间充质干细胞来源外泌体在恶性肿瘤中的作用及应用前景CSCD

间充质干细胞(MSCs)是一类具有高度自我更新能力及多向分化潜能的干细胞,能分化为多种不同细胞。研究表明间充质干细胞来源的外泌体(MSC-EXO)是肿瘤微环境的主要组成部分,并且对恶性肿瘤的发生发展发挥着重要作用。外泌体是由真核细胞分泌的一类细胞外囊泡,能够在细胞间传递生物活性脂质、核酸以及蛋白质等生物活性分子,广泛参与细胞之间的信息交流。本文就间充质干细胞来源的外泌体在恶性肿瘤中发挥的作用及其应用前景作一综述。     

间充质干细胞源性外泌体及其在肿瘤治疗中的研究进展

外泌体（exosomes）是细胞内多囊泡体（multivesicular bodies,MVBs）与细胞膜融合后释放到细胞外直径为40~100nm的囊泡样小体。作为一种重要的细胞间信息传递分子及遗传物质传递载体,外泌体内含有蛋白质、RNA等多种活性物质,广泛分布于血液、尿液等体液中。目前发现多种类型细胞均可产生外泌体,尤其是间充质干细胞（MSCs）被认为是产生外泌体能力最强的细胞,并且MSCs源性外泌体（MSC-exosomes）与MSCs同样具有向炎症组织及肿瘤组织迁移的特性,为肿瘤治疗提供了一种新思路。由此,本文将从MSC-exosomes生物学特性、分离鉴定方法、肿瘤治疗潜能三方面进行综述。     

间充质干细胞来源的外泌体在肝癌治疗中的研究进展

间充质干细胞(mesenchymal stem cells,MSCs)具有强大的分泌能力,主要通过分泌细胞因子和细胞外囊泡(extracellular vesicles,EVs)对周围的细胞产生作用,而外泌体是EVs的一个主要亚群。MSCs来源的外泌体(mesenchymal stem cell-derived exo-some,MSC-Exo)作为MSCs胞内信号的重要组成部分,在肝癌等疾病治疗的研究中具有与MSCs相似的作用,能克服复杂的体内递送障碍,实现远距离输送,能被受体细胞吸收,无免疫排斥,无致瘤性,易于获得且方便贮存。MSC-Exo的脂质膜可以包裹并保护其内容物免受体液中降解酶的影响,使其成为天然的良好载体,可用于装载抗肝癌药物,因而在未来肝癌的治疗方面,MSCExo具有一定的临床应用前景。本文就MSC-Exo应用于肝癌治疗方面的研究进行综述,为肝癌的治疗提供新思路。      

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。     

外泌体在肿瘤转移前微环境形成中的作用

肿瘤的转移前微环境（pre-metastatic niche，PMN）特指原发肿瘤灶为肿瘤细胞远处播散和定植准备的微环境，此微环境的六个特征包括炎症、免疫抑制、血管生成/血管通透性、亲器官性、重编程和淋巴管生成。PMN形成的关键成分包括肿瘤源性分泌因子、细胞外囊泡（含外泌体）、骨髓源性细胞、免疫抑制细胞和宿主基质细胞等，其中，外泌体作为细胞间重要的信使，在肿瘤PMN的形成中具有重要作用。本综述就外泌体在肿瘤PMN形成中的作用进行探讨。     

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。     

肿瘤微环境中间充质干细胞与癌症干细胞的关系及其在乳腺癌进展中的作用

乳腺癌是女性最高发的恶性肿瘤,在治疗过程中复发、转移、耐药等将显著降低患者的疗效,因此解决复发转移和耐药问题成为研究者关注的方向。近年来,癌症干细胞（cancer stem cells,CSCs）和间充质干细胞（mesenchymal stem cells,MSCs）在肿瘤微环境中调控癌症发生和发展的作用被广泛研究。本文就MSCs和CSCs在乳腺癌进展中的作用以及两者的潜在联系进行阐述,为后续开发新的治疗方案以改善乳腺癌患者预后提供方向和借鉴。     

肿瘤来源的外泌体PD-L1在肿瘤中的研究进展

【摘要】外泌体是由正常细胞或肿瘤细胞产生的具有生物活性的细胞外囊泡,它通过自身携带的核酸、脂质、蛋白质等物质参与细胞间物质以及信息的交换。肿瘤来源的外泌体富含程序性死亡配体（PD L1）,它可通过与程序性死亡受体1（PD 1）结合“协助”肿瘤细胞逃避免疫系统的监视。肿瘤来源的外泌体PD L1在促进肿瘤的发生发展以及预测肿瘤免疫治疗疗效方面发挥着重要作用。文章将对外泌体PD L1免疫抑制作用机制及其在不同肿瘤中的研究进行汇总,探讨外泌体PD L1作为生物标志物的潜力。     

