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。     

肿瘤细胞外泌体在肿瘤免疫中的作用

正外泌体作为一种纳米级囊泡逐渐成为现在肿瘤免疫的研究热点。外泌体中含有大量的蛋白质、脂质、核酸等物质,在细胞间的信息传递中起着重要作用[1]。肿瘤细胞来源的外泌体(Tumor-derived exosome,TEX)不仅可以抑制宿主免疫应答,促进肿瘤转移,在一定条件下也能够起到抗肿瘤免疫作用,因     

不同来源外泌体与肿瘤发病相关性的研究与进展

文题释义： 干细胞在肿瘤治疗中的作用：干细胞是起源于中胚层的一种多能干细胞,具有在体外易于培养、多向分化性、免疫调节性、低免疫原性及归巢等特性,在组织工程修复中起着重要作用,由于干细胞具有归巢的特性,被认为是肿瘤治疗的首选生物载体,在肿瘤细胞融合中发挥着重要作用。 外泌体：外泌体的生成是细胞在活化过程中或受到外界刺激时,引发的一系列复杂的细胞内分泌变化,向细胞外释放的脂质双层结构囊泡,介导细胞间的广泛交流,参与细胞与组织的生理、病理过程。 背景：外泌体是一种纳米级具有膜结构的囊泡样小体,可以来源于多种不同的细胞,如干细胞、肿瘤细胞、肿瘤干细胞等,外泌体中含有大量生物活性分子,可介导细胞与细胞之间的交流。 目的：综述不同来源外泌体与肿瘤发生的相关研究动态及未来可能研究的方向。 方法：以“外泌体、肿瘤、骨髓间充质干细胞、肿瘤干细胞、HH信号通路”等为中文关键词,以“exosomes,tumors,bone marrow mesenchymal stem cells,caner stem cells,HH signaling pathway”等为英文关键词,检索2015年1月至2019年6月收录在PubMed数据库、中国知网及中国万方数据库的文献,最终纳入文献80篇,其中英文文献27篇,中文文献53篇。 结果与结论：①血清来源外泌体在非小细胞癌、肝癌、胃癌、结肠癌、胰腺癌及乳腺癌等肿瘤的诊断中具有一定的研究潜力,其有可能成为肿瘤检测的一种潜在替代诊断标志物;②肿瘤来源外泌体可通过促进肿瘤细胞的生长、增殖、迁移及侵袭,调节免疫及肿瘤相关基因和蛋白的表达发挥调控肿瘤作用;③干细胞来源外泌体可促进肿瘤细胞侵袭和转移,其对肿瘤的调控可能是通过激活HH信号通路介导的;④此外,肿瘤干细胞来源外泌体可通过促进肿瘤相关耐药基因的表达从而增强肿瘤细胞对化疗的耐药,通过研究肿瘤干细胞来源外泌体与耐药基因之间的相关机制,有可能发现肿瘤治疗的潜在靶点。 ORCID:0000-0003-3619-1497(崔国宁) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

外泌体与肿瘤发展相关性的研究进展

外泌体是一类直径介于30～100 nm之间的胞外囊泡,包含多种蛋白质、核酸与脂类成分,可由大多数细胞分泌.外泌体在细胞间通讯中发挥着重要作用.越来越多的研究表明,外泌体可通过多种途径将其内含物运送至受体细胞,进而调控受体细胞的功能,特别是促进肿瘤细胞的生长与转移,但其中的机制尚未完全清楚.同时,凭借其传递特性,外泌体在运载药物与肿瘤诊断方面也具有巨大潜能.本综述主要介绍外泌体的基本概况及其与肿瘤发展相关的最新进展,为肿瘤的诊疗提供新的靶点与方向.     

