外泌体环状RNA在泌尿系统肿瘤中的研究进展

外泌体是一种包含了复杂RNA和蛋白质的膜性囊泡，其主要来源于细胞内溶酶体微粒内陷形成的多囊泡体，经多囊泡体外膜与细胞膜融合后释放到胞外基质中。外泌体在肿瘤微环境中介导细胞间通讯，其功能取决于来源的细胞类型。环状RNA是一类由前体mRNA反向剪接生成的非编码RNA，在外泌体中富集且稳定表达。外泌体环状RNA在疾病中发挥了重要的调控作用，其作为肿瘤标志物和治疗靶点的临床应用前景与价值现已成为研究热点。本文就外泌体环状RNA在泌尿系统肿瘤中的研究进展作一综述。     

肿瘤微环境中的外泌体:新的治疗途径

肿瘤微环境参与了癌症的发生、发展和对治疗的反应,近年来研究发现外泌体在肿瘤微环境中发挥重要作用。外泌体(exosomes)是一类直径30~100nm的囊泡小体,包含蛋白质,脂类和功能性RNA分子等。肿瘤来源的外泌体(cancer cell derived exosomes,CCEs)是肿瘤微环境中的重要成员,可以促使成纤维细胞和间质细胞向肌成纤维细胞分化,重塑细胞外基质,诱导上皮间质转化(epithelial mesenchymal transition,EMT),帮助肿瘤细胞免疫逃逸,引发血管生成,从而促进肿瘤的生长和转移。因此,基于肿瘤微环境中外泌体的疗法为肿瘤治疗开辟了新的途径,如干预外泌体的合成或分泌抑制肿瘤转移,作为药物载体转运各种抗癌药物(mi RNAs和si RNAs等)以及在免疫治疗中避免被免疫系统识别和清除等。     

外泌体调控肿瘤侵袭转移的研究进展

外泌体(exosomes)是一种由多种类型细胞分泌的磷脂双层膜囊泡，直径在30～100 nm之间。它们存在于几乎所有体液中，如血液、脑脊液、尿液、胆汁、乳汁等。外泌体能够携带多种物质，介导细胞间通讯并反映来源细胞的状态。外泌体在肿瘤进展中发挥了重要的作用，它们可以通过促进肿瘤细胞上皮-间质转化(epithelial-mesenchymal transition,EMT)、形成转移前微环境(pre-metastatic niche,PMN)以及促进促炎症和免疫抑制微环境的形成，促进肿瘤的侵袭转移。本文综述了外泌体调控肿瘤侵袭转移的作用机制，包括外泌体介导的细胞间信号传递、外泌体调控肿瘤细胞增殖、迁移和侵袭等方面。此外，本文还探讨了外泌体在肿瘤微环境中的作用及其与免疫逃逸的关系，期望为深入研究外泌体对肿瘤的调控作用提供新的思路、为肿瘤治疗提供新的靶点和策略。     

外泌体与肿瘤关系的研究进展北大核心CSCD

外泌体(又称外秘小体,exosomes)是一种能被多种活细胞分泌,直径为30~100nm,并广泛分布于多种体液中的微囊泡结构。近10年来研究发现外泌体富含蛋白质、DNA、RNA和脂质等生物活性分子,这些物质在肿瘤转移前微环境的形成、侵袭与转移中发挥重要的作用。外泌体以其独特的方式包裹着核酸和蛋白质,在细胞间有效稳定地发挥信息交流的作用。为更好地了解外泌体促进肿瘤发生发展的机制,该文将对外泌体的结构和生物学功能,以及在肿瘤微环境中如何影响肿瘤发生发展进行综述。     

外泌体及其在肿瘤诊疗中的意义

外泌体(exosome)是由多种活细胞分泌的囊泡小体,其中含有蛋白质和RNA等多种组分。这种机体内普遍存在的纳米级被膜结构能够参与细胞间的物质交换和信息交流,在多种生理和病理过程中发挥重要作用。外泌体在外周血、尿液、唾液、腹水、羊水等体液中具有很高的丰度,而不同组织来源的外泌体在组成和功能方面存在差异,同时这种差异受到细胞外基质和微环境的动态调控。肿瘤来源或肿瘤相关的外泌体是调控肿瘤发生发展的重要机制,对肿瘤外泌体的分析和检测可以辅助肿瘤的早期诊断、疗效评价和预后分析。此外,外泌体及其修饰加工产物还可以作为基因或药物的有效载体,用于肿瘤治疗。关于外泌体的研究是肿瘤学的一个新兴领域,在转化医学的研究模式下,将极大推动肿瘤学研究进展,为肿瘤临床诊断和治疗带来新的契机。     

