小豪 读文献
肿瘤发生转移标志着癌症的恶化，其中脑转移最为凶险。人体躯干和大脑之间血液交换存在着一道天然的屏障——血脑屏障。血脑屏障对大脑起着至关重要的保护作用，对进入大脑的物质具有较强的选择性。因此，一旦发生脑转移，就会导致许多的药物无法进入大脑，从而无法实现对脑肿瘤转移很好的治疗。近日，美国波士顿儿童医院的学者通过对转移性乳腺癌进行研究发现，肿瘤来源的细胞外囊泡，可以通过“迷惑”血脑屏障，改变胞吞的作用，从而进入大脑中，释放信号分子，改变大脑微环境，使脑内环境更加的适应肿瘤的转移和生长。
Tumor-Derived Extracellular Vesicles Breach theIntact Blood Brain Barrier via Transcytosis
图片来源：文献原文
The restrictive nature of the blood brain barrier (BBB) creates a major challenge for brain drug delivery with current nanomedicines lacking the ability to cross the BBB. Extracellular vesicles (EVs) have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer and have been suggested as promising therapeutics and drug delivery vehicles. However, the ability of native tumor-derived EVs to breach the BBB and the mechanism(s) involved in this process remain unknown. Here, we demonstrate that tumorderived EVs can breach the intact BBB in vivo and by using state-of-the-art in vitro and in vivo models of the BBB, we have identified transcytosis as the mechanism underlying this process. Moreover, high spatiotemporal resolution microscopy demonstrated that the endothelial recycling endocytic pathway is involved in this transcellular transport. We further identify and characterize the mechanism by which tumor-derived EVs circumvent the low physiologic rate of transcytosis in the BBB by decreasing the brain endothelial expression of rab7 and increasing the efficiency of their transport. These findings identify previously unknown mechanisms by which tumor-derived EVs breach an intact BBB during the course of brain metastasis and can be leveraged to guide and informthe development of drug delivery approaches to deliver therapeutic cargoes across the BBB for treatment of a variety of brain diseases including, but not limited to, brain malignancies.
细胞外囊泡促进肿瘤脑内转移
血脑屏障对大脑的严密保护，给药物入脑带来了极大的挑战，即使纳米药物也很难穿过血脑屏障。细胞外囊泡是一种可用于治疗和载药的囊泡状结构，在脑肿瘤转移等脑部疾病的发展过程中起到重要的作用。但是，细胞外囊泡怎样穿过血脑屏障，以及穿过血脑屏障的机制仍然不是特别清楚。通过体内和体外的实验证实，肿瘤起源的细胞外囊泡具有通过血脑屏障的能力。并且研究发现转胞吞作用在这一过程中起到重要作用。通过时空高分辨显微镜的研究证明，这一跨细胞转运过程通过回收内吞作用的途径发生。进一步的研究发现，细胞外囊泡通过调低rab7蛋白的表达，从而改善血脑屏障低效率的转胞吞作用，进而增加了细胞外囊泡入脑的转运效率。这些发现确定了一种肿瘤来源外泌体与血脑屏障作用的新机制，并且通过这一机制可促使肿瘤的脑内转移。这种新机制的发现为药物跨血脑屏障入脑的策略提供了新的思路。这一新的脑靶向思路不但可以用于多种脑部疾病的治疗，同时也包括用于脑部肿瘤的治疗。
文献来源
DOI:10.1021/acsnano.9b04397
备注：浦美医学每周推出一个专题的“文献速递”汇编，如需详细了解内容或全文请联系我们（浦美小编：微信号pumeixiaobian）。文献内容均由浦美医学编译自原文，疏漏之处敬请读者指正。
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