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Exosomal Mirnas in Tumor Microenvironment

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Exosomal Mirnas in Tumor Microenvironment Tan et al. Journal of Experimental & Clinical Cancer Research (2020) 39:67 https://doi.org/10.1186/s13046-020-01570-6 REVIEW Open Access Exosomal miRNAs in tumor microenvironment Shiming Tan1†, Longzheng Xia1†, Pin Yi1,2, Yaqian Han1, Lu Tang1,2, Qing Pan1,2, Yutong Tian1,2, Shan Rao1, Linda Oyang1, Jiaxin Liang1, Jinguan Lin1, Min Su1, Yingrui Shi1, Deliang Cao1,3, Yujuan Zhou1* and Qianjin Liao1* Abstract Tumor microenvironment (TME) is the internal environment in which tumor cells survive, consisting of tumor cells, fibroblasts, endothelial cells, and immune cells, as well as non-cellular components, such as exosomes and cytokines. Exosomes are tiny extracellular vesicles (40-160nm) containing active substances, such as proteins, lipids and nucleic acids. Exosomes carry biologically active miRNAs to shuttle between tumor cells and TME, thereby affecting tumor development. Tumor-derived exosomal miRNAs induce matrix reprogramming in TME, creating a microenvironment that is conducive to tumor growth, metastasis, immune escape and chemotherapy resistance. In this review, we updated the role of exosomal miRNAs in the process of TME reshaping. Keywords: exosomal miRNAs, tumor microenvironment (TME), CAFs, angiogenesis, immune microenvironment Background immunosuppression, and drug resistance for tumor develop- TME is a complex ecosystem and an important player in all ment [10–14]. stages of tumorigenesis. TME consists of cancer cells, MicroRNAs (miRNAs) are a class of short ncRNAs cancer-associated fibroblasts (CAFs), endothelial cells, im- with 19-25 nucleotides in length [15]. Through regulat- mune cells, extracellular matrix (ECM), microvessels, and ing gene expression, miRNAs regulate a variety of im- biomolecules infiltrated [1–5]. Compared with the normal portant biological functions, such as proliferation, internal environment, TME is more prominently character- apoptosis, differentiation, migration, invasion and drug ized by hypoxia. Hypoxia caused by rapid appreciation of resistance. Genetic or epigenetic changes in cancer cells tumor cells leads to release of matrix metalloproteinases can induce abnormal expression of miRNAs, thus caus- (MMPs), hypoxia inducible factor-1α (HIF-1α), vascular ing abnormal expression of their target genes [16–21]. endothelial growth factor (VEGF) and other stimulating fac- miRNAs function through 6-7 base complementary tors. Reshaping TME provides a niche for interaction be- binding to target mRNA and inhibition of target gene tween tumor cells and surrounding fibroblasts, endothelial expression at the level of protein [22–24]. From the lit- cells, and immune cells [4, 6–9]. These cells interact with erature, miRNAs can work as oncogenes to promote the tumor cells through TME to induce a variety of biological formation and biological changes of TME [25–28]. For events,suchasappreciation,migration,angiogenesis, example, miR-9 and miR-200s induce normal fibroblasts (NFs) in TME to transform into CAFs and promote tumor metastasis [29, 30], miR-526b and miR-655 pro- * Correspondence: [email protected]; [email protected] mote angiogenesis and lymphangiogenesis in TME [31], † Shiming Tan and Longzheng Xia contributed equally to this work. and miR-340-5p and miR-561 induce formation of im- 1Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, munosuppressive microenvironment [32, 33]. How these Central South University, 283 Tongzipo Road, Changsha 410013, Hunan, biologically active miRNAs are transmitted and function China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Tan et al. Journal of Experimental & Clinical Cancer Research (2020) 39:67 Page 2 of 15 in cells and TME is an important breakthrough in the generally divided into two categories: ectosomes and study of TME. exosomes. Ectosomes are vesicles formed from the Recently, exosomes are considered to be the key medi- plasma membrane sprouting outwards, including micro- ators responsible for the heterogeneity of the TME and vesicles, microparticles and large vesicles with a size carry biologically active cargos, such as protein, metabo- range of 50-1000nm in