间充质干细胞在肿瘤治疗中的研究进展

间充质干细胞 (mesenchymal stem cells,MSCs)是具有多向分化潜能的非造血干细胞,除了具有造血支持、免疫调节和多向分化(分化为骨、软骨和脂肪)的特性外, 还具有特异性地迁移到损伤部位和肿瘤组织的特性.MSCs与肿瘤微环境之间存在复杂的交互作用:一方面, MSCs可直接作用于肿瘤细胞,抑制其生长;另一方面,MSCs还可作为细胞载体,传递和表达多种抗肿瘤因子.因此,MSCs有望成为新的抗肿瘤治疗的策略.本文对近年来MSCs在肿瘤基因治疗领域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。     

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.     

Biology and therapeutic potential of mesenchymal stem cell‐derived exosomes

Mesenchymal stem cells (MSC) are multipotent stromal cells with the potential to differentiate into several cell types. MSC‐based therapy has emerged as a promising strategy for various diseases. Accumulating evidence suggests that the paracrine effects of MSC are partially exerted by the secretion of soluble factors, in particular exosomes. MSC‐derived exosomes are involved in intercellular communication through transfer of proteins, RNA, DNA and bioactive lipids, which might constitute a novel intercellular communication mode. This review illustrates the current knowledge on the composition and biological functions as well as the therapeutic potential of MSC‐derived exosomes in cancer, with a focus on clinical translation opportunities.     

外泌体在胃癌诊疗中的研究进展

胃癌的发病率和死亡率均较高,早诊早治极为关键,需要更加灵敏的诊断技术与精准的治疗手段,才能在胃癌早期及时发现并将其有效遏制。外泌体是细胞分泌的一种囊泡,其携带多种具有生物活性的小分子,如蛋白质、RNA、DNA等。外泌体可作为细胞间通讯的一种功能介质,传递多种生物信息并介导受体细胞的生物进程。在肿瘤中,外泌体不仅积极参与肿瘤微环境的信息传递,而且具有调节细胞免疫应答的能力。近年来外泌体在肿瘤领域的相关研究取得了一系列进展,其参与胃癌增殖、侵袭、复发和转移、耐药以及新生血管形成等方面的调控。外泌体在胃癌的早期诊断与精准治疗方面具有重要意义,值得深入探索。本文就外泌体在胃癌诊疗中的研究进展进行综述。     

Role of stem cell derived exosomes in tumor biology

Exosomes are nano‐scale messengers loaded with bio‐molecular cargo of RNA, DNA, and Proteins. As a master regulator of cellular signaling, stem cell (both normal, and cancer stem cells) secreted exosome orchestrate various autocrine and paracrine functions which alter tumor micro‐environment, growth and progression. Exosomes secreted by one of the two important stem cell phenotypes in cancers a) Mesenchymal stem cells, and b) Cancer stem cells not only promote cancerous growth but also impart therapy resistance in cancer cells. In tumors, normal or mesenchymal stem cell (MSCs) derived exosomes (MSC‐exo) modulate tumor hallmarks by delivering unique miRNA species to neighboring cells and help in tumor progression. Apart from regulating tumor cell fate, MSC‐exo are also capable of inducing physiological processes, for example, angiogenesis, metastasis and so forth. Similarly, cancer stem cells (CSCs) derived exosomes (CSC‐exo) contain stemness‐specific proteins, self‐renewal promoting regulatory miRNAs, and survival factors. CSC‐exo specific cargo maintains tumor heterogeneity and alters tumor progression. In this review we critically discuss the importance of stem cell specific exosomes in tumor cell signaling pathways with their role in tumor biology.     

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。     

Exosomal miR-30a and miR-222 derived from colon cancer mesenchymal stem cells promote the tumorigenicity of colon cancer through targeting MIA3

