PNAS：胞外体揭开脑瘤的秘密

　　

生物通报道：“人们一直认为细胞是封闭的实体，通过分泌可溶的信号分子进行交流。近来研究显示，细胞能够通过包裹着遗传物质和信号蛋白的胞外体，交换更为复杂的信息。这是细胞通讯机制中的新观点，”Lund大学的肿瘤学教授Dr Mattias Belting说。

胞外体exosome是仅30nm的小囊泡，它们在细胞内产生，能够作为转运工具将多种物质转移到周围细胞。目前，人们已经在血液、唾液、尿液、乳汁等多种体液中发现了胞外体。

胶质瘤患者的肿瘤细胞会释放出胞外体，Mattias Belting的研究团队对此进行了研究。他们发现，胶质瘤细胞释放的胞外体能够反映肿瘤的低氧状态，并且在肿瘤发展过程中介导低氧依赖性的血管细胞活化，文章发表在美国国家科学院院刊PNAS杂志上。

低氧是肿瘤发展和侵袭的一个主要调节因素，研究显示，恶性脑瘤GBM（多形性胶质母细胞瘤）分泌的胞外体介导了低氧依赖性的细胞间信号传导。这些胞外体被释放到脑部健康细胞，在正常组织中为肿瘤的有效扩散做准备。Lund大学的研究人员指出，胞外体的蛋白质组和mRNA谱能够反映胶质瘤的侵袭性。

研究人员对胶质瘤细胞和患者样本进行了低氧实验，发现胞外体富含低氧调节相关的mRNA和蛋白，而且其中的一些物质与患者预后差有关。研究显示，低氧状态下GBM释放的胞外体，会影响内皮细胞，促进血管生成。内皮细胞被这些胞外体编程，开始分泌一些强力的生长因子和细胞因子，启动PI3K/AKT信号激活和细胞迁移。

“我们成功开发了一种方法，能够通过相对简单的血液测试，分离脑瘤患者的胞外体。我们的分析显示，胞外体内容物能以独特的方式反映肿瘤的侵袭性，”博后研究员Paulina Kucharzewska说。

研究人员指出，将胞外体作为生物学指标，可以帮助医生有效治疗患者，并监控患者对治疗的反应。这对于不易进行组织活检的脑瘤来说特别有价值。此外，分析血液中的胞外体，对其他肿瘤来说也很重要。肿瘤组织的异质性会影响组织活检的效果，组织样本可能无法完全代表特定肿瘤的生物学特性，而胞外体能够为人们提供更综合性的信息。

Mattias Belting及其团队参加了刚刚在波士顿召开的胞外体第二届国际会议。“这一新兴的研究领域令人兴奋。我认为该领域中最具影响力的研究者，可能有一天会获得诺贝尔奖，”Dr Belting说。

 

（生物通编辑：叶予）

生物通推荐原文摘要：

Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development

Hypoxia, or low oxygen tension, is a major regulator of tumor development and aggressiveness. However, how cancer cells adapt to hypoxia and communicate with their surrounding microenvironment during tumor development remain important questions. Here, we show that secreted vesicles with exosome characteristics mediate hypoxia-dependent intercellular signaling of the highly malignant brain tumor glioblastoma multiforme (GBM). In vitro hypoxia experiments with glioma cells and studies with patient materials reveal the enrichment in exosomes of hypoxia-regulated mRNAs and proteins (e.g., matrix metalloproteinases, IL-8, PDGFs, caveolin 1, and lysyl oxidase), several of which were associated with poor glioma patient prognosis. We show that exosomes derived from GBM cells grown at hypoxic compared with normoxic conditions are potent inducers of angiogenesis ex vivo and in vitro through phenotypic modulation of endothelial cells. Interestingly, endothelial cells were programmed by GBM cell-derived hypoxic exosomes to secrete several potent growth factors and cytokines and to stimulate pericyte PI3K/AKT signaling activation and migration. Moreover, exosomes derived from hypoxic compared with normoxic conditions showed increased autocrine, promigratory activation of GBM cells. These findings were correlated with significantly enhanced induction by hypoxic compared with normoxic exosomes of tumor vascularization, pericyte vessel coverage, GBM cell proliferation, as well as decreased tumor hypoxia in a mouse xenograft model. We conclude that the proteome and mRNA profiles of exosome vesicles closely reflect the oxygenation status of donor glioma cells and patient tumors, and that the exosomal pathway constitutes a potentially targetable driver of hypoxia-dependent intercellular signaling during tumor development.