外泌体在肿瘤细胞与TAMs之间相互作用中“桥梁”和调控作用的研究进展北大核心

外泌体是一类直径为30~100 nm的圆盘囊泡,其内包含许多组分,诸如复杂RNA和蛋白质等,主要参与细胞间的信号转导。肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)是肿瘤微环境中普遍存在的巨噬细胞,通过对肿瘤生长、免疫逃逸、侵袭和转移、耐药性等多方面的作用影响肿瘤进程。外泌体在肿瘤相关巨噬细胞的招募、极化及抗肿瘤免疫调控等方面发挥着重要的调节功能。同时,TAMs以外泌体为媒介作用于肿瘤细胞,从而构成了外泌体、TAMs与肿瘤细胞之间相互作用的调控通路。综上所述,本文旨在阐明肿瘤细胞与TAMs之间,以外泌体为“桥梁”相互影响的潜在机制,以及靶向肿瘤细胞和TAMs来源的外泌体在恶性肿瘤治疗中的展望。     

外泌体影响乳腺癌转移机制的研究进展

乳腺癌是女性发病率最高的恶性肿瘤。早期乳腺癌患者中的30%能够检测到循环肿瘤细胞,这是导致约90%乳腺癌患者转移致死的主要原因。外泌体是一系列具有生物功能的小囊泡,携带多种活性成分,不同类型供体细胞来源的外泌体均可影响乳腺癌细胞和基质细胞,在肿瘤微环境中发挥不同的作用,调控乳腺癌的转移。笔者从外泌体影响肿瘤微环境、转移前生态位形成、循环肿瘤细胞在血液和靶器官中存活机制等方面,综述了外泌体在乳腺癌进展和转移中的作用。     

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.     

癌相关成纤维细胞来源的外泌体在肺恶性肿瘤中的研究进展

肿瘤微环境(tumor microenvironment,TME)是分布在肿瘤细胞周围的动态网络,癌相关成纤维细胞(cancer-associated fibroblasts,CAFs)作为肿瘤微环境中的一部分,不但与正常成纤维细胞密切相关,而且可以分泌多种物质(包括外泌体)参与肿瘤微环境的调控.外泌体不仅与肺恶性肿瘤...     

外泌体在胰腺癌中的研究进展

胰腺癌是消化系统较致命的恶性肿瘤之一,病死率极高,预后极差,这主要是因为胰腺癌早期诊断困难、局部侵袭和早期转移等,且缺乏有效的治疗手段。外泌体可由多种细胞分泌,主要由蛋白质、核酸和相关脂类构成。外泌体在肿瘤细胞和微环境间的通讯中起着至关重要的作用,主要促进肿瘤细胞的增殖和转移,刺激新生血管生成,激活基质中的成纤维细胞,抑制宿主的免疫反应。本文就外泌体在胰腺癌细胞增殖转移、胰腺癌诊断及对化疗耐药中的作用进行综述,为早期诊断和治疗胰腺癌提供思考和借鉴。     

外泌体检测在骨肿瘤诊疗中的意义

体液活检是近些年恶性肿瘤研究的热点。液态活检包括游离DNA（circulating free DNA,cfDNA）检测、循环肿瘤细胞（circulating tumor cells,CTCs）检测、细胞外泌体检测。对于间叶组织来源的骨肉瘤和尤文肉瘤而言,由于肿瘤异质性明显同时又缺乏经典的肿瘤标志物,以细胞标志物为手段的循环肿瘤细胞检测在骨肉瘤和尤文肉瘤等间叶组织来源恶性肿瘤的预后监测中的作用受到明显制约。体液中存在的肿瘤细胞外泌体因携带其”母体”肿瘤细胞的部分功能性蛋白及基因,并作为肿瘤液态活检的一种新途径,受到大家的广泛关注,其也可能在骨肉瘤和尤文肉瘤的发病、诊断和治疗中发挥着重要作用。本文旨在对外泌体的特性、在恶性肿瘤进展中发挥的重要作用及应用前景进行综述,以期为实现其在临床中的推广应用提供参考。      

循环血液外泌体miRNA在卵巢癌发生发展中作用及其诊断价值的研究进展

卵巢癌（ovarian cancer,OC）是女性恶性肿瘤死亡的主要原因。由于卵巢癌无症状发展,缺乏早期诊断标志物,大多数患者在晚期才被诊断出来。早期检测卵巢癌可显著提高总生存率,在过去的几十年里,微小RNA（miRNA）在癌症的发展中起着重要的作用,因此引起了极大的关注。miRNA可以在循环血液中稳定存在(如包裹在外泌体中),并可通过外泌体的分泌和转移在肿瘤细胞之间和肿瘤细胞微环境的沟通中发挥重要的作用。此外,外泌体miRNA在卵巢癌中的表达是失调的,可能反映肿瘤的恶性特征。因此评估外泌体来源的循环miRNA可能会为卵巢癌提供一类新的非侵袭性生物标志物。本综述概述了有关外泌体miRNA在卵巢癌发生发展过程中的作用以及循环血液外泌体miRNA作为卵巢癌早期诊断潜在生物标志物的现状。     