外泌体中miRNAs调控骨肉瘤细胞转移的分子机制研究进展*

骨肉瘤是最常见的原发恶性骨肿瘤,患者预后不良大多因为其转移。研究发现,外泌体可以在细胞间包装运载多种如蛋白质、dsDNA、RNAs及miRNAs等生物活性物质,有大量研究发现外泌体中的miRNA在骨肉瘤的转移过程中异常表达。本文主要介绍外泌体的生物学特征并针对外泌体中的miRNAs的分选机制、外泌体中miRNAs调节骨肉瘤的转移机制的研究进展以及外泌体中的miRNAs在骨肉瘤诊疗中的应用潜力进行综述。     

外泌体在肿瘤血管新生中的作用

肿瘤的生长与转移依赖于充足的血管生成以及血液供养,越来越多的研究证实肿瘤来源的外泌体参与促进肿瘤血管新生。本文通过综述外泌体如何驱动血管新生,为改进现有的抗血管生成疗法增加新的选择。     

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].     

外泌体介导miRNAs在脑胶质瘤治疗中的作用与应用

文题释义：脑胶质瘤：是恶性程度高、侵袭性强的中枢神经系统肿瘤,临床手术辅以放疗和化疗是当前胶质瘤的主要治疗手段。即使采取多种高强度的治疗措施,胶质瘤患者的预后不良和复发率仍然很高,术后的生存时间并没有明显延长。 外泌体miRNAs：外泌体可稳定存在于血液、尿液、脑脊液等体液中,其内包含2 838种miRNAs,这些miRNAs不仅在胶质瘤的增殖、侵袭、耐药和免疫等方面发挥着重要的调控作用,同时在胶质瘤的诊治及预后等方面也具有广阔的应用前景。  摘要背景：近年来,外泌体已成为肿瘤领域的研究热点,其可以通过携带大量生物活性分子,直接运送至受体细胞,参与细胞间的信息交流。而miRNAs作为外泌体中含量最高、种类最多的非编码RNA,在胶质瘤的增殖﹑侵袭﹑耐药和免疫等方面发挥着重要的作用。另外,miRNAs在胶质瘤的辅助诊断、治疗导向和预后评估等方面也具有潜在的应用价值。目的：阐述外泌体miRNAs的分选机制、在胶质瘤中的调控作用以及临床应用,为进一步探究外泌体miRNAs与胶质瘤的相关性提供文献和理论基础,同时在胶质瘤的诊治等方面也具有积极的意义。方法：由第一作者以“胶质瘤,外泌体,miRNAs,分选机制,生物标志物”为中文检索词,以“glioma,exosomes,miRNAs,sorting mechanism,biomarkers”为英文检索词,通过计算机检索CNKI、万方数据库、PubMed数据库以及EI数据库,检索出相关文献118篇,根据纳入与排除标准,并进行文献增补,筛选出52篇文献进行汇总、归纳,主要包括外泌体miRNAs分选机制、在胶质瘤中的调控作用以及临床应用等相关内容。结果与结论：目前,尽管采取多种高强度的联合治疗方案,胶质瘤的有效治疗仍然不能满足临床需求,在这种情况下提出外泌体介导miRNAs应用于脑胶质瘤基因治疗,是对脑胶质瘤患者临床治疗的重要补充。外泌体介导的miRNAs不仅可以在脑胶质瘤的发生发展、侵袭转移、放化疗耐药、免疫调控等方面发挥调控作用,同时还作为一种生物标志物在脑胶质瘤的分级诊断﹑预后评估﹑治疗用途等方面具有潜在的应用价值。这对于进一步探究外泌体miRNAs与胶质瘤的相关性提供了夯实的理论基础,同时在胶质瘤的创新诊治等方面也具有积极的临床意义。ORCID: 0000-0003-4851-5110(郑克彬) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

外泌体在肿瘤微环境中的免疫抑制作用

外泌体(exosome)作为一种纳米级囊泡,在细胞间的信息传递中起着重要作用。越来越多的研究表明,肿瘤细胞来源外泌体(tumor-derived exosomes,TEXs)携带有与亲代肿瘤细胞相似的免疫抑制性分子,介导了肿瘤细胞与NK细胞、树突状细胞、髓源性抑制细胞、巨噬细胞、效应性T细胞、调节性T细胞和调节性B细胞的通讯,从而抑制肿瘤微环境中的抗肿瘤免疫应答。此外,近年来研究发现免疫细胞来源的外泌体在免疫抑制性肿瘤微环境的形成过程中也起一定作用。现针对外泌体的生物学特征及其在免疫抑制性肿瘤微环境形成过程中的作用进行综述。     

