Research Institute of the McGill University Health Centre, Glen Site, McGill University, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada.
Research Institute of the McGill University Health Centre, Glen Site, McGill University, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada.
Semin Cell Dev Biol. 2017 Jul;67:11-22. doi: 10.1016/j.semcdb.2017.01.003. Epub 2017 Jan 8.
Pathogenesis of human cancers bridges intracellular oncogenic driver events and their impact on intercellular communication. Among multiple mediators of this 'pathological connectivity' the role of extracellular vesicles (EVs) and their subsets (exosomes, ectosomes, oncosomes) is of particular interest for several reasons. The release of EVs from cancer cells represents a unique mechanism of regulated expulsion of bioactive molecules, a process that also mediates cell-to-cell transfer of lipids, proteins, and nucleic acids. Biological effects of these processes have been implicated in several aspects of cancer-related pathology, including tumour growth, invasion, angiogenesis, metastasis, immunity and thrombosis. Notably, the emerging evidence suggests that oncogenic mutations may impact several aspects of EV-mediated cell-cell communication including: (i) EV release rate and protein content; (ii) molecular composition of cancer EVs; (iii) the inclusion of oncogenic and mutant macromolecules in the EV cargo; (iv) EV-mediated release of genomic DNA; (v) deregulation of mechanisms responsible for EV biogenesis (vesiculome) and (vi) mechanisms of EV uptake by cancer cells. Intriguingly, EV-mediated intercellular transfer of mutant and oncogenic molecules between subpopulations of cancer cells, their indolent counterparts and stroma may exert profound biological effects that often resemble (but are not tantamount to) oncogenic transformation, including changes in cell growth, clonogenicity and angiogenic phenotype, or cause cell stress and death. However, several biological barriers likely curtail a permanent horizontal transformation of normal cells through EV-mediated mechanisms. The ongoing analysis and targeting of EV-mediated intercellular communication pathways can be viewed as a new therapeutic paradigm in cancer, while the analysis of oncogenic cargo contained in EVs released from cancer cells into biofluids is being developed for clinical use as a biomarker and companion diagnostics. Indeed, studies are underway to further explore the multiple links between molecular causality in cancer and various aspects of cellular vesiculation.
人类癌症的发病机制涉及细胞内致癌驱动事件及其对细胞间通讯的影响。在这种“病理性连接”的多种介质中，细胞外囊泡（EVs）及其亚群（外泌体、ectosomes、oncosomes）的作用因其多种原因而特别引人关注。癌细胞释放 EV 代表了一种独特的受调控的生物活性分子排出机制，该过程还介导了脂质、蛋白质和核酸的细胞间转移。这些过程的生物学效应已被牵涉到与癌症相关病理学的多个方面，包括肿瘤生长、侵袭、血管生成、转移、免疫和血栓形成。值得注意的是，新出现的证据表明，致癌突变可能影响 EV 介导的细胞间通讯的几个方面，包括：（i）EV 释放率和蛋白含量；（ii）癌症 EV 的分子组成；（iii）致癌和突变大分子在 EV 货物中的包含；（iv）EV 介导的基因组 DNA 释放；（v）负责 EV 发生的机制（vesiculome）的失调；（vi）癌细胞摄取 EV 的机制。有趣的是，EV 介导的突变和致癌分子在癌细胞亚群、惰性对应物和基质之间的细胞间转移可能会产生深远的生物学效应，这些效应通常类似于（但不等同于）致癌转化，包括细胞生长、克隆形成和血管生成表型的改变，或导致细胞应激和死亡。然而，几种生物学障碍可能会限制通过 EV 介导的机制使正常细胞发生永久性的横向转化。对 EV 介导的细胞间通讯途径的持续分析和靶向可以被视为癌症的一种新的治疗范例，而对癌细胞释放到生物流体中的 EV 中包含的致癌货物的分析正在作为一种生物标志物和伴随诊断用于临床。事实上，正在进行研究以进一步探索癌症中分子因果关系与细胞囊泡化的各个方面之间的多种联系。
