RNA结合蛋白HuR对外泌体生成机制的调控

外泌体是一类直径为30～150 nm的膜囊泡,几乎所有的细胞都能够分泌外泌体,它含有许多来源于细胞的成分.近年来,越来越多的证据表明外泌体介导的信号蛋白、RNA、核酸等多种分子的传递有助于肿瘤的发生发展,包括重塑细胞外基质、促进血管生成、干扰免疫反应、促进肿瘤细胞的增殖迁移以及塑造肿瘤转移前微环境等[1].     

肿瘤来源的外泌体在肿瘤发生发展中的作用及机制

肿瘤细胞与微环境中各种细胞间的信息传递在肿瘤转移中发挥着重要的作用,而外泌体是细胞间通讯的重要媒介之一。肿瘤来源的外泌体可通过其携带的蛋白、核酸等多种物质,促进肿瘤的上皮-间质转化(EMT)、血管新生、癌相关成纤维细胞的转化、肿瘤免疫逃逸及前转移微环境的形成,进而促进肿瘤的生长及侵袭转移。     

外泌体在肝癌中的研究进展及应用前景

外泌体是一种重要的细胞间物质和信息交流的工具,它通过细胞间传递基因和蛋白信号,调节肿瘤微环境,进而介导肿瘤细胞的凋亡、分化、血管生成和转移。外泌体通过多种机制促进肝癌的发生发展,其在肝癌的早期诊断、耐药性检测、预后评估及治疗均密切相关。因此,对于外泌体的研究,可为肝癌的治疗提供新的方向和机遇。     

调节性T细胞外泌体对肿瘤调节作用的研究进展

外泌体是由细胞分泌的异质性纳米级胞外囊泡,富含多种RNA、DNA片段、脂质和蛋白质等生物活性物质,能参与细胞间的物质交换与信息交流转送。作为细胞间交流和传递信息的一种新媒介,其在免疫应答、血管生成、炎症反应、细胞凋亡及肿瘤发生发展等过程中均有重要的调节作用。调节性T细胞分泌外泌体参与调节免疫应答、器官移植、自身免疫病以及肿瘤的发生发展与转移等过程。本文主要综述调节性T细胞来源外泌体的研究进展和生物学特征,与肿瘤细胞来源外泌体的异同点及其在肿瘤微环境的形成维持、肿瘤诊断与治疗方面的潜在应用价值。     

外泌体在前列腺癌诊疗中的研究进展

前列腺癌(PCa)是男性常见的恶性肿瘤。外泌体是存在于人体多种体液中的双层膜囊泡,携带核酸、蛋白等物质,介导细胞间通讯。外泌体可以促进前列腺癌的生长,协助免疫逃逸及化学治疗耐药,诱导血管生成、上皮细胞间充质转化(EMT)并为转移前生态位的形成提供条件,进而促进前列腺癌的侵袭和转移。基于肿瘤细胞与正常细胞分泌的外泌体成分不同,外泌体可作为前列腺癌诊断、预测侵袭转移、评估患者预后及药物疗效的生物标志物,并有望作为药物运输载体,在肿瘤的精准治疗中具有广阔的前景。     

外泌体与胰腺癌的发生发展、诊断和治疗

在胰腺癌微环境中,不同细胞来源的外泌体通过传递RNA等物质促进了肿瘤的生长、迁移和侵袭,并促进胰腺癌产生对吉西他滨的耐药性。外泌体携带了大量胰腺癌相关信息,可以通过从体液中捕获外泌体并分析其内容物来早期诊断胰腺癌,利用芯片技术可以使检测更加简便快捷。通过阻断外泌体的生成和传递,或者利用外泌体靶向运送抗肿瘤药物是潜在的治疗胰腺癌的方法之一。     

间充质干细胞源性外泌体在创面修复中的研究进展

外泌体是由细胞通过旁分泌途径产生的一种直径在30～100 nm的囊泡结构。作为活细胞分泌的一种亚细胞成分,外泌体广泛参与细胞间的信息交流。多项研究表明,间充质干细胞源性外泌体调控创面修复的多个过程。它可以通过抑制创面过度炎症反应,促进创面血管新生,促进成纤维细胞增殖、迁移,以及抑制创面瘢痕形成来促进创面的修复与再生。本文就间充质干细胞源性外泌体在创面修复中的作用及相关机制进行综述,为外泌体在临床中的应用提供依据。     

