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      The Role of Extracellular Vesicles in Disease Progression and Detection of Hepatocellular Carcinoma

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          Abstract

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          Extracellular vesicles (EVs) are particles naturally released from cells and mediate intercellular communication. Recently, emerging studies have shown that EVs play a crucial role in regulating progression of hepatocellular carcinoma (HCC), which is one of the leading causes of cancer-related death worldwide. With the advances of technologies in isolating EVs from patients’ blood, EVs are regarded as promising biomarkers for detecting HCC at an earlier stage. This review provides an overview of the current EVs isolation methods, the biological roles of EVs in mediating disease progression, and the feasibility of EVs’ use for detection of HCC.

          Abstract

          Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer-related death worldwide. Despite the improvements in surveillance and treatment, the prognosis of HCC remains poor. Extracellular vesicles (EVs) are a heterogeneous group of phospholipid bilayer-enclosed particles circulating in the bloodstream and mediating intercellular communication. Emerging studies have shown that EVs play a crucial role in regulating the proliferation, immune escape, and metastasis of HCC. In addition, because EVs are present in the circulation at relatively early stages of disease, they are getting attention as an attractive biomarker for HCC detection. Over the past decade, dedicated efforts have been made to isolate EVs more efficiently and make them useful tools in different clinical settings. In this review article, we provide an overview of the EVs isolation methods and highlight the role of EVs as mediators in the pathogenesis and progression of HCC. Lastly, we summarize the potential applications of EVs in early-stage HCC detection.

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          Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

          ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
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            Shedding light on the cell biology of extracellular vesicles

            Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.
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              A global view of hepatocellular carcinoma: trends, risk, prevention and management

              Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                20 June 2021
                June 2021
                : 13
                : 12
                : 3076
                Affiliations
                [1 ]California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095, USA; Yi-TeLee@ 123456mednet.ucla.edu (Y.-T.L.); icybingliang@ 123456gmail.com (I.Y.L.); YazhenZhu@ 123456mednet.ucla.edu (Y.Z.); HRTseng@ 123456mednet.ucla.edu (H.-R.T.)
                [2 ]Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA; Jasmine.Wang@ 123456cshs.org
                [3 ]Department of Surgery, University of California, Los Angeles, CA 90095, USA; BVTran@ 123456mednet.ucla.edu (B.V.T.); VAgopian@ 123456mednet.ucla.edu (V.G.A.)
                [4 ]Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90048, USA
                [5 ]Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Sungyong.You@ 123456cshs.org
                [6 ]Division of Cancer Biology and Therapeutics, Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
                [7 ]Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
                [8 ]Comprehensive Transplant Center Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
                Author notes
                [* ]Correspondence: JuDong.Yang@ 123456cshs.org ; Tel.: +1-310-423-1971
                Author information
                https://orcid.org/0000-0003-3513-1783
                Article
                cancers-13-03076
                10.3390/cancers13123076
                8233859
                34203086
                2155a824-efea-4915-aa04-837e99b6a05b
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 01 June 2021
                : 17 June 2021
                Categories
                Review

                hepatocellular carcinoma,extracellular vesicles,disease progression,cancer detection,biomarker,liquid biopsy

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