外泌体在肿瘤侵袭转移中作用的研究进展

外泌体(exosome)是多种细胞分泌的一种40~100 nm的由磷脂双层膜包裹的微囊体,其组成主要包括脂质体、蛋白质、DNA及mi RNA等。研究表明外泌体通过携带生物活性物质参与了机体许多重要的生理及病理过程,尤其是在肿瘤的侵袭及转移方面。外泌体主要通过诱导肿瘤转移的启动、促进肿瘤血管生成、参与肿瘤转移前微环境形成及肿瘤微环境的免疫调控等途径,在肿瘤侵袭转移中发挥重要作用。     

外泌体源性miRNAs在肺癌发生发展中的作用

外泌体(exosomes)是细胞分泌的纳米级细胞外囊泡.外泌体通过释放其内的生物活性大分子,比如微小RNA(microRNA,miRNA)到受体细胞,从而介导细胞间交流通讯. MiRNAs作为一类主要在转录后水平负向调控靶mRNAs的非编码RNAs,其在外泌体中含量最为丰富.在肺癌中,miRNAs经肿瘤细胞分泌的外泌体转运释放而发挥重要的作用.本文主要讨论了外泌体源性miRNAs在肺癌发生发展的各个阶段,包括血管生成、细胞增殖、侵袭转移、免疫逃逸、耐药等方面的作用,以及其在作为新型肺癌诊断和预后标志物方面的临床价值.     

外泌体在白血病中的重要调控作用

目前,白血病复发是患者死亡的主要原因之一。肿瘤细胞和微环境的相互作用,以及隐匿在骨髓中的肿瘤干细胞,促进了白血病的复发和向淋巴组织的转移,因此白血病的治疗、转移和复发问题受到广泛关注。外泌体是由绝大多数细胞分泌的双层脂质膜囊泡,可以调控细胞间的交流和信息传递。在白血病细胞、基质细胞和内皮细胞之间的相互联系中都涉及到外泌体,白血病细胞来源的外泌体存在于白血病患者的血浆中,能把其携带的白血病相关抗原及微小RNA呈递给靶细胞,促进白血病肿瘤细胞的增殖,有助于肿瘤细胞实现免疫逃避,保护白血病细胞抵抗化疗药物导致的细胞毒性作用,促进血管生成及肿瘤细胞的迁移。因此,外泌体与白血病的转移、治疗及预后密切相关,可以用来检测和监测白血病的进展。本文综述了外泌体的来源、形成与分泌机制,以及外泌体在白血病发生前、发展中、预后和免疫治疗中所扮演的重要角色。     

外泌体源性微小RNA在肝细胞癌及其早期诊断中的作用

肝细胞癌(hepatocellular carcinoma,HCC)是全球第六大最常见的恶性肿瘤。外泌体中微小RNA(microRNAs,miRNAs)可通过在细胞间传递交流来参与调控血管生成、上皮-间充质转化和介导免疫微环境等多种通路途径,从而促进HCC细胞的生长增殖和迁移侵袭,以及诱导肿瘤细胞耐药。此外,外泌体源性miRNAs展现了显著的组织特异性和作为新颖生物标志物的巨大潜力,已成为当前HCC早期液体活检研究的热门领域。本文综述了外泌体源性miRNAs在HCC发生发展和耐药中的作用机制,揭示了其潜在的系统性分子调控网络,归纳了其在HCC早期诊断中的应用价值。     

外泌体在肿瘤免疫逃逸和耐受中的作用

肿瘤细胞能够通过多种机制抵御免疫防御或药物的抗肿瘤作用.近年研究发现,外泌体能够直接介导癌症的进展和远端转移灶的形成.更为重要的是,在肿瘤免疫微环境中,肿瘤来源外泌体不仅能够抑制树突状细胞(DC)、巨噬细胞、T细胞、NK细胞等免疫细胞功能,还能促进骨髓来源的抑制性细胞(MDSC)、调节性T细胞(Treg)等的免疫抑制功能,进而降低抗肿瘤免疫应答过程,帮助肿瘤细胞逃避机体免疫细胞识别.本文将概述肿瘤外泌体及其携带的关键介质分子在介导肿瘤免疫逃逸和耐受过程中扮演的角色,并对这一研究领域的最新进展作一综述.     