外泌体治疗脊髓损伤的研究进展

外泌体是细胞分泌到胞外环境的膜囊泡,是治疗脊髓损伤的一种新策略。间充质干细胞分泌的外泌体在脊髓损伤的治疗中具有抗凋亡、抗炎和促血管生成的作用,同时能促进神经细胞间的交流,并可作为外源性遗传物质的载体。与其亲代细胞相比,外泌体可穿越血脑屏障,更加稳定,降低了施用活细胞所固有的安全风险。     

胶质瘤血管新生及其调控机制

体内外研究表明实体性肿瘤的生长是依赖血管的,其直径一旦超过2 mm,若没有新生的血管供血则肿瘤的生长就会停止。胶质瘤是人体内血管化程度最高恶性的肿瘤之一。胶质瘤的血管发生与其他实体性肿瘤血管发生一样,由血管形成及血管新生两种方式构成：前者由内皮祖细胞或者血管母细胞形成新的血管;而后者是由组织中既存的成熟血管的内皮细胞发生增殖和游走形成小血管。血管新生是肿瘤血管生成的主要形式,胶质瘤血管新生的机制研究以及抑制其血管生成是胶质瘤治疗的一个新途径,成为近年来的研究热点,本文就胶质瘤血管新生及其调控机制作一综述。     

血管生长调节因子与基因治疗

血管新生为肿瘤生长和转移所依赖 ,因此抑制血管新生可作为一种全新的肿瘤治疗策略。一系列的血管生长抑制因子已经在离体和活体实验中得到证实 ,其中血管抑素和内皮抑素是近来研究的热点 ;同时 ,在肿瘤生长和转移过程中 ,还存在一些血管生长促进因子 ,其中ＶＥＧＦ及其相关受体在肿瘤血管新生中起着非常重要的作用。在此 ,我们对血管生长调节因子的作用机制及其在基因治疗中的潜在应用作一综述。一、血管生成和血管新生人体血管系统的生成有两处不同的过程 :1 血管生成(ｖａｓｃｕｌｏｇｅｎｅｓｉｓ) ,即胚胎发育早期 ,中胚层来源的内皮细…     

High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis

Ovarian cancer, the most lethal gynecological cancer, related closely to tumor stage. High-grade ovarian cancer always results in a late diagnose and high recurrence, which reduce survival within five years. Until recently, curable therapy is still under research and anti-angiogenesis proves a promising way. Tumor-derived exosomes are essential in tumor migration and metastases such as angiogenesis is enhanced by exosomes. In our study, we have made comparison between high-grade and unlikely high-grade serous ovarian cancer cells on exosomal function of endothelial cells proliferation, migration and tube formation. Exosomes derived from high-grade ovarian cancer have a profound impact on angiogenesis with comparison to unlikely high-grade ovarian cancer. Proteomic profiles revealed some potential proteins involved in exosomal function of angiogenesis such as ATF2, MTA1, ROCK1/2 and so on. Therefore, exosomes plays an influential role in angiogenesis in ovarian serous cancer and also function more effectively in high-grade ovarian cancer cells.     

肿瘤来源的胞外体对肿瘤进展的影响

胞外体是真核细胞在正常生理过程中分泌的一种具有多种细胞膜结构的小囊泡,作为一类重要的细胞间信号分子,胞外体具有多种生物活性成分,其异常分泌是恶性肿瘤的标志.胞外体与肿瘤细胞生长、肿瘤血管生成、免疫抑制及化疗耐药关系密切.因此,探究胞外体的形成过程、主要组成成分及肿瘤相关的胞外体在肿瘤进展、免疫调节中的作用有助于进一步了解肿瘤进展过程,具有重要意义.     

Exosomes in tumor microenvironment influence cancer progression and metastasis

Exosomes are small membrane vesicles of endocytic origin with a size of 50–100 nm. They can contain microRNAs, mRNAs, DNA fragments, and proteins, which are shuttled from a donor cell to recipient cells. Many different cell types including immune cells, mesenchymal cells, and cancer cells release exosomes. There is emerging evidence that cancer-derived exosomes contribute to the recruitment and reprogramming of constituents associated with tumor environment. Here, we discuss different mechanisms associated with biogenesis, payload, and transport of exosomes. We highlight the functional relevance of exosomes in cancer, as related to tumor microenvironment, tumor immunology, angiogenesis, and metastasis. Exosomes may exert an immunosuppressive function as well as trigger an anti-tumor response by presenting tumor antigens to dendritic cells. Exosomes may serve as cancer biomarkers and aid in the treatment of cancer.     

Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments

Cancer cells, both in vivo and in vitro, have been demonstrated to release membranous structures, defined as microvesicles or exosomes, consisting of an array of macromolecules derived from the originating cells, including proteins, lipids, and nucleic acids. While only recently have the roles of these vesicular components in intercellular communication become elucidated, significant evidence has demonstrated that tumor exosomes can exert a broad array of detrimental effects on the immune system—ranging from apoptosis of activated cytotoxic T cells to impairment of monocyte differentiation into dendritic cells, to induction of myeloid-suppressive cells and T regulatory cells. Immunosuppressive exosomes of tumor origin can be found within neoplastic lesions and in biologic fluids from cancer patients, implying a potential role of these pathways in in vivo tumor progression and systemic paraneoplastic syndromes. Through the expression of molecules involved in angiogenesis promotion, stromal remodeling, signaling pathway activation through growth factor/receptor transfer, chemoresistance, and genetic intercellular exchange, tumor exosomes could represent a central mediator of the tumor microenvironment. By understanding the nature of these tumor-derived exosomes/microvesicles and their roles in mediating cancer progression and modulating the host immune response will significantly impact therapeutic approaches targeting exosomes.     

Melanoma exosomes enable tumor tolerance in lymph nodes

Melanoma preferentially spreads via lymph nodes. Melanoma exosomes can induce angiogenesis and immune suppression. However, a role for melanoma exosomes in facilitating tumor tolerance in lymph nodes has not been considered. Herein, the hypothesis that melanoma exosome mediated induction of vascular endothelial cell (VEC) derived tumor necrosis factor alpha (TNF-α) results in lymphatic endothelial cell (LEC) mediated tumor tolerance is explored. To support this hypothesis, experiments involving ex vivo lymph node associated VECs, LECs, dendritic cells and T lymphocytes are proposed based upon a previously established fluorescent exosome lymph node trafficking model. The implication of the hypothesis in the context of melanoma exosome mediated induction of tumor tolerance in lymph nodes is then discussed.     

外泌体和细胞因子促进牙髓血管生成的作用与调控机制

文题释义： 牙髓再生：被定义为牙根结构、牙本质、牙髓牙本质复合体的更换，包括其血运、神经的重建，以弥补牙齿低血运和低感觉带来的使用寿损。牙髓再生治疗现已作为牙髓感染或坏死的一个新的治疗选择，组织工程技术促进牙髓再生，即将具有增殖分化潜能的干细胞和适宜的生物活性支架物质植入患牙牙根内，在一定生长因子的诱导下，产生新的牙本质牙髓复合体。 血管生成：是指从已有的毛细血管或毛细血管后静脉发展而形成新的血管，主要包括激活期血管基底膜降解；血管内皮细胞的激活、增殖、迁移；重建形成新的血管和血管网。血管形成是一个促血管形成因子和抑制因子协调作用的复杂过程，正常情况下二者处于平衡状态，一旦此平衡打破就会激活血管系统使血管生成过度，或抑制血管系统使血管退化。 背景：随着组织工程技术在口腔领域的应用，构建一种组织工程化的牙髓进行牙髓-牙本质复合体的再生治疗成为可能，而在牙髓再生过程中，形成有功能的血运系统是其必要条件。血管生成是指从已有的毛细血管中形成新的血管，对牙髓再生和维持牙髓内环境稳定具有重要意义。 目的：综述外泌体和促进血管生成的细胞因子在牙髓血管生成过程中作用机制的研究进展。 方法：应用计算机检索PubMed数据库和CNKI数据库，英文关键词为“tissue engineering，pulp regeneration，regenerative endodontics，angiogenesis，neovascularization，angiogenic，signal molecules，exosomes，factors，role，mechanism”，中文关键词为“牙髓再生，组织工程，血管生成，血管再生，信号分子，外泌体，因子，机制”，重点查阅从2017至2019年的相关文献并总结。  结果与结论：组织工程中移植的牙髓组织能否存活取决于其能否快速形成有功能的血运系统。牙髓再生过程中血管生成是一个不可缺少的过程，许多文献研究了外泌体和多种促血管生成的细胞因子在促进牙髓血管生成中的作用，然而牙髓血管生成的调控机制还有待进一步研究。 ORCID: 0000-0003-3438-2310(陈婷) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

