肿瘤微环境中外泌体功能研究进展

细胞外囊泡是一种十分重要的细胞间通讯的方式,尤其是外泌体在生理、病理过程中的调控作用越来越受到研究人员的关注。而在肿瘤微环境中,肿瘤细胞、免疫细胞、基质细胞都是外泌体的主要来源,外泌体中包裹的大量生物活性分子,对下游靶细胞的表型分化、生理功能、代谢状态有着重要的作用。探究肿瘤微环境中外泌体的调控作用,对进一步认识肿瘤发生、进展、转移、耐药、免疫逃逸等过程有着十分重要的意义,并且可作为肿瘤患者早期诊断和预后评价的重要指标。本文将主要介绍外泌体在肿瘤微环境中的作用。     

外泌体与肿瘤干细胞动态平衡

外泌体是直径为30-100 nm,表达特异性表面分子,如CD63、CD81等的胞外囊泡,其内包有DNA、mRNA、ncRNAs、蛋白以及脂类等生物活性物质。通过转运其包含物,外泌体可调控受体细胞的信号通路及蛋白表达,在介导肿瘤细胞与其肿瘤微环境中其他细胞间的细胞通讯和物质交流中起重要作用。肿瘤干细胞是存在于肿瘤组织内,具有自我更新和分化潜能的细胞亚群,被认为是导致肿瘤传统治疗失败和复发的根源。然而,肿瘤干细胞与非干性肿瘤细胞之间实则处于分化和去分化的动态平衡状态,肿瘤干细胞不再是肿瘤治疗的固定靶点,因此,阻断其相互转化尤为重要,更是较好的肿瘤治疗策略。外泌体作为细胞间信息传递的载体,是否参与调控肿瘤干细胞与非干性肿瘤细胞之间的相互转化,靶向外泌体及其信号通路是否有利于减少肿瘤干细胞的生成,最终根治肿瘤,值得深入研究。     

不同细胞来源外泌体对肿瘤微环境的重塑作用

囊泡转运是细胞间沟通的重要方式。随着蛋白质组学、代谢组学、RNA组学等多组学联合研究的发展和进步,研究人员发现外泌体是细胞间通讯的重要信号转导媒介和介质。外泌体携带大量生物活性分子,对细胞生物学功能的发挥具有重要的调控作用,影响肿瘤细胞的特性。越来越多的证据表明,外泌体的功能与其来源的细胞及其内含物成分密切相关。肿瘤来源外泌体以自分泌和旁分泌的方式诱导癌细胞和基质细胞生理功能和代谢状态的改变,基质细胞来源外泌体参与建立、支持和营养肿瘤细胞的肿瘤微环境,并且不同免疫细胞来源外泌体可能呈现截然相反的功能。本文就不同细胞来源外泌体在肿瘤微环境中的作用和机制进行综述,为外泌体在肿瘤诊断、治疗及预后评估中的应用提供参考。     

外泌体在胃肠道肿瘤诊治中的应用

外泌体(exosomes,EXOs)是一种由各种细胞分泌的广泛存在于人体各种体液中的直径为30～150 nm的细胞外囊泡.外泌体富含有蛋白质、核酸和脂质等生物活性成分,可通过参与细胞间的物质交换及信号传递作用参与多种生理病理过程.近来研究显示,胃肠道肿瘤相关的外泌体在调控肿瘤发生和发展过程中发挥重要作用,对相关外泌体的...     

外泌体在肿瘤负向免疫调控中的作用

外泌体(exosome)是一类直径30～100 nm的囊泡样小体,其含有蛋白质、mRNA、微小RNA(miRNA)、DNA片段等,是细胞间物质和信息转导的重要媒介.外泌体参与肿瘤的发生、发展、侵袭和转移等各个过程,其在肿瘤免疫中发挥双向调控功能.本文重点阐述外泌体在肿瘤负向免疫调控中的作用,如肿瘤来源外泌体(tumor-derived exosome,TEX)能够阻碍DC的分化和成熟,促进巨噬细胞极化,减弱B细胞功能及诱导调节性B细胞(regulatory B cell,Breg)产生,促骨髓前体细胞分化为髓系抑制性细胞(myeloid-derived suppressor cell,MDSC),减弱NK及T淋巴细胞的杀伤功能,诱导调节性T细胞(regulatoryT cell,Treg)等;又如免疫细胞来源外泌体(immunocyte-derived exosome,IEX),主要为Treg、CD8+T细胞来源的外泌体,同样具有免疫抑制功能.     