Roles of exosomal circRNAs in tumour immunity and cancer progression

Tumour immunity plays an important role in the development of cancer. Tumour immunotherapy is an important component of antitumour therapy. Exosomes, a type of extracellular vesicle, act as mediators of intercellular communication and molecular transfer and play an essential role in tumour immunity. Circular RNAs (circRNAs) are a new type of noncoding RNA that are enriched within exosomes. In this review, we describe the effects of exosomal circRNAs on various immune cells and the mechanisms of these effects, including macrophages, neutrophils, T cells, and Natural killer (NK) cells. Next, we elaborate on the latest progress of exosome extraction. In addition, the function of exosomal circRNAs as a potential prognostic and drug sensitivity marker is described. We present the great promise of exosomal circRNAs in regulating tumour immunity, predicting patient outcomes, and evaluating drug efficacy.Subject terms: Tumour immunology, Cancer microenvironment, Tumour biomarkers, Oncogenes     

Exosomal circRNAs as novel cancer biomarkers: Challenges and opportunities

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.     

Anchorage-independent growth of breast carcinoma cells is mediated by serum exosomes

We hereby report studies that suggest a role for serum exosomes in the anchorage-independent growth (AIG) of tumor cells. In AIG assays, fetal bovine serum is one of the critical ingredients. We therefore purified exosomes from fetal bovine serum and examined their potential to promote growth of breast carcinoma cells in soft agar and Matrigel after reconstituting them into growth medium (EEM). In all the assays, viable colonies were formed only in the presence of exosomes. Some of the exosomal proteins we identified, have been documented by others and could be considered exosomal markers. Labeled purified exosomes were up-taken by the tumor cells, a process that could be competed out with excess unlabeled vesicles. Our data also suggested that once endocytosed by a cell, the exosomes could be recycled back to the conditioned medium from where they can be up-taken by other cells. We also demonstrated that low concentrations of exosomes activate MAP kinases, suggesting a mechanism by which they maintain the growth of the tumor cells in soft agar. Taken together, our data demonstrate that serum exosomes form a growth promoting platform for AIG of tumor cells and may open a new vista into cancer cell growth in vivo.     

Proteome characterization of melanoma exosomes reveals a specific signature for metastatic cell lines

Exosomes are important mediators in cell‐to‐cell communication and, recently, their role in melanoma progression has been brought to light. Here, we characterized exosomes secreted by seven melanoma cell lines with varying degrees of aggressivity. Extensive proteomic analysis of their exosomes confirmed the presence of characteristic exosomal markers as well as melanoma‐specific antigens and oncogenic proteins. Importantly, the protein composition differed among exosomes from different lines. Exosomes from aggressive cells contained specific proteins involved in cell motility, angiogenesis, and immune response, while these proteins were less abundant or absent in exosomes from less aggressive cells. Interestingly, when exposed to exosomes from metastatic lines, less aggressive cells increased their migratory capacities, likely due to transfer of pro‐migratory exosomal proteins to recipient cells. Hence, this study shows that the specific protein composition of melanoma exosomes depends on the cells’ aggressivity and suggests that exosomes influence the behavior of other tumor cells and their microenvironment.     

Exosomal annexin A6 induces gemcitabine resistance by inhibiting ubiquitination and degradation of EGFR in triple-negative breast cancer

Exosomes are carriers of intercellular information that regulate the tumor microenvironment, and they have an essential role in drug resistance through various mechanisms such as transporting RNA molecules and proteins. Nevertheless, their effects on gemcitabine resistance in triple-negative breast cancer (TNBC) are unclear. In the present study, we examined the effects of exosomes on TNBC cell viability, colony formation, apoptosis, and annexin A6 (ANXA6)/EGFR expression. We addressed their roles in gemcitabine resistance and the underlying mechanism. Our results revealed that exosomes derived from resistant cancer cells improved cell viability and colony formation and inhibited apoptosis in sensitive cancer cells. The underlying mechanism included the transfer of exosomal ANXA6 from resistant cancer cells to sensitive cancer cells. Isobaric peptide labeling–liquid chromatography–tandem mass spectrometry and western blotting revealed that ANXA6 was upregulated in resistant cancer cells and their derived exosomes. Sensitive cancer cells exhibited resistance with increased viability and colony formation and decreased apoptosis when ANXA6 was stably overexpressed. On the contrary, knockdown ANXA6 restored the sensitivity of cells to gemcitabine. Co-immunoprecipitation expression and GST pulldown assay demonstrated that exosomal ANXA6 and EGFR could interact with each other and exosomal ANXA6 was associated with the suppression of EGFR ubiquitination and downregulation. While adding lapatinib reversed gemcitabine resistance induced by exosomal ANXA6. Moreover, ANXA6 and EGFR protein expression was correlated in TNBC tissues, and exosomal ANXA6 levels at baseline were lower in patients with highly sensitive TNBC than those with resistant TNBC when treated with first-line gemcitabine-based chemotherapy. In conclusion, resistant cancer cell-derived exosomes induced gemcitabine resistance via exosomal ANXA6, which was associated with the inhibition of EGFR ubiquitination and degradation. Exosomal ANXA6 levels in the serum of patients with TNBC might be predictive of the response to gemcitabine-based chemotherapy.Subject terms: Breast cancer, Predictive markers     

