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The Role of Extracellular Vesicles from Different Origin in The Xie et al. Molecular Cancer (2019) 18:83 https://doi.org/10.1186/s12943-019-0985-3 REVIEW Open Access The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers Changqing Xie1,2, Ning Ji2, Zhangui Tang1*, Jing Li2* and Qianming Chen2 Abstract The proliferation and metastasis ability of tumors are mediate by the "mutual dialogue" between cells in the tumor microenvironment (TME). Extracellular vesicles (EVs), mainly exosomes and microvesicles, play an important role in achieving intercellular substance transport and information transfer in the TME. Initially considered "garbage dumpsters" and later referred to as "signal boxes", EVs carry "cargo" (proteins, lipids, or nucleic acids) that can redirect the function of a recipient cell. Currently, the molecular mechanisms and clinical applications of EVs in head and neck cancers (HNCs) are still at an early stage and need to be further investigate. In this review, we provide insight into the TME of HNCs, classifying and summarizing EVs derived from different cell types and illuminating their complex signaling networks involved in mediating tumor proliferation, invasion and metastasis, vascular angiogenesis and cancer drug resistance. In addition, we highlight the application of EVs in HNCs, underlining the special pathological and physiological environment of HNCs. The application of tumor heterogeneous EVs in saliva and circulating blood diagnostics will provide a new perspective for the early screening, real-time monitoring and prognostic risk assessment of HNCs. Given the concept of precise and individual therapy, nanostructured EVs are equipped with superior characteristics of biocompatibility, low immunogenicity, loadability and modification ability, making these molecules one of the new strategies for HNCs treatment. Keywords: Tumor microenvironment, Extracellular vesicles, Exosomes Microvesicles, Cell-to-cell communication, Head and neck cancers Introduction nasopharynx [1]. In addition, the jaw, salivary glands, Head and neck cancers (HNCs) is one of the most com- and maxillary sinuses are also included, and more than mon malignant tumors in the world. The head and neck 90% HNCs are squamous cell carcinomas (SCCs) [2, 3]. section addresses nonmelanoma skin cancer (NMSCs) of Data from the International Agency for Research on the head and neck as well as those malignancies that Cancer (IARC), based on GLOBOCAN worldwide esti- arise from the mucosal surfaces of the upper mates, show that approximately 600,000 new cancer aero-digestive tract (UADT) and salivary glands, thyroid cases are reported (accounting for approximately 3% to cancers are part of a separate section in the AJCC Can- 5% of all malignancies), and 350,000 cancer-related cer Staging Manual, eighth edition [1]. The HNCs de- deaths occur (accounting for approximately 4% of the scribed herein will mainly include almost all mucous world total) worldwide each year, bringing serious chal- malignancies of the oral cavity (e.g., tongue, buccal, gin- lenges to social and public health [4–6]. giva, lip, and palate), oropharynx, larynx and Numerous epidemiological studies have reached a con- sensus that tobacco and alcohol consumption, both of * Correspondence: [email protected]; [email protected] which have synergistic effects, are the major risk factors 1Department of Oral and Maxillofacial Surgery, Xiangya Stomalogical Hospital & for HNCs. In high-income countries, 71% and 37% of School of Stomatology, Central South University, Changsha 410078, Hunan, China 2State Key Laboratory of Oral Diseases & National Clinical Research Center for patients with oral cancer died from smoking and alcohol, Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral respectively, compared with 33% and 14% in low- and Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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. Xie et al. Molecular Cancer (2019) 18:83 Page 2 of 15 middle-income countries [5, 7, 8]. A growing number of development of EVs can be divided into three periods. studies have suggested that betel-quid chewing with or The first period was in the 1960s. Researchers extracted a without tobacco [9, 10], and human papilloma virus precipitate from normal blood by high-speed centrifuga- (HPV) infection (HPV16/18) are intimately related to tion and confirmed that this precipitate, similar to the the occurrence of HNCs. These two risk factors