外泌体蛋白质在消化系统恶性肿瘤中的诊断价值

消化系统恶性肿瘤是人类常见的恶性肿瘤之一,其高发病率和晚期的低生存率给患者、家庭和社会带来沉重的疾病负担。然而,现有肿瘤筛查手段大多具有侵入性或操作复杂等特征,不利于开展大规模的人群筛查和长期随访,所以基于循环肿瘤DNA(circulating tumor DNA,ctDNA)、循环肿瘤细胞（circulating tumor cell,CTC）和外泌体（exosome）等新型生物标志物的液体活检技术具有广阔的发展前景。外泌体是由活细胞分泌、具有脂质双层膜的细胞外囊泡,相比于其他标志物其具有稳定性高、分布广泛、数量多等优势。外泌体携带的各种蛋白质能够反映来源细胞的特征,对于肿瘤早期诊断具有重要的研究价值。本文对近5年外泌体蛋白质作为消化系统恶性肿瘤早期诊断生物标志物的研究成果进行综述,并总结上述研究的主要特征和局限性,为促进外泌体蛋白质的临床转化提供参考依据。     

外泌体环状RNA在前列腺癌中的研究现状

环状RNA(circular RNA,circRNA)是一种具有共价闭环结构的非编码RNA,可在肿瘤细胞的增殖、凋亡、侵袭和耐药等多种生物学过程中发挥重要的调控作用。外泌体是一种细胞外囊泡,参与细胞间的物质运输和信息传递,能够携带脂质、蛋白质和核酸等多种生物活性分子。外泌体中circRNA富集且稳定存在,外泌体来源的circRNA在泌尿系统恶性肿瘤的早期诊断、病情进展及预后评估中发挥重要作用。本文就circRNA的生物学特性和功能及外泌体circRNA在前列腺癌中的研究现状进行综述。     

肿瘤细胞外泌体microRNA调控血管生成机制的研究进展

外泌体在促进肿瘤细胞生长和转移的过程中发挥着非常重要的作用.肿瘤细胞分泌的外泌体包含了来自肿瘤细胞的信息,其中包括蛋白质、脂类以及微小RNA(microRNA,miRNA)在内的核酸物质等.在肿瘤的发生发展过程中,肿瘤细胞会将对自己有利的信息通过外泌体分泌到周围的微环境中,从而促进肿瘤细胞的生长和转移,这也是肿瘤患者高...     

外泌体在肿瘤细胞及其临床应用中的研究进展

外泌体是直径为40~130 nm的纳米级囊泡结构，是一类重要的细胞间通信分子，含有大量的蛋白质、核酸和脂质物质。外泌体不仅对肿瘤免疫、肿瘤侵袭与转移及肿瘤耐药方面有关键的调节作用，在肿瘤的诊断与治疗方面也具有重要价值。本文介绍了外泌体的定义、发生和形成过程。此外，详细总结了外泌体的提取方法。最后，深入的讨论了外泌体在载药、放疗、化疗和耐药中的临床应用，旨在为外泌体的分子机理和临床研究提供新思路。     

Exosomes reveal the dual nature of radiotherapy in tumor immunology

Radioresistance is the potential cause of cancer metastasis and recurrence. Radiation‐induced changes in exosomes can partially explain the undesirable prognosis of radiotherapy (RT). Exosomes, newly discovered ways of cell communication, carry the characteristics of their origin, resulting in their diversity. Various exosomes in the tumor microenvironment exert different function in immune response. In this review, the dual effect of RT on the immune system was described, and the effect of radiotherapy on tumors via exosomes was explored. The molecules in exosomes after RT were described to play immunosuppressive and immunocompetent roles: immune‐related receptors and cell signaling molecules involved in both adaptive and innate immune system were present. CD69, TIGIT, TIM‐3, LAG‐3 and the tumor necrosis factor (TNF) family that signal to T cells were shown to be regulated by exosomes after irradiation. The change in innate immunity‐derived like receptors, Leukocyte Immunoglobin‐Like Receptors (LILR) was described, as well as B7‐H3, V‐domain containing Ig suppressor of T cell activation (VISTA), and CD155 on tumor cells. These changed molecules inhibit and activate the immune system through different mechanisms. By analyzing the relationship between exosome‐derived molecules and immunity, this review shows that radiotherapy can induce immunosuppression and immune clearance through exosomes, thereby treating tumors and improving patient prognosis.     

The cancer exosomes: Clinical implications,applications and challenges

The exosome is a small functional vesicle enriched in selected proteins, lipids and nucleic acids, displaying distinct molecular heterogeneity. Exosomes released can transform the extracellular matrix microenvironments, transmit signals and molecules to recipient cells and trigger changes in their pathophysiological functions. Tumor-derived exosomes mediate the interactions of tumor cells and microenvironment significantly, and they stimulate tumor growth and development through specific signaling pathways related to metastasis, therapeutic resistance and immunosuppression. Exosome biogenesis from tumors often represents abundant biological information, and novel and efficient isolation and detection methods of exosomes provide a promising approach for tumor diagnosis and prognosis estimation. Moreover, exosome can even be developed as therapeutic agents for multiple disease models based on effective material transport characteristics and biofilm specificity. This review reports the clinical implications and challenges of exosomes in cancer progression, therapy resistance, metastasis and immune escape, and underlying cancerogenic pathological phenotypes including fibrosis and viral infection.     