Tumor-derived exosomal components: the multifaceted roles and mechanisms in breast cancer metastasis

Breast cancer (BC) is the most frequently invasive malignancy and the leading cause of tumor-related mortality among women worldwide. Cancer metastasis is a complex, multistage process, which eventually causes tumor cells to colonize and grow at the metastatic site. Distant organ metastases are the major obstacles to the management of advanced BC patients. Notably, exosomes are defined as specialized membrane-enclosed extracellular vesicles with specific biomarkers, which are found in a wide variety of body fluids. Recent studies have demonstrated that exosomes are essential mediators in shaping the tumor microenvironment and BC metastasis. The transferred tumor-derived exosomes modify the capability of invasive behavior and organ-specific metastasis in recipient cells. BC exosomal components, mainly including noncoding RNAs (ncRNAs), proteins, lipids, are the most investigated components in BC metastasis. In this review, we have emphasized the multifaceted roles and mechanisms of tumor-derived exosomes in BC metastasis based on these important components. The underlying mechanisms mainly include the invasion behavior change, tumor vascularization, the disruption of the vascular barrier, and the colonization of the targeted organ. Understanding the significance of tumor-derived exosomal components in BC metastasis is critical for yielding novel routes of BC intervention.Subject terms: Breast cancer, Cancer microenvironment, Non-coding RNAs     

Cisplatin-resistant osteosarcoma cell-derived exosomes confer cisplatin resistance to recipient cells in an exosomal circ_103801-dependent manner

Studies have shown that exosomes can mediate the chemoresistance of drug-resistant cells by transmitting circular RNAs (circRNAs). However, the role of exosome-derived hsa_circ_103801 (exosomal hsa_circ_103801) in osteosarcoma (OS) remains unclear. The level of hsa_circ_103801 was upregulated in the serum exosomes from patients with OS, and OS patients with high hsa_circRNA_103801 expression had a shorter survival time relative to patients with low hsa_circ_103801 expression. The expression of hsa_circ_103801 was upregulated in cisplatin-resistant MG63 (MG63/CDDP) cells compared with that in MG63 cells. In addition, hsa_circ_103801 was highly enriched in exosomes derived from CDDP-resistant OS cells and could be delivered to MG63 and U2OS cells through exosomes. Exosomes derived from CDDP-resistant cells were shown to reduce the sensitivity of MG63 and U2OS cells to CDDP, inhibit apoptosis, and increase the expression of multidrug resistance-associated protein 1 and P-glycoprotein. Moreover, exosomal hsa_circ_103801 could strengthen the promotive effect of exosomes on the chemoresistance of MG63 and U2OS cells to CDDP. Hence, serum exosomal hsa_circ_103801 may serve as an effective prognostic biomarker for OS, and exosomal hsa_circ_103801 could be a potential target for overcoming OS chemoresistance.     

Pro-angiogenic effect of PC-3 exosomes in endothelial cells in vitro

The progression to a castration-resistant prostate cancer can occur after treatment with androgen deprivation therapy, resulting in poor prognosis and ineffective therapy response. Hormone dependence transition has been associated with increased tumor vascularization. Considering that exosomes are important components in communication between tumor cells and the microenvironment, we examined the angiogenic potential of exosomes released from Pca cell lines with distinctive profiles of androgen response through exosomes isolation, microscopy and uptake, functional assays follow up by microarray, RT-qPCR and bioinformatics analysis. HUVEC cells treated with PC-3 exosomes (androgen independent) showed increased invasion and tube formation ability. In order to identify microRNAs (miRNAs) related to the angiogenic response, the characterization of exosomal miRNA profile was performed. As result we suggest that the miR-27a-3p could be involved in the pro-angiogenic effect of PC-3 exosomes.     

Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.Subject terms: Breast cancer, Metastasis