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Cancers
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Models of Experimental Liver Cancer
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Models of Experimental Liver Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 109311

Special Issue Editor

Prof. Dr. Diego F. Calvisi

E-Mail Website
Guest Editor
Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany
Interests: liver cancer; hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; mouse models; cancer genetics and epigenetics; signal transduction; cancer metabolism; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Primary liver cancer (PLC) ranks among the most frequent and deadly tumors worldwide, with a steadily increasing incidence and few therapeutic options. PLC consists of two main histological subtypes in the adult, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), and of hepatoblastoma (HBL) in children. Due to the paucity of symptoms and the absence of reliable biomarkers for early detection, PLC is most often detected in advanced stages, when curative therapies are not applicable and loco-regional approaches are of limited patient benefit. To overcome this gloomy scenario, a number of in vitro and in vivo experimental models have been generated and are currently under development. These models have been highly useful to understand the genetic predisposition to liver cancer, the malignant properties of chemicals and environmental factors, the histopathological alterations occurring along liver tumor development and progression, the identification of diagnostic and prognostic markers, and the oncogenic potential of aberrantly activated or inactivated signaling pathways. Recent and future models will be extremely helpful to address pivotal unsolved questions, such as intratumor heterogeneity, functional interplay between PLC cells and the tumor microenvironment, the role of signaling pathways crosstalk, metabolic addiction, and response/resistance to conventional and tailored therapies.

Given the importance of PLC in the field of medicine and research, the journal Cancers is launching this Special Issue. Our aim is to bring together a collection of original research articles and incisive reviews providing fertile ground for insightful discussions and new ideas for the understanding and the treatment of this pernicious disease.

Prof. Dr. Diego F. Calvisi
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Research