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。     

肿瘤外泌体对CD8+T细胞功能的影响及机制研究进展

外泌体（exosomes）是介导细胞间通讯的细胞外囊泡。它携带来源细胞的多种生物活性分子,并可将其输送给受体细胞,进而影响细胞功能。肿瘤来源外泌体可通过多种机制介导肿瘤的免疫逃逸。本文就肿瘤外泌体对肿瘤杀伤主力军CD8+T细胞的调控作用进行总结,分析其相关作用机制,以期为肿瘤免疫治疗的研发提供新的思路。     

外泌体在多发性骨髓瘤中的作用及其临床应用

外泌体是由细胞分泌的内含蛋白或核酸等活性物质、直径为35~120 nm的脂质双分子层囊泡。外泌体通过调控细胞间通讯,不仅参与调控细胞的正常生理过程,同时参与包括肿瘤在内的多种疾病的病理过程。肿瘤来源的外泌体参与肿瘤细胞与微环境的相互作用,并通过与转移、免疫抑制等相关信号通路刺激肿瘤的发生与发展。多发性骨髓瘤（multiple myeloma,MM）是最为常见的血液系恶性肿瘤之一,其具体发病机制尚未完全清楚,且缺乏安全、高效的诊疗手段。而外泌体因携带丰富的生物学信息,为肿瘤的治疗提供了一个新的靶点。因此,本文就外泌体在MM发生和发展中的作用及其以外泌体为基础的诊疗新方向作一综述。     

外泌体环状RNA在肿瘤微环境中的潜在应用研究进展

外泌体是细胞间通信的多功能调节剂,通过携带各种信息在肿瘤患者的生理和病理状态下起作用。越来越多的研究已经确定了环状RNA(circRNA)在多种细胞中具有关键的调节作用,来自供体细胞的外泌体circRNA可以局部或远程调节受体细胞,以促进肿瘤的发展和传播,并在肿瘤微环境（TME）中发挥关键作用,从而显著增强肿瘤免疫、代谢、血管生成、耐药性、上皮-间充质转化（EMT）、侵袭和转移。本文主要综述了外泌体circRNA在TME中的潜在作用,强调了外泌体circRNA是肿瘤的生物标志物和潜在治疗靶点,为今后肿瘤的诊断和治疗提供帮助。     

外泌体在膀胱肿瘤中的研究进展

外泌体在肿瘤的发生、发展过程中发挥着重要的作用。外泌体是一个由细胞主动分泌的直径约为40～100 nm的双层囊泡小体,细胞类型不同,其产生的外泌体亦不相同。外泌体普遍存在于人体体液中,其内容物丰富,含核酸、蛋白质、脂质等,在细胞与细胞的信息交流中起重要的作用,与肿瘤的发生、浸润、转移和耐药密切相关。外泌体作为肿瘤学新型研究的热点,其在膀胱癌临床诊断和治疗方面有重要的研究价值。本文对外泌体的生物合成、内容物及其在膀胱癌中的研究进展作一综述。     

外泌体微小RN A--肿瘤发生发展的新型调节分子

肿瘤微环境是影响肿瘤细胞侵袭转移的关键因素,外泌体是微环境中细胞间信号交流的一种形式,微小RNA（miRNA）广泛参与了生物体多种生理过程,它们在肿瘤内环境稳定方面起着重要的作用。其中肿瘤外泌体中的miRNA具有诱导肿瘤细胞增殖,细胞外基质重塑,促进迁移、侵袭和肿瘤相关血管形成等功能。通过作用于外泌体产生和释放的机制,可阻断致癌基因的表达,为肿瘤的发生发展及治疗提供新的思路。     

外泌体在肝癌发生发展中的研究进展

肝细胞癌（HCC）是最常见的恶性肿瘤之一,死亡率高,预后极差。HCC的发生涉及多种癌基因或抑癌基因的突变,但具体的分子机制尚不清楚。外泌体是细胞外囊泡的一种,可介导细胞间的物质交换和信息交流,近年来发现外泌体在肝癌的发生发展中具有关键作用,可应用于肝癌的诊断与治疗。本文就外泌体的组成与功能及其在肝癌的发生发展、诊断与治疗中的作用作一综述。     

中介素与肿瘤

中介素可通过多种信号通路促进肿瘤血管生成,并受肿瘤细胞缺氧影响表达增加.近年来,国内外出现多项中介素与肿瘤发生、发展、侵袭之间相互关系及作用机制的研究,有望为肿瘤治疗提供新靶点.     