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。     

Possible carcinogenesis of tumor suppressor let-7

Cancer stem cells (CSCs), a group showing high capacities of sphere-forming and self renewal, are blamed for tumor initiation, recurrence and therapy resistance. Therefore, therapeutics specifically targeting and perishing CSCs may be promising. Let-7 miRNAs, one of the earliest discovered miRNAs, were considered as novel and vital agents to eliminate cancer and CSCs. However, in recent researches, many regulatory loops among let-7 and its targeted genes were noticed; the regulation of let-7 caused by its hunting mRNAs helped to form the hypotheses that hunters and preys may swap their roles when in confrontations. Besides, the evil side of let-7 was discovered occasionally, therefore, we hypothesize that dual characteristics of let-7 do exist, which will have significant impacts on anticancer research. Targeted therapies against cancer and CSCs by using let-7 or other miRNAs as weapons should be thought twice before clinical application.     

Identification of miRNA profiling in prediction of tumor recurrence and progress and bioinformatics analysis for patients with primary esophageal cancer: Study based on TCGA database

Object

This study focused on the identification of prognostic miRNAs for the prediction of tumor recurrence and progress in esophageal cancer.

MicroRNAs in the Diagnosis and Treatment of Cancer

Immune cells are recruited into the tumor microenvironment and regulate anti- and pro-tumor signals. MicroRNAs (miRNAs) markedly control the immune system responses in cancer development. miRNAs that affect the immune system could be interesting targets for immunomodulation against cancer, either through the activation of effector cells or through the down-regulation of regulatory cells. Bioinformatic calculations can predict the immune system and miRNA interactions. In this review, we discuss the most recent studies about miRNA as the main regulator of recruitment and the activation of the immune system in the tumor microenvironment and finally we propose several miRNAs that could serve as therapeutic molecules in the immunotherapy of cancer.     

Differential expression of microRNAs in colorectal cancer: Different patterns between isolated cancer gland and stromal cells

Although microRNAs (miRNAs) play an important role in invasive tumor lesions, which involve cancer tissues mixed with stromal tissues, the differences in miRNA expression between cancer and stromal cells remain unclear. We selected 13 miRNAs and examined their differential expression patterns in cancer gland cells and surrounding stromal cells isolated from 24 colorectal cancer (CRC) specimens using a crypt isolation method. Although six miRNAs were upregulated in gland cells, only three were upregulated in the corresponding stromal cells, in the cancer compared with non‐cancer specimens. Next, we examined the differences in miRNA expression between isolated cancer gland and stromal cells. Five miRNAs showed statistical differences in their cancer‐related differential expression patterns between isolated cancer gland and stromal cells. We then compared these miRNA expression patterns in isolated cancer gland and stromal cells with those in fresh intact tumor tissues, consisting of cancer nests and stromal tissue, obtained from the 24 CRCs. The expression patterns of three miRNAs in the intact cancer tissue samples did not correspond with those in the isolated components. Identification of the expression patterns of miRNAs in both the cancer gland and stromal cell components of the tumor microenvironment greatly contributes to evaluating epigenetic regulation in CRC.     