Exosomes and their role in the micro-/macro-environment: a comprehensive review

The importance of extracellular vesicles (EVs) in cell-cell communication has long been recognized due to their ability to transfer important cellular cargoes such as DNA, mRNA, miRNAs, and proteins to target cells. Compelling evidence supports the role of EVs in the horizontal transfer of cellular material which has the potential to influence normal cellular physiology and promote various disease states. Of the different types of EVs, exosomes have garnered much attention in the past decade due to their abundance in various biological fluids and ability to affect multiple organ systems. The main focus of this review will be on cancer and how cancer-derived exosomes are important mediators of metastasis, angiogenesis, immune modulation, and the tumor macro-/microenvironment. We will also discuss exosomes as potential biomarkers for cancers due to their abundance in biological fluids, ease of uptake, and cellular content. Exosome use in diagnosis, prognosis, and in establishing treatment regimens has enormous potential to revolutionize patient care.     

TLR2-Mediated Expansion of MDSCs Is Dependent on the Source of Tumor Exosomes

Exosomes released from tumor cells having been shown to induce interleukin-6 release from myeloid-derived suppressor cells in a Toll-like receptor 2/Stat3-dependent manner. In this study, we show that exosomes released from tumor cells re-isolated from syngeneic mice are capable of inducing interleukin-6 in a Toll-like receptor 2-independent manner, whereas the data generated from exosomes of tumor cells having undergone numerous in vitro passages induce interleukin-6 in a Toll-like receptor 2-dependent manner. This discrepancy may be due to the source of tumor cells used to generate the exosomes for this study. These results suggest that exosomes released from tumor cells that are not within a tumor microenvironment may not realistically represent the role of tumor exosomes in vivo. This is an important consideration since frequently passing tumor cells in vivo is an accepted practice for studying tumor exosome-mediated inflammatory responses.Communication between cells through exosomes has recently become a phenomenon of increasing interest. In particular, tumor cells communicate with immune cells, leading to immune suppression.^1–6 One of the challenging issues is that the data generated from tumor cell-derived exosomes released from in vitro cultured tumor cells may not represent the real effects caused by exosomes released from tumor cells being grown under immune pressure (a true physiological microenvironment). However, due to technical obstacles, it is difficult to isolate exosomes from solid tumor tissues.The tumor microenvironment is enriched with the inflammatory factors that promote angiogenesis, turnover of the extracellular matrix, and tumor cell motility.^7,8 Understanding the molecular mechanisms of how surrounding inflammatory factors promote tumor progression represents one of the major challenges in cancer research.It is well-known that Toll-like receptor (TLR) stimulation leads to the induction of pro-inflammatory factors. The adaptor protein myeloid differentiation antigen 88 (MyD88) is a central adaptor required by all TLRs except TLR3. MyD88 has been found to play a critical tumorigenic role in a mouse model by upregulating the expression of tumor promoting genes, growth factors and various cytokines and chemokines.^9,10 However, it remains to be determined whether these tumor promoting effects are mediated by specific TLRs.Myeloid-derived suppressor cells (MDSCs) contribute to the negative regulation of immune responses during tumor progression. In addition to their suppressive effects on T cell immune responses,¹¹ MDSCs have also been reported to regulate innate immune responses by modulating natural killer cell tumor cytotoxicity¹² and macrophage cytokine profiles.^13–15 There are a number of host factors that contribute to the expansion of MDSCs. Exosomes released from tumor cells have been shown to induce the production of MDSCs.^5,6 Further, our data¹⁶ and others¹ support the view that tumor exosomes play a role in the expansion of MDSCs in a MyD88 dependent manner. However, our data¹⁶ does not support the idea that TLR2 plays a role in the induction of MDSCs. We used tumor exosomes released from re-isolated tumor cells from syngeneic mice¹⁶ to test whether the tumor microenvironment plays a role in causing this discrepancy.Here, we demonstrate that exosomes released from tumor cells passaged in vitro 40 or more times function in a TLR-dependent manner; whereas, exosomes released from tumor cells passed in vivo in immune competent mice expand MSDCs numbers in a MyD88-dependent manner.