缺氧诱导的细胞外囊泡在肿瘤进展中的作用

缺氧是大多数恶性肿瘤微环境的重要特征,并且与患者预后不良密切相关。细胞外囊泡是细胞分泌的脂质双层膜的细胞外结构,其携带的蛋白、脂质、RNA等生物活性物质可被靶细胞摄取,介导细胞间信息传递功能。研究发现缺氧可促进细胞外囊泡的形成与释放,改变细胞外囊泡的含量及组成。此外,缺氧微环境诱导的肿瘤细胞起源的细胞外囊泡参与一系列肿瘤进展的病理过程,包括肿瘤血管形成、细胞外基质重塑、免疫功能调控、肿瘤侵袭及转移等。本文就缺氧诱导的细胞外囊泡与肿瘤细胞及微环境多种基质细胞之间信号传递及调控机制作一综述。     

血小板及其来源的细胞外囊泡在恶性肿瘤中的临床价值

血小板的主要功能是参与止血、维持血管完整性、促进血栓形成。近年来,越来越多的研究证据显示,血小板在肿瘤的生长、增殖、侵袭、转移等过程中也发挥着关键作用。并且这些功能与血小板活化后释放的细胞外囊泡密切相关。血小板活化后释放的细胞外囊泡是一种非均匀的纳米级小泡,包括微粒和外泌体,均表现出原细胞的特性,可携带遗传物质（微小RNA、信使RNA等）、酶、蛋白质和小分子,介导细胞间物质转运的通讯。基于此,血小板与恶性肿瘤之间的相互作用,引起了研究者们的关注。全文就血小板及其来源的细胞外囊泡与恶性肿瘤的相关性研究进行综述,旨在揭示两者既能作为肿瘤的新型标志物的潜力,又能在肿瘤治疗领域发挥巨大的潜能。     

细胞外囊泡在血液系统肿瘤中的研究进展

细胞外囊泡（extracellular vesicles，EVs）是由各种细胞类型所形成的一组不均匀的膜性结构，它们被释放到周围的微环境中，或通过循环传播到远处。由于EVs能够转运脂质、mRNA和蛋白质等生物活性物质，因此EVs是肿瘤细胞与周围微环境或远处转移前生态位之间沟通的关键媒介。它存在于包括血液、尿液等人体各种体液中，稳定性好，是疾病潜在生物标志物的极佳来源。最重要的是，细胞外囊泡在促进肿瘤细胞增殖、转移、改善肿瘤患者的治疗及预后等多方面同样发挥着重要的作用，尤其是在血液系统肿瘤方面。因此，本文就EVs在血液恶性肿瘤中的研究进展进行综述。     

肿瘤来源胞外囊泡在肿瘤微环境中的作用

肿瘤来源胞外囊泡（CCEVs）是肿瘤细胞产生并释放到胞外的脂质双层囊泡,内含多种脂质、蛋白质、RNA等物质,与肿瘤微环境（TME）中的肿瘤相关成纤维细胞（CAFs）、免疫细胞、内皮细胞及胞外间质等进行信息交换,从而影响肿瘤进展。本文根据近年有关CCEVs的研究,总结了CCEVs在TME中的作用,即:CCEVs通过所携带的遗传物质和活性分子作用于TME中的各种细胞,促进肿瘤增殖、侵袭转移、血管新生、胞外间质重塑及调控肿瘤免疫反应。基于CCEVs在TME和肿瘤进展中的作用及自身分泌的特异性,CCEVs或将成为肿瘤分子诊断的有效生物标志物和肿瘤靶向治疗的新靶点。     

胞外囊泡及其促进胰腺癌侵袭转移的机制

胞外囊泡（EV）由原核生物及真核生物所分泌,广泛存在于血液、尿液、腹腔积液、胆汁等各种体液及肿瘤微环境中。EV 在细胞生长、运动、信号传导以及肿瘤细胞的侵袭转移中发挥重要作用。胰腺癌恶性程度高,侵袭转移能力强,EV 可通过促进细胞增殖、抑制免疫反应、促进血管形成和基质重塑等机制促进胰腺癌的侵袭转移。     

间充质干细胞来源的外泌体在肝癌治疗中的研究进展

间充质干细胞(mesenchymal stem cells,MSCs)具有强大的分泌能力,主要通过分泌细胞因子和细胞外囊泡(extracellular vesicles,EVs)对周围的细胞产生作用,而外泌体是EVs的一个主要亚群。MSCs来源的外泌体(mesenchymal stem cell-derived exosome,MSC-Exo)作为MSCs胞内信号的重要组成部分,在肝癌等疾病治疗的研究中具有与MSCs相似的作用,能克服复杂的体内递送障碍,实现远距离输送,能被受体细胞吸收,无免疫排斥,无致瘤性,易于获得且方便贮存。MSC-Exo的脂质膜可以包裹并保护其内容物免受体液中降解酶的影响,使其成为天然的良好载体,可用于装载抗肝癌药物,因而在未来肝癌的治疗方面,MSCExo具有一定的临床应用前景。本文就MSC-Exo应用于肝癌治疗方面的研究进行综述,为肝癌的治疗提供新思路。     

