Intercellular transfer of the oncogenic receptor EGFrvIII by microvesicles derived from tumour cells
Intercellular transfer of the oncogenic receptor EGFrvIII by microvesicles derived from tumour cells
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DOI：
10.1038/ncb1725
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发表时间：
2008-05-01
影响因子：
21.3
通讯作者：
Rak, Janusz
中科院分区：
文献类型：
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作者：
Al-Nedawi, Khalid;Meehan, Brian;Rak, Janusz
侵袭性人脑肿瘤(胶质瘤)通常表达一种截短的致癌形式的表皮生长因子受体，即EGFRvIII。在每个肿瘤中，只有一小部分胶质瘤细胞实际上可能表达EGFRvIII；然而，大多数细胞表现出转化的表型(1)。在这里，我们证明了EGFRvIII可以通过膜来源的微囊(‘onosome’)的细胞间转移在胶质瘤细胞之间‘共享’。在惰性胶质瘤细胞中表达EGFRvIII可刺激含有EGFRvIII的脂筏相关微泡的形成。然后，含有这种受体的微囊被释放到荷瘤小鼠的细胞环境和血液中，并可以与缺乏EGFRvIII的癌细胞的质膜结合。这一事件导致了致癌活性的转移，包括转化信号通路(MAPK和Akt)的激活，EGFRvIII调节基因(血管内皮生长因子，Bclx(L)，p27)表达的变化，形态变化和锚定非依赖性生长能力的增加。因此，癌细胞的膜微泡有助于癌基因及其相关转化表型在癌细胞亚群中的水平传播。
Aggressive human brain tumours ( gliomas) often express a truncated and oncogenic form of the epidermal growth factor receptor, known as EGFRvIII. Within each tumour only a small percentage of glioma cells may actually express EGFRvIII; however, most of the cells exhibit a transformed phenotype(1). Here we show that EGFRvIII can be 'shared' between glioma cells by intercellular transfer of membrane-derived microvesicles ('oncosomes'). EGFRvIII expression in indolent glioma cells stimulates formation of lipid-raft related microvesicles containing EGFRvIII. Microvesicles containing this receptor are then released to cellular surroundings and blood of tumour-bearing mice, and can merge with the plasma membranes of cancer cells lacking EGFRvIII. This event leads to the transfer of oncogenic activity, including activation of transforming signalling pathways ( MAPK and Akt), changes in expression of EGFRvIII-regulated genes (VEGF, Bcl- x(L), p27), morphological transformation and increase in anchorage-independent growth capacity. Thus, membrane microvesicles of cancer cells can contribute to a horizontal propagation of oncogenes and their associated transforming phenotype among subsets of cancer cells.