外泌体miRNA作为肿瘤标志物在消化系肿瘤的研究进展

外泌体是由活细胞分泌,普遍存在于唾液、血浆和乳汁等体液中的纳米级囊泡。外泌体中含有诸多功能性的DNA、蛋白质以及非编码RNA等活性物质,外泌体可以在细胞间穿梭广泛参与细胞间信息传递和物质交换。研究发现肿瘤外泌体中一些特定miRNA具有生物学特性和靶向特异性,可以调节机体在代谢紊乱中的生物活动,从多方面参与肿瘤发生发展,具有成为肿瘤治疗和预后标志物的潜力。因此,探寻外泌体中特定miRNA在消化系统肿瘤中的作用及其作为生物标志物的可能性,从而为消化系统肿瘤的预防和诊疗提供新思路具有重要意义。全文针对外泌体miRNA在消化系统肿瘤的研究进展作一综述。     

Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes

The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT-MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT-MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5-fluorocytosine (5-FC) effectively triggered dose-dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5-FC to 5-fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT-MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.     

外泌体在癌症诊治中的作用与机制

外泌体是一种新型的癌症生物标志物，它由所有体液中各种活细胞分泌的双层纳米囊泡构成，含有丰富的蛋白质、DNA、mRNA和非编码RNA。目前外泌体被认为是细胞间通讯的另一种机制，参与细胞间交换蛋白质、脂质和遗传物质。越来越多的研究表明，外泌体在肿瘤的发生、生长、进展、转移、耐药性和免疫逃逸中发挥重要作用。在本文中，我们根据外泌体生物学的最新进展，详细阐述了外泌体影响肿瘤之间通信的具体机制，并报道了外泌体可能成为癌症诊断中有前途的生物标志物，并代表癌症治疗的新靶点。     

Role of exosomes in the immune microenvironment of ovarian cancer

Exosomes are excretory vesicles that can deliver a variety of bioactive cargo molecules to the extracellular environment. Accumulating evidence demonstrates exosome participation in intercellular communication, immune response, inflammatory response and they even play an essential role in affecting the tumor immune microenvironment. The role of exosomes in the immune microenvironment of ovarian cancer is mainly divided into suppression and stimulation. On one hand exosomes can stimulate the innate and adaptive immune systems by activating dendritic cells (DCs), natural killer cells and T cells, allowing these immune cells exert an antitumorigenic effect. On the other hand, ovarian cancer-derived exosomes initiate cross-talk with immunosuppressive effector cells, which subsequently cause immune evasion; one of the hallmarks of cancer. Exosomes induce the polarization of macrophages in M2 phenotype and induce apoptosis of lymphocytes and DCs. Exosomes further activate additional immunosuppressive effector cells (myeloid-derived suppressor cells and regulatory T cells) that induce fibroblasts to differentiate into cancer-associated fibroblasts. Exosomes also induce the tumorigenicity of mesenchymal stem cells to exert additional immune suppression. Furthermore, besides mediating the intercellular communication, exosomes carry microRNAs (miRNAs), proteins and lipids to the tumor microenvironment, which collectively promotes ovarian cancer cells to proliferate, invade and tumors to metastasize. Studying proteins, lipids and miRNAs carried by exosomes could potentially be used as an early diagnostic marker of ovarian cancer for designing treatment strategies.     

Exosomes: a new delivery system for tumor antigens in cancer immunotherapy

Exosomes are small membrane vesicles that are released into the extracellular environment during fusion of multivesicular bodies with plasma membrane. Exosomes are secreted by various cell types including hematopoietic cells, normal epithelial cells and even some tumor cells. They are known to carry MHC class I, various costimulatory molecules and some tetraspanins. Recent studies have shown the potential of using native exosomes as immunologic stimulants. Here, we demonstrate a novel means of using exosomes engineered to express a specific tumor antigen to generate an immune response against tumors. We expressed a target tumor antigen, human MUC1 (hMUC1), in 2 MHC type-distinct mouse cell lines, CT26 and TA3HA. Analysis of exosomes purified from these cells revealed that exosomes contained the target MUC1 antigen on their surfaces as well as other well-described exosomal proteins, including Hsc70 and MHC class I molecules. In addition, both autologous and allogenic exosomes were able to stimulate the activation of immune cells and suppress hMUC1-expressing tumor growth in a MUC1-specific and dose-related manner. Therefore, these data suggest that exosomes can be engineered from tumor cell lines to deliver a target immunogen capable of inducing an effective immune response and that they may represent a new cell-free tumor vaccine.