BackgroundMultipotent mesenchymal stem cells (MSCs) derived from virus tumors have been reported to contribute to malignant cell growth, invasion, and metastasis. However, the mechanism of communication between MSCs and colon cancer cells is poorly understood. Recent studies have suggested that exosomes are an important player in crosstalk between cells and could significantly suppress the invasion ability of human cancer cells (hCCs) when transfected with a microRNA inhibitor. However, to date, no study has illuminated the miRNA changes in exosomes derived from hCC-MSCs.MethodsColon cancer stem cells were cultured in medium and passaged to develop fibroblast-like morphology. Exosomes were collected using ExoQuick precipitation and exosome morphology was visualized by transmission electron microscopy. Small RNA sequencing was analyzed using an Illumina HiSeq4000 analyzer, and the expression of MIA3 was assessed by real-time PCR and Western blot. The functional roles of miR-30a and miR-222 in colon cancer cells were evaluated through cell and animal experiments.ResultsOur results showed that the characteristics of MSC-like cells (hCC-MSCs) derived from human colon cancer stem cells were comparable to those of bone marrow-derived MSCs, including surface antigens and the ability to multi-differentiate to osteocytes and adipocytes. Furthermore, we screened the microRNA (miRNA) profiles of exosomes derived from hCC-MSCs and the corresponding parent hCC-MSCs. We found a significant enrichment in the miR-30a and miR-222 level in hCC-MSC-derived exosomes. Furthermore, in vitro and in vivo experiments demonstrated that miR-30a and miR-222 bound to their shared downstream target, MIA3, to promote the ability of colon cells to proliferate, migrate, and metastasize, thus evidencing their functional roles as oncogenic miRNAs.ConclusionsThese data suggest that hCC-MSC-secreted exosomes promote colon cancer cell proliferation and metastasis through delivering miR-30a and miR-222. Subsequently, exosomal miR-30a and miR-222 simultaneously target MIA3, suppress its expression, and promote colon cell proliferation, migration, and metastasis.     

Intracellular prodrug gene therapy for cancer mediated by tumor cell suicide gene exosomes

Recently, we reported about exosomes possessing messenger RNA (mRNA) of suicide gene secreted from mesenchymal stem/stromal cells (MSCs) engineered to express the suicide gene—fused yeast cytosine deaminase::uracil phosphoribosyltransferase (yCD::UPRT). The yCD::UPRT‐MSC exosomes are internalized by tumor cells and intracellularly convert prodrug 5‐fluorocytosine (5‐FC) to cytotoxic drug 5‐fluorouracil (5‐FU). Human tumor cells with the potential to metastasize release exosomes involved in the creation of a premetastatic niche at the predicted organs. We found that cancer cells stably transduced with yCD::UPRT gene by retrovirus infection released exosomes acting similarly like yCD::UPRT‐MSC exosomes. Different types of tumor cells were transduced with the yCD::UPRT gene. The homogenous cell population of yCD::UPRT‐transduced tumor cells expressed the yCD::UPRT suicide gene and secreted continuously exosomes with suicide gene mRNA in their cargo. All tumor cell suicide gene exosomes upon internalization into the recipient tumor cells induced the cell death by intracellular conversion of 5‐FC to 5‐FU and to 5‐FUMP in a dose‐dependent manner. Most of tumor cell‐derived suicide gene exosomes were tumor tropic, in 5‐FC presence they killed tumor cells but did not inhibit the growth of human skin fibroblast as well as DP‐MSCs. Tumor cell‐derived suicide gene exosomes home to their cells of origin and hold an exciting potential to become innovative specific therapy for tumors and potentially for metastases.     

外泌体在肺癌中的研究进展

外泌体（exosomes）是由多种细胞分泌的具有脂质双分子层结构的纳米级膜囊小泡，其内含有蛋白质、脂质、核酸等大量生物活性物质。研究表明，外泌体在肺癌的发生发展过程中发挥着重要作用，尤其是在肺癌的早期诊断、侵袭和转移、预后评估以及治疗等方面的作用成为目前研究的热点。因此，关于外泌体的研究将在转化医学的研究模式下，为肺癌临床早期诊断、治疗及预后评估带来新的契机。本文对外泌体在肺癌中的研究进展作一综述。     

Mesenchymal stem cell-derived exosomes for gastrointestinal cancer

Gastrointestinal (GI) malignancies, a series of malignant conditions originating from the digestive system, include gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. GI cancers have been regarded as the leading cancer-related cause of death in recent years. Therefore, it is essential to develop effective treatment strategies for GI malignancies. Mesenchymal stem cells (MSCs), a type of distinct non-hematopoietic stem cells and an important component of the tumor microenvironment, play important roles in regulating GI cancer development and progression through multiple mechanisms, such as secreting cytokines and direct interactions. Currently, studies are focusing on the anti-cancer effect of MSCs on GI malignancies. However, the effects and functional mechanisms of MSC-derived exosomes on GI cancer are less studied. MSC-derived exosomes can regulate GI tumor growth, drug response, metastasis, and invasion through transplanting proteins and miRNA to tumor cells to activate the specific signal pathway. Besides, the MSC-derived exosomes are also seen as an important drug delivery system and have shown potential in anti-cancer treatment. This study aims to summarize the effect and biological functions of MSC-derived exosomes on the development of GI cancers and discuss their possible clinical applications for the treatment of GI malignancies.