中介素与肿瘤

中介素可通过多种信号通路促进肿瘤血管生成,并受肿瘤细胞缺氧影响表达增加。近年来,国内外出现多项中介素与肿瘤发生、发展、侵袭之间相互关系及作用机制的研究,有望为肿瘤治疗提供新靶点。     

Non-classical HLA-G antigen and its role in the cancer progression

Various changes take place during the progression of cancer, some of which are favorable for tumor development and may help to escape the immunosurvillance. These include changes in the microenvironment around the developing tumor, which could be produced in response to phenotypic alterations or could modulate the expression of certain markers of tumor development. One such newly discovered molecule is HLA-G, which has been found to have immunosuppressive and immunomodulatory roles in the cancer development. The regulatory sequences, as seen, may be induced by various factors that may be present in tumor microenvironment. A recent study has investigated the antigen -G as a marker of susceptibility to chemotherapy. Further, its expression on tumors and how it can be exploited for diagnosis and therapy is discussed in this article.     

循环外泌体PD-L1表达水平与PD-1/PD-L1抑制剂治疗恶性肿瘤疗效的相关性研究现状

外泌体作为具有生物学功能的小囊泡,是近年肿瘤研究领域关注的热点。研究发现,肿瘤细胞分泌的外泌体表达的程序性死亡受体配体1(programmed death ligand 1,PD-L1),可在肿瘤患者外周血液中检测到,可能参与并抑制机体免疫反应。近年来,一些研究发现,外泌体PD-L1可能影响程序性死亡受体1（programmed death 1,PD-1）/PD-L1抑制剂的抑制效应。反之,亦然。应用PD-1/PD-L1抑制剂治疗,可影响外泌体PD-L1的表达水平。二者有怎样的联系和相关性？本文就循环外泌体PD-L1在不同肿瘤免疫反应及抗PD-1/PD-L1免疫治疗中的研究进展作一综述。     

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.     

Cyclooxygenases, prostanoids, and tumor progression

In response to various growth factors, hormones or cytokines, arachidonic acid can be mobilized from phospholipids pools and converted to bioactive eicosanoids through cyclooxygenase (COX), lipoxygenase (LOX) or P-450 epoxygenase pathway. The COX pathway generates five major prostanoids (prostaglandin D₂, prostaglandin E₂, prostaglandin , prostaglandin I₂ and thromboxane A₂) that play important roles in diverse biological processes. Studies suggest that different prostanoids and their own synthase can play distinct roles in tumor progression and cancer metastasis. COX-2 and PGE₂ synthase have been most well documented in the regulation of various aspects of tumor progression and metastasis. PGE₂, for example, can stimulate angiogenesis or other signaling pathways by binding to its receptors termed EPs. Therefore, targeting downstream prostanoids may provide a new avenue to impede tumor progression. In this review, aberrant expression and functions of several prostanoid synthetic enzymes in cancer will be discussed. The possible regulation of tumor progression by prostaglandins and their receptors will also be discussed.     

Mesenchymal stem cell signaling in cancer progression

Mesenchymal (multipotent) stem/stromal cells (MSCs) may affect cancer progression through a number of secreted factors triggering activation of various cell signaling pathways. Depending on receptor status, phosphatase and tensin homolog (PTEN) status, or Wnt activation in the cancer cells, the signals may either result in increased growth and metastasis or lead to inhibition of growth with increased cell death. Thus, MSCs can play a dual role in cancer progression depending on the cellular context wherein they reside. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway has a central role in regulating tumor growth, and several MSC secreted factors stimulate activation of this pathway. A comprehensive understanding of the signals regulating MSC–tumor cross-talk is highly important for the development of MSCs as potential therapeutic vehicles. Thus, the presented review focuses on factors released by MSCs and on the dual role they may have on various stages of tumorigenesis.     

Tracing the tumor lineage

Defining the pathways through which tumors progress is critical to our understanding and treatment of cancer. We do not routinely sample patients at multiple time points during the progression of their disease, and thus our research is limited to inferring progression a posteriori from the examination of a single tumor sample. Despite this limitation, inferring progression is possible because the tumor genome contains a natural history of the mutations that occur during the formation of the tumor mass. There are two approaches to reconstructing a lineage of progression: (1) inter‐tumor comparisons, and (2) intra‐tumor comparisons. The inter‐tumor approach consists of taking single samples from large collections of tumors and comparing the complexity of the genomes to identify early and late mutations. The intra‐tumor approach involves taking multiple samples from individual heterogeneous tumors to compare divergent clones and reconstruct a phylogenetic lineage. Here we discuss how these approaches can be used to interpret the current models for tumor progression. We also compare data from primary and metastatic copy number profiles to shed light on the final steps of breast cancer progression. Finally, we discuss how recent technical advances in single cell genomics will herald a new era in understanding the fundamental basis of tumor heterogeneity and progression.