肿瘤及肿瘤基质细胞释放的外泌体对肿瘤耐药产生的影响

恶性肿瘤已成为当今严重威胁人类健康的疾病之一,存在早发现难、治愈率低和预后差等三大难点.虽然,化疗是癌症治疗的主要手段,但由此产生的耐药也是当今影响疗效的最棘手问题之一,从而使患者面对无药可用的尴尬境地.外泌体(exosomes)作为细胞间信息传递的重要通讯员,在肿瘤耐药传递方面发挥重要作用.研究发现,肿瘤细胞和肿瘤微环境(tumor microenvironment,TME)中的基质细胞均可分泌携带耐药相关分子(包括蛋白质和miRNAs等)的外泌体,并通过外泌体在TME中相互作用,传递耐药分子,从而增强肿瘤细胞对药物的耐受性;同时肿瘤细胞外泌体还可以介导药物外排,从而影响药效;基质细胞也可与肿瘤细胞相互作用影响肿瘤细胞对药物的敏感性.同时,这些机制的发现也为克服肿瘤耐药提供了新思路,研究表明通过去除或抑制含耐药分子的外泌体,或者通过改变外泌体的成分(减少耐药分子或增加抗耐药分子),可在一定程度上逆转耐药.本文就肿瘤及肿瘤基质细胞释放的外泌体在肿瘤耐药中的作用以及由此而来的耐药逆转的研究进展作一综述.     

胸腔积液细胞外囊泡作为晚期非小细胞肺癌生物标志物的研究进展

肺癌是世界上最常见的恶性肿瘤之一,其中约80%为非小细胞肺癌(non-small cell lung cancer, NSCLC)。恶性胸腔积液作为晚期NSCLC的常见并发症,与患者的生活质量及预后息息相关。细胞外囊泡(extracellular vesicles, EVs)是由细胞释放的纳米级微粒,内含有蛋白质、核酸和脂质等成分,在血浆、胸腔积液和唾液等多种体液中存在。肿瘤相关EVs的研究为人们揭示肿瘤发生发展机制及实现EVs的临床应用开辟了新道路。近年研究发现,胸腔积液中的EVs是晚期NSCLC诊疗中的理想生物标志物。现就胸腔积液EVs作为晚期NSCLC生物标志物的研究进展作一综述,以期能展现其在NSCLC诊断、治疗、预后等方面的应用价值。     

外泌体源性细胞外microRNAs 在泌尿系统恶性肿瘤中的研究进展*

microRNAs（miRNAs）是一种内源性单链非编码微小RNAs分子,可通过碱基互补方式与靶mRNA 的3’非翻译区（3’UTR ）特异性结合诱导其降解或抑制其翻译,从而在转录后水平有效地沉默靶基因的蛋白表达。miRNAs因可以上述方式调节癌基因或抑癌基因表达,故其广泛参与了肿瘤的发生发展过程。本文概括了miRNAs的起源、功能及生物体液中外泌体（exosome）源性细胞外miRNAs的稳定性。同时对从尿液外泌体中寻找泌尿系统恶性肿瘤潜在miRNA 标记物的现实可行性以及尿液中外泌体源性miRNAs在前列腺癌、膀胱癌及肾癌中作为生物标记物的潜能进行综述。     

外泌体在癌症诊治中的应用及其分离技术进展

摘 要：随着精准医学的发展,通过分子诊断来指导患者的个体化诊治已逐渐成为临床专家的共识。液体活检作为一种简单快捷、非侵入性、可重复性强的病理检测手段,在癌症的早期诊断、监测、预后及指导用药方面具有重要意义。外泌体作为液体活检中最具潜力的检测对象之一,被发现参与多种癌症的发生、发展、预后等过程,同时,外泌体也被认为是癌症治疗和药物运输的强有力工具。全文针对近年来外泌体在癌症诊治中的应用及其分离技术进展进行综述。     

Proteomic analysis of urinary and tissue-exudative extracellular vesicles to discover novel bladder cancer biomarkers