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules consisting of 19-22 nucleotides that are involved in a variety of biological processes, including development, differentiation, apoptosis and cell proliferation. In cancer research, a growing body of evidence has indicated that miRNAs are aberrantly expressed in many types of human cancers and can function either as tumor suppressors or oncogenes. Bioinformatic predictions suggest that miRNAs regulate more than 30% of protein-coding genes. Aberrant expression of miRNAs in cancer cells causes destruction of miRNA-regulated messenger RNA networks. Therefore, the identification of miRNA-regulated cancer pathways is important for understanding the molecular mechanisms of human cancer. Searching for the aberrant expression of miRNAs in cancer cells is the first step in the functional analysis of miRNAs in cancer cells. Genome-wide miRNA expression signatures can rapidly and precisely reveal aberrant expression of miRNA in cancers. The miRNA expression signatures of human cancers have revealed that miR-375 is significantly downregulated in cancer cells. Our recent data on maxillary sinus, hypopharyngeal and esophageal squamous cell carcinomas have suggested that miR-375 is frequently downregulated and functions as a tumor suppressor that targets several oncogenic genes in cancer cells. In this review, we focus on several types of human squamous cell carcinoma and describe the aberrant expression of miRNAs and the cancer pathways they regulate in these diseases.     

MicroRNAs and colon and rectal cancer: differential expression by tumor location and subtype

MicroRNAs are thought to have an impact on cell proliferation, apoptosis, stress responses, maintenance of stem cell potency, and metabolism and are, therefore, important in the carcinogenic process. In this study, we examined 40 colon tumors, 30 rectal tumors, and 30 normal tissue samples (10 proximal colon, 10 distal colon, and 10 rectal paired with cancer cases) to examine miRNA expression profiles in colon and rectal tumors. MiRNA expression levels were adjusted for multiple comparisons; tumor tissue was compared with noncancerous tissue from the same site. A comparison of normal tissue showed 287 unique miRNAs that were significantly differentially expressed at the 1.5-fold level and 73 with over a two-fold difference in expression between colon and rectal tissue. Examination of miRNAs that were significantly differentially expressed at the 1.5-fold level by tumor phenotype showed 143 unique miRNAs differentially expression for microsatellite instability positive (MSI+) colon tumors; 129 unique miRNAs differentially expressed for CpG Island Methylator Phenotype positive (CIMP+) colon tumors; 135 miRNAs were differentially expressed for KRAS2-mutated colon tumors, and 139 miRNAs were differentially expressed for TP53-mutated colon tumors. Similar numbers of differentially expressed miRNAs were observed for rectal tumors, although the miRNAs differentially expressed differed. There were 129 unique miRNAs for CIMP+, 143 unique miRNAs for KRAS2-mutated, and 136 unique miRNAs for TP53-mutated rectal tumors. These results suggest the importance of miRNAs in colorectal cancer and the need for studies that can confirm these results and provide insight into the diet, lifestyle, and genetic factors that influence miRNA expression.     

Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model

It has been demonstrated that numerous microRNAs (miRNAs) have potent tumor-suppressing effects on a variety of cancers, implicating a possible application of miRNA in tumor therapy. Oncolytic adenovirus is a suitable vector to deliver tumor suppressor genes for treatment of cancers. However, it remains unknown whether co-expression of tumor suppressor genes and miRNAs can contribute to a more potent antitumor capacity within an oncolytic adenovirus delivery system. In this study, we found that expression of miRNA-34a was reduced in hepatocellular carcinoma (HCC), and the reduced expression of miRNA-34a was associated with worse outcome of HCC patients. Thus, we developed an oncolytic adenoviral vector, AdCN205, to co-express miRNA-34a and IL-24 driven by an adenovirus endogenous E3 promoter in HCC cells. High levels of miRNA-34a and IL-24 expression were detected in AdCN205-IL-24-miR-34a-infected HCC cells. AdCN205-IL-24-miR-34a significantly induced dramatic antitumor activity, as compared with that induced by AdCN205-IL-24 or AdCN205-miR-34a alone. Transfer of miRNA-34a into HCC cells inhibited the expression of its target genes, Bcl-2 and SIRT1. Treatment of established xenograft HCC tumors with AdCN205-IL-24-miR-34a in a mouse model resulted in complete tumor regression without recurrence. Taken together, our data provide a promising and reasonable delivery strategy of double-aimed cancer therapy, in which miRNAs and tumor-suppressing genes are used simultaneously.