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32 pages, 7766 KiB  
Article
Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen
by Ming-Hui Yang, Marcelo Chen, Hsiao-Hsuan Mo, Wan-Chi Tsai, Yu-Chi Chang, Chin-Chuan Chang, Ko-Chin Chen, Hsin-Yi Wu, Cheng-Hui Yuan, Che-Hsin Lee, Yi-Ming Arthur Chen and Yu-Chang Tyan
Cancers 2020, 12(2), 409; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020409 - 10 Feb 2020
Cited by 15 | Viewed by 3565
Abstract
Hepatocellular carcinoma (HCC) is among the ten most commonly diagnosed cancers and the fourth leading cause of cancer-related death. Patients with hepatitis B virus (HBV) infection are prone to developing chronic liver diseases (i.e., fibrosis and cirrhosis), and the HBV X antigen plays [...] Read more.
Hepatocellular carcinoma (HCC) is among the ten most commonly diagnosed cancers and the fourth leading cause of cancer-related death. Patients with hepatitis B virus (HBV) infection are prone to developing chronic liver diseases (i.e., fibrosis and cirrhosis), and the HBV X antigen plays an important role in the development of HCC. The difficulty in detecting HCC at the early stages is one of the main reasons that the death rate approximates the incidence rate. The regulators controlling the downstream liver protein expression from HBV infection are unclear. Mass spectrometric techniques and customized programs were used to identify differentially expressed proteins which may be involved in the development of liver fibrosis and HCC progression in hepatitis B virus X protein transgenic mice (HBx mice). FSTL1, CTSB, and TGF-β enhanced the signaling pathway proteins during the pathogenesis of HBx. Missing proteins can be essential in cell growth, differentiation, apoptosis, migration, metastasis or angiogenesis. We found that LHX2, BMP-5 and GDF11 had complex interactions with other missing proteins and BMP-5 had both tumor suppressing and tumorigenic roles. BMP-5 may be involved in fibrosis and tumorigenic processes in the liver. These results provide us an understanding of the mechanism of HBx-induced disorders, and may serve as molecular targets for liver treatment. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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21 pages, 9533 KiB  
Article
Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models
by Blanca Cucarull, Anna Tutusaus, Miguel Subías, Milica Stefanovic, Tania Hernáez-Alsina, Loreto Boix, María Reig, Pablo García de Frutos, Montserrat Marí, Anna Colell, Jordi Bruix and Albert Morales
Cancers 2020, 12(2), 332; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020332 - 01 Feb 2020
Cited by 13 | Viewed by 4691
Abstract
Background: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in [...] Read more.
Background: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in vivo HCC models, we tested regorafenib’s effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment. Results: In hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients. Conclusion: Regorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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15 pages, 2799 KiB  
Article
High Somatic Mutation and Neoantigen Burden Do Not Correlate with Decreased Progression-Free Survival in HCC Patients not Undergoing Immunotherapy
by Angela Mauriello, Roberta Zeuli, Beatrice Cavalluzzo, Annacarmen Petrizzo, Maria Lina Tornesello, Franco M. Buonaguro, Michele Ceccarelli, Maria Tagliamonte and Luigi Buonaguro
Cancers 2019, 11(12), 1824; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121824 - 20 Nov 2019
Cited by 33 | Viewed by 4421
Abstract
Cancer genome instability leads to accumulation of mutations which may result into tumor-specific mutated “neoantigens”, not be affected by central T-cell tolerance. Such neoantigens are considered the optimal target for the patient’s anti-tumor T cell immunity as well as for personalized cancer immunotherapy [...] Read more.
Cancer genome instability leads to accumulation of mutations which may result into tumor-specific mutated “neoantigens”, not be affected by central T-cell tolerance. Such neoantigens are considered the optimal target for the patient’s anti-tumor T cell immunity as well as for personalized cancer immunotherapy strategies. However, only a minor fraction of predicted neoantigens are relevant to the clinical outcome. In the present study, a prediction algorithm was applied using datasets of RNA sequencing from all 377 Hepatocellular carcinoma (HCC) patients available at The Cancer Genome Atlas (TCGA), to predict neoantigens to be presented by each patient’s autologous HLA molecules. Correlation with patients’ survival was performed on the 115 samples for whom the exact date of death was known. A total of 30 samples were used for the training set, and 85 samples were used for the validation sets. Neither the somatic mutations nor the number nor the quality of the predicted neoantigens correlate as single parameter with survival of HCC patients who do not undergo immunotherapy treatment. Furthermore, the preferential presentation of such neoantigens in the context of one of the major histocompatibility complex MHC class I molecules does not have an impact on the survival. On the contrary, the expression of Granzyme A (GZMA) is significantly correlated with survival and, in the context of high GZMA, a direct correlation between number and quality of neoantigens with survival is observed. This is in striking contrast to results described in cancer patients undergoing immunotherapy, in which a strong correlation between Tumor Mutational Burden (TMB), number of predicted neoantigens and survival has been reported. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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18 pages, 13098 KiB  
Article
An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation
by Michael Svinarenko, Sarah-Fee Katz, Umesh Tharehalli, Medhanie A. Mulaw, Harald J. Maier, Yoshiaki Sunami, Sarah K. Fischer, Yuexin Chen, Sabine Heurich, Lena Erkert, Andrea Tannapfel, Thomas Wirth, Reinhold Schirmbeck, Thomas Seufferlein and André Lechel
Cancers 2019, 11(10), 1410; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101410 - 21 Sep 2019
Cited by 4 | Viewed by 3245
Abstract
Background: Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver [...] Read more.
Background: Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver carcinogenesis. Methods: We used inducible liver-specific transgenic mouse strains to analyze the consequences of NF-κB/p65 activation mimicking chronic inflammation and subsequent p53 loss. Results: Ikk2ca driven NF-κB/p65 activation in mice results in liver fibrosis, the formation of ectopic lymphoid structures and carcinogenesis independent of p53 expression. Subsequent deletion of Trp53 led to an increased tumor formation, metastasis and a shift in tumor differentiation towards intrahepatic cholangiocarcinoma. In addition, loss of Trp53 in an inflammatory liver resulted in elevated chromosomal instability and indicated a distinct aberration pattern. Conclusions: In conclusion, activation of NF-κB/p65 mimicking chronic inflammation provokes the formation of liver carcinoma. Collateral disruption of Trp53 supports tumor progression and influences tumor differentiation and heterogeneity. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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17 pages, 6965 KiB  
Article
Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
by Xianqiong Liu, Junjie Hu, Xinhua Song, Kirsten Utpatel, Yi Zhang, Pan Wang, Xinjun Lu, Jie Zhang, Meng Xu, Tao Su, Li Che, Jingxiao Wang, Matthias Evert, Diego F. Calvisi and Xin Chen
Cancers 2019, 11(7), 930; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11070930 - 03 Jul 2019
Cited by 9 | Viewed by 4908
Abstract
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog [...] Read more.
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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13 pages, 1327 KiB  
Article
From a Philosophical Framework to a Valid Prognostic Staging System of the New “Comprehensive Assessment” for Transplantable Hepatocellular Carcinoma
by Stefano Di Sandro, Vincenzo Bagnardi, Alessandro Cucchetti, Andrea Lauterio, Riccardo De Carlis, Laura Benuzzi, Maria Danieli, Francesca Botta, Leonardo Centonze, Marc Najjar and Luciano De Carlis
Cancers 2019, 11(6), 741; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060741 - 28 May 2019
