Skjellegrind Håvard K, Fayzullin Artem, Johnsen Erik O, Eide Lars, Langmoen Iver A, Moe Morten C, Vik-Mo Einar O
Vilhelm Magnus Laboratory for Neurosurgical Research, Department of Neurosurgery and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
Center for Eye Research, Department of Ophthalmology, Oslo University Hospital, Oslo, Norway.
Neurochem Res. 2016 Jul;41(7):1545-58. doi: 10.1007/s11064-016-1868-2. Epub 2016 Feb 25.
Glioblastoma is the most common and malignant brain cancer. In spite of surgical removal, radiation and chemotherapy, this cancer recurs within short time and median survival after diagnosis is less than a year. Glioblastoma stem cells (GSCs) left in the brain after surgery is thought to explain the inevitable recurrence of the tumor. Although hypoxia is a prime factor contributing to treatment resistance in many cancers, its effect on GSC has been little studied. Especially how differentiation influences the tolerance to acute hypoxia in GSCs is not well explored. We cultured GSCs from three patient biopsies and exposed these and their differentiated (1- and 4-weeks) progeny to acute hypoxia while monitoring intracellular calcium and mitochondrial membrane potential (ΔΨm). Undifferentiated GSCs were not hypoxia tolerant, showing both calcium overload and mitochondrial depolarization. One week differentiated cells were the most tolerant to hypoxia, preserving intracellular calcium stability and ΔΨm during 15 min of acute hypoxia. After 4 weeks of differentiation, mitochondrial mass was significantly reduced. In these cells calcium homeostasis was maintained during hypoxia, although the mitochondria were depolarized, suggesting a reduced mitochondrial dependency. Basal metabolic rate increased by differentiation, however, low oxygen consumption and high ΔΨm in undifferentiated GSCs did not provide hypoxia tolerance. The results suggest that undifferentiated GSCs are oxygen dependent, and that limited differentiation induces relative hypoxia tolerance. Hypoxia tolerance may be a factor involved in high-grade malignancy. This warrants a careful approach to differentiation as a glioblastoma treatment strategy.
胶质母细胞瘤是最常见且恶性程度最高的脑癌。尽管进行了手术切除、放疗和化疗，但这种癌症仍会在短时间内复发，确诊后的中位生存期不到一年。手术后留在大脑中的胶质母细胞瘤干细胞（GSCs）被认为是肿瘤不可避免复发的原因。尽管缺氧是许多癌症中导致治疗耐药性的主要因素，但其对GSCs的影响研究较少。特别是分化如何影响GSCs对急性缺氧的耐受性尚未得到充分探索。我们从三名患者的活检组织中培养了GSCs，并将这些细胞及其分化（1周和4周）后的子代暴露于急性缺氧环境中，同时监测细胞内钙和线粒体膜电位（ΔΨm）。未分化的GSCs不耐受缺氧，表现出钙超载和线粒体去极化。分化1周的细胞对缺氧耐受性最强，在急性缺氧15分钟期间保持细胞内钙稳定性和ΔΨm。分化4周后，线粒体质量显著降低。在这些细胞中，缺氧期间钙稳态得以维持，尽管线粒体发生了去极化，这表明线粒体依赖性降低。基础代谢率因分化而增加，然而，未分化GSCs中的低氧消耗和高ΔΨm并未提供缺氧耐受性。结果表明，未分化的GSCs依赖氧气，有限的分化诱导相对缺氧耐受性。缺氧耐受性可能是高级别恶性肿瘤的一个因素。这使得作为胶质母细胞瘤治疗策略的分化方法需要谨慎对待。