may thromboplastic protein fraction, which is the predecessor lead to the younger age distribution and the increased of EVs, can reverse coagulation dysfunction [20]. Subse- rate of females in HNCs in recent years [11]. quently, it was further confirmed that activated platelets The treatment of local and early HNCs mainly in- can release lipid-rich particles, referred to as “platelet volves resection with clear 1- to 2-cm margins [3]. In pa- dust”, which contain platelet factor 3 and can accelerate tients with advanced stage cancers and cervical lymph coagulation [21]. The second period was the 1970s and node metastasis, radical surgery combined with radio- 1980s. Multiple studies have demonstrated the presence therapy/chemotherapy adjunctive therapy is required [2, of membrane-like vesicle structures in other solid tissues, 3]. The strong invasion, migration and metastasis of physiological fluids, and cell culture supernatants [22–24]. HNCs leads to clinical treatment difficulty and poor In addition to vesicles that originate directly from mem- prognosis. Over the past several decades, although there brane shedding, researchers have revealed that vesicle has been many innovations in HNCs treatment strat- structures are also derived from the intracellular secretion egies, the overall 5-year survival rate is still only approxi- pathway of multivesicular endosomes (MVEs) or multive- mately 60% [2, 3, 5, 12]. Consequently, investigating the sicular bodies (MVBs), which are named exosomes [25, molecular mechanism and screening precise biomolecu- 26]. The third period is after the 1990s, during which the lar markers of HNCs development is a tremendous chal- cell-cell communication function of EVs has gradually lenge and opportunity. gained value, beginning with a landmark discovery of Increasing numbers of studies have demonstrated that Epstein-Barr virus (EBV) infected B-cells capable of se- the interaction between tumor cells and the tumor creting molecules for the enrichment of major histocom- microenvironment plays a crucial role in manipulating patibility complex (MHC) class II-stimulated CD4+ T the tumor immune response, tumor progression and lymphocytes involved in the immune response [27, 28]. metastasis [13]. The tumor microenvironment has EVs are rich in lipids, polypeptides, proteins, RNA, DNA unique heterogeneity and diversity, which not only refers and other bioactive substances. EVs could be involved in to the homeostatic intracellular environment of tumor various physiological and pathological processes, including cells but also the extracellular stromal cells (for example, cell cycle, apoptosis [29], angiogenesis [30], thrombosis fibroblasts, mesenchymal stem cells, various immune formation [31], immune inflammation [32], fibrosis [33], cells, vascular endothelial cells, etc.) and multiple and tumor development [34, 35]. tumor-promoting bioactive molecules [14]. Compared to The extraction methods for EVs have been very ma- the normal tissue environment, the tumor microenviron- ture and commercialized [36]. Classical methods widely ment has many different physical and chemical proper- recognized by academic researchers, include ultracentri- ties, which characterized by low oxygen, low pH and fugation [37], gel exclusion chromatography [38], immu- high interstitial pressure [15–18]. Due to this peculiarity, noprecipitation [39], high performance liquid complex network signal communication between cells in chromatography [40], flow cytometry [41], microfluidic the tumor microenvironment is triggered via several chip [42] and other technologies, can acquire different growth factors, cytokines, proteolytic enzymes and other subsets EVs. Western blotting, transmission electron mi- active factors and is initially beneficial to tumor cell pro- croscopy, dynamic light scattering, and nanoparticle liferation, migration, invasion, angiogenesis and radio- tracking analysis can identify these molecules. However, therapy/chemotherapy resistance. Among these these methods cannot completely purify specific subpop- biological mediators, extracellular vesicles (EVs), which ulations, the products are often enriched with mixed function as information messengers, have gradually vesicles in which one subgroup is dominant. These vesi- attracted the attention of researchers. cles have more or less overlapping or similar particle sizes, morphologies, origins, contents, and functions. At Background of extracellular
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