diameter. Exosomes are small lites, nucleic acids (e.g. ncRNAs), to shuttle between extracellular vesicle (sEVs) in a size range of 40-160nm tumor cells and TME, thereby affecting tumor develop- in diameter with an endosomal origin. EVs have bio- ment [34–37]. Among the biologically active substances, logical activities and mediate intercellular communica- tumor-derived exosomal miRNAs can induce TME het- tion [36]. During tumor progression, EVs derived from erogeneity while changes in TME promote tumor pro- different cells (tumor cells, stromal cells, immune cells, gression. This paradigm, similar to a positive feedback etc.) play an important role and participate in the forma- loop, makes the uncontrollable growth of the tumor tion of TME [44, 52–54]. [38–43]. In this article we updated the interaction of In this review, we mainly focused on the exosomes. exosomal miRNAs and TME. However, because of absence of strict standards for exo- some isolation and purification methods, the Inter- The overview of microenvironment and exosomes national Society for Extracellular Vesicles encouraged in cancer researchers to establish minimum requirements and The components of tumor microenvironment strictly control the integrity, size, molecular cargo, and Growth, metastasis and treatment resistance of tumors functionality of the vesicle population [38, 55–57], so are inseparable from the support of TME, a dynamic that we narrowed the research of exosomes based on the ecosystem containing multiple cell types and non- widely accepted methods. Exosomes are small extracellu- cellular components. Some of the basic biological behav- lar vesicles (40-160 nm in diameter) formed by dynamic ioral features of tumors, such as proliferation, migration, exocytosis [58–60]. Exosomes originate from the luminal invasion, apoptosis inhibition, immune evasion, angio- cavity or early intracellular bodies in the circulation genesis, and metabolic reprogramming are all affected by pathway of the plasma membrane. These membranes or TME. The complex communication network in TME is early intracellular bodies will sag inward to form intra- the basis for the regulation of these biological functions, luminal vesicles (ILV), which will further develop into including autocrine and paracrine. Exocrine-mediated multivesicular bodies (MVB) [61, 62]. In general, multi- communication is an important emerging pathway in vesicular bodies are fused with lysosomes to be de- paracrine signal transduction [2]. graded, but some multivesicular bodies are fused to the Non-tumor cells in TME, such as fibroblasts, endothelial cell surface under the traction of intracellular molecular cells and immune cells, are affected by tumor-related ac- motors and eventually secreted outside the cell, which tive substances, and their original cellular functions called exosomes [36, 63]. undergo tumor-like changes, constantly adapt to new en- Exosomes are involved in the biology of many diseases. vironments and promote tumor growth. Due to the influ- Exosomes can regulate the immune response and in- ence of TME, NFs are activated into CAFs. CAFs are the flammation, possibly through transfer and presentation most abundant stromal cells in TME, producing an ECM of antigen peptides, to induce expression of inflamma- that differs from normal ECM in terms of stiffness and tory genes in recipient cells [64, 65]. In metabolism and alignment, which support tumor cells migration [9]. Hyp- cardiovascular diseases, exosomes induce metabolic dis- oxia in TME causes tumor to secrete angiogenic factors to orders in adipocytes and islet cells [66, 67]. Exosomes act on endothelial cells and promote angiogenesis [44, 45]. may impair the formation of neurotoxic oligomers and The immune cells in TME show diversity, and they block promote neurodegeneration [68–70]. More importantly, the immune response. The inflammatory molecules exosomes are associated with tumor growth, angiogen- around the tumor cells also cause the system to fail to esis, metastasis, sensitivity to chemotherapy, and im- recognize and eliminate cancer cells [38, 46, 47]. These mune evasion [47, 71, 72]. make TME a complex heterogeneous environment and often leads to an uncontrollable trend in the development miRNAs sorting
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