University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
Philos Trans R Soc Lond B Biol Sci. 2018 Jan 5;373(1737). doi: 10.1098/rstb.2016.0477.
Glioblastoma multiforme (GBM) is a devastating tumour with abysmal prognoses. We desperately need novel approaches to understand GBM biology and therapeutic vulnerabilities. Extracellular vesicles (EVs) are membrane-enclosed nanospheres released locally and systemically by all cells, including tumours, with tremendous potential for intercellular communication. Tumour EVs manipulate their local environments as well as distal targets; EVs may be a mechanism for tumourigenesis in the recurrent GBM setting. We hypothesized that GBM EVs drive molecular changes in normal human astrocytes (NHAs), yielding phenotypically tumour-promoting, or even tumourigenic, entities. We incubated NHAs with GBM EVs and examined the astrocytes for changes in cell migration, cytokine release and tumour cell growth promotion via the conditioned media. We measured alterations in intracellular signalling and transformation capacity (astrocyte growth in soft agar). GBM EV-treated NHAs displayed increased migratory capacity, along with enhanced cytokine production which promoted tumour cell growth. GBM EV-treated NHAs developed tumour-like signalling patterns and exhibited colony formation in soft agar, reminiscent of tumour cells themselves. GBM EVs modify the local environment to benefit the tumour itself, co-opting neighbouring astrocytes to promote tumour growth, and perhaps even driving astrocytes to a tumourigenic phenotype. Such biological activities could have profound impacts in the recurrent GBM setting.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.
多形性胶质母细胞瘤（GBM）是一种预后极差的破坏性肿瘤。我们迫切需要新的方法来了解 GBM 的生物学和治疗弱点。细胞外囊泡（EVs）是所有细胞（包括肿瘤细胞）局部和系统性释放的膜封闭纳米球，具有巨大的细胞间通讯潜力。肿瘤 EVs 可以改变其局部环境和远处靶标；EVs 可能是复发性 GBM 中肿瘤发生的一种机制。我们假设 GBM EVs 会导致正常人星形胶质细胞（NHAs）发生分子变化，从而产生表型上促进肿瘤或甚至致瘤的实体。我们将 NHAs 与 GBM EV 孵育，并通过条件培养基检查星形胶质细胞的细胞迁移、细胞因子释放和肿瘤细胞生长促进的变化。我们测量了细胞内信号转导和转化能力（软琼脂中星形胶质细胞的生长）的变化。用 GBM EV 处理的 NHAs 显示出迁移能力增强，同时细胞因子产生增强，从而促进肿瘤细胞生长。用 GBM EV 处理的 NHAs 表现出类似于肿瘤细胞本身的肿瘤样信号模式，并在软琼脂中形成集落。GBM EV 改变局部环境以利于肿瘤本身，利用邻近的星形胶质细胞促进肿瘤生长，甚至可能促使星形胶质细胞向致瘤表型发展。这些生物学活性可能在复发性 GBM 环境中产生深远影响。本文是讨论会议议题“细胞外囊泡和肿瘤微环境”的一部分。