Proteomic analysis of urinary extracellular vesicles (EVs) is a powerful approach to discover potential bladder cancer (BCa) biomarkers, however urine contains numerous EVs derived from the kidney and normal urothelial epithelium, which can obfuscate information related to BCa cell-derived EVs. In this study, we combined proteomic analysis of urinary EVs and tissue-exudative EVs (Te-EVs), which were isolated from culture medium of freshly resected viable BCa tissues. Urinary EVs were isolated from urine samples of 11 individuals (7 BCa patients and 4 healthy individuals), and Te-EVs were isolated from 7 BCa tissues. We performed tandem mass tag (TMT)-labeling liquid chromatography (LC-MS/MS) analysis for both urinary EVs and Te-EVs and identified 1960 proteins in urinary EVs and 1538 proteins in Te-EVs. Most of the proteins identified in Te-EVs were also present in urinary EVs (82.4%), with 55 of these proteins showing upregulated levels in the urine of BCa patients (fold change > 2.0; P < .1). Among them, we selected 22 membrane proteins as BCa biomarker candidates for validation using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis on urine samples from 70 individuals (40 BCa patients and 30 healthy individuals). Six urinary EV proteins (heat-shock protein 90, syndecan-1, myristoylated alanine-rich C-kinase substrate (MARCKS), MARCKS-related protein, tight junction protein ZO-2, and complement decay-accelerating factor) were quantified using SRM/MRM analysis and validated as significantly upregulated in BCa patients (P < .05). In conclusion, the novel strategy that combined proteomic analysis of urinary EVs and Te-EVs enabled selective detection of urinary BCa biomarkers.     

Glioblastoma‐derived extracellular vesicles modify the phenotype of monocytic cells

Glioblastoma multiforme (GBM) is the most common primary brain tumor and is without exception lethal. GBMs modify the immune system, which contributes to the aggressive nature of the disease. Particularly, cells of the monocytic lineage, including monocytes, macrophages and microglia, are affected. We investigated the influence of GBM‐derived extracellular vesicles (EVs) on the phenotype of monocytic cells. Proteomic profiling showed GBM EVs to be enriched with proteins functioning in extracellular matrix interaction and leukocyte migration. GBM EVs appeared to skew the differentiation of peripheral blood‐derived monocytes to alternatively activated/M2‐type macrophages. This was observed for EVs from an established cell line, as well as for EVs from primary cultures of GBM stem‐like cells (GSCs). Unlike EVs of non‐GBM origin, GBM EVs induced modified expression of cell surface proteins, modified cytokine secretion (e.g., an increase in vascular endothelial growth factor and IL‐6) and increased phagocytic capacity of the macrophages. Most pronounced effects were observed upon incubation with EVs from mesenchymal GSCs. GSC EVs also affected primary human microglia, resulting in increased expression of Membrane type 1‐matrix metalloproteinase, a marker for GBM microglia and functioning as tumor‐supportive factor. In conclusion, GBM‐derived EVs can modify cells of the monocytic lineage, which acquire characteristics that resemble the tumor‐supportive phenotypes observed in patients.     

EB病毒与乳腺癌的相关性研究进展

乳腺癌的病因尚未明确,已知的危险因素包括生殖因素、影响体内性激素水平因素和遗传易感因素,但这些因素也只能解释约50%腺癌病例。近年来有研究试图从病毒感染的角度探讨乳腺癌的病因,EB病毒（Epstein—Barrvirus,EBV）正是研究热点之一。但EBV与乳腺癌的关系仍存在着很大的争议。本文就EBV生物学特点、EBV与乳腺癌的相关性研究（包括癌组织中的EBV检测、血清学研究、细胞学实验和临床特点分析）作一综述,并提出目前存在的问题和今后研究的方向。     

The role of extracellular vesicles in phenotypic cancer transformation

Background

Cancer has traditionally been considered as a disease resulting from gene mutations. New findings in biology are challenging gene-centered explanations of cancer progression and redirecting them to the non-genetic origins of tumorigenicity. It has become clear that intercellular communication plays a crucial role in cancer progression. Among the most intriguing ways of intercellular communication is that via extracellular vesicles (EVs). EVs are membrane structures released from various types of cells. After separation from the mother membrane, EVs become mobile and may travel from the extracellular space to blood and other body fluids.

Conclusions

Recently it has been shown that tumour cells are particularly prone to vesiculation and that tumour-derived EVs can carry proteins, lipids and nucleic acids causative of cancer progression. The uptake of tumour-derived EVs by noncancerous cells can change their normal phenotype to cancerous. The suppression of vesiculation could slow down tumour growth and the spread of metastases. The purpose of this review is to highlight examples of EV-mediated cancer phenotypic transformation in the light of possible therapeutic applications.     

细胞外基质与肿瘤干细胞相互作用的研究进展

细胞外基质(extracellular matrix,ECM)是由蛋白质与糖类等生物大分子在细胞表面或细胞间构成的复杂网络结构.细胞外基质的过量沉积或结构形态异常是肿瘤微环境(tumor microenvironment,TME)的重要特征之一.肿瘤干细胞(cancer stem cells,CSC)指肿瘤内部一类具有...     

miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity

Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)₈ cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer.