纠正这一点。这些结果为神经胶质瘤的治疗提供了新的见解。
