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      Experimental Models of Hepatocellular Carcinoma—A Preclinical Perspective

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          Abstract

          Simple Summary

          Hepatocellular carcinoma (HCC) is characterized by a broad molecular and genetic heterogeneity, which makes it a challenging subject in terms of the underlying mechanisms, response and resistance to treatment, and finding novel therapeutic options. Nowadays, new experimental models (3D in vitro models, in vivo mouse and non-mouse models, and computational studies) allow more detailed studies of hepatocellular carcinoma pathogenesis and treatment. Here, we provide insights into the current preclinical models frequently applied for the study of hepatocellular carcinoma.

          Abstract

          Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.

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          Hepatocellular carcinoma

          Hepatocellular carcinoma appears frequently in patients with cirrhosis. Surveillance by biannual ultrasound is recommended for such patients because it allows diagnosis at an early stage, when effective therapies are feasible. The best candidates for resection are patients with a solitary tumour and preserved liver function. Liver transplantation benefits patients who are not good candidates for surgical resection, and the best candidates are those within Milan criteria (solitary tumour ≤5 cm or up to three nodules ≤3 cm). Image-guided ablation is the most frequently used therapeutic strategy, but its efficacy is limited by the size of the tumour and its localisation. Chemoembolisation has survival benefit in asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread. Finally, sorafenib, lenvatinib, which is non-inferior to sorafenib, and regorafenib increase survival and are the standard treatments in advanced hepatocellular carcinoma. This Seminar summarises the scientific evidence that supports the current recommendations for clinical practice, and discusses the areas in which more research is needed.
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            Hepatocellular Carcinoma

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              Organoids in cancer research

              The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models. Such preclinical models are essential for more efficient translation of basic cancer research into novel treatment regimens for patients with cancer. Wild-type organoids can be grown from embryonic and adult stem cells and display self-organizing capacities, phenocopying essential aspects of the organs they are derived from. Genetic modification of organoids allows disease modelling in a setting that approaches the physiological environment. Additionally, organoids can be grown with high efficiency from patient-derived healthy and tumour tissues, potentially enabling patient-specific drug testing and the development of individualized treatment regimens. In this Review, we evaluate tumour organoid protocols and how they can be utilized as an alternative model for cancer research.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                21 July 2021
                August 2021
                : 13
                : 15
                : 3651
                Affiliations
                [1 ]Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; blidy@ 123456umft.ro (A.B.); florin.hut@ 123456umft.ro (F.H.); octavian.cretu@ 123456umft.ro (O.M.C.)
                [2 ]Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; iasmina.marcovici@ 123456umft.ro
                [3 ]Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania
                Author notes
                [* ]Correspondence: dorinacoricovac@ 123456umft.ro (D.C.); cadehelean@ 123456umft.ro (C.A.D.)
                [†]

                These authors contributed equally to this paper.

                Author information
                https://orcid.org/0000-0002-5760-8872
                Article
                cancers-13-03651
                10.3390/cancers13153651
                8344976
                34359553
                f6a5afa5-55a0-4fde-93f7-61b650af9e45
                © 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
                : 27 June 2021
                : 17 July 2021
                Categories
                Review

                hepatocellular carcinoma,2d cell lines,3d tumor spheroids,organoids,organ-on-a-chip,mouse models,in silico,machine learning,artificial intelligence algorithms

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