Fayzullin Artem, Sandberg Cecilie J, Spreadbury Matthew, Saberniak Birthe Mikkelsen, Grieg Zanina, Skaga Erlend, Langmoen Iver A, Vik-Mo Einar O
Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
Transl Oncol. 2019 Jan;12(1):122-133. doi: 10.1016/j.tranon.2018.09.014. Epub 2018 Oct 3.
Tumor cell invasion is a hallmark of glioblastoma (GBM) and a major contributing factor for treatment failure, tumor recurrence, and the poor prognosis of GBM. Despite this, our understanding of the molecular machinery that drives invasion is limited.
Time-lapse imaging of patient-derived GBM cell invasion in a 3D collagen gel matrix, analysis of both the cellular invasive phenotype and single cell invasion pattern with microarray expression profiling.
GBM invasion was maintained in a simplified 3D-milieue. Invasion was promoted by the presence of the tumorsphere graft. In the absence of this, the directed migration of cells subsided. The strength of the pro-invasive repulsive signaling was specific for a given patient-derived culture. In the highly invasive GBM cultures, the majority of cells had a neural progenitor-like phenotype, while the less invasive cultures had a higher diversity in cellular phenotypes. Microarray expression analysis of the non-invasive cells from the tumor core displayed a higher GFAP expression and a signature of genes containing VEGFA, hypoxia and chemo-repulsive signals. Cells of the invasive front expressed higher levels of CTGF, TNFRSF12A and genes involved in cell survival, migration and cell cycle pathways. A mesenchymal gene signature was associated with increased invasion.
The GBM tumorsphere core promoted invasion, and the invasive front was dominated by a phenotypically defined cell population expressing genes regulating traits found in aggressive cancers. The detected cellular heterogeneity and transcriptional differences between the highly invasive and core cells identifies potential targets for manipulation of GBM invasion.
肿瘤细胞侵袭是胶质母细胞瘤（GBM）的一个标志，也是治疗失败、肿瘤复发和GBM预后不良的主要促成因素。尽管如此，我们对驱动侵袭的分子机制的了解仍然有限。
对患者来源的GBM细胞在三维胶原凝胶基质中的侵袭进行延时成像，通过微阵列表达谱分析细胞侵袭表型和单细胞侵袭模式。
GBM侵袭在简化的三维环境中得以维持。肿瘤球移植促进了侵袭。若不存在肿瘤球移植，细胞的定向迁移则会减弱。促侵袭排斥信号的强度对于特定患者来源的培养物具有特异性。在高侵袭性的GBM培养物中，大多数细胞具有神经祖细胞样表型，而侵袭性较低的培养物在细胞表型上具有更高的多样性。对肿瘤核心的非侵袭性细胞进行微阵列表达分析显示，其GFAP表达较高，且具有包含VEGFA、缺氧和化学排斥信号的基因特征。侵袭前沿的细胞表达较高水平的CTGF、TNFRSF12A以及参与细胞存活、迁移和细胞周期途径的基因。间充质基因特征与侵袭增加相关。
GBM肿瘤球核心促进侵袭，侵袭前沿由一群表型明确的细胞主导，这些细胞表达调节侵袭性癌症中发现的特征的基因。在高侵袭性细胞和核心细胞之间检测到的细胞异质性和转录差异确定了可用于操控GBM侵袭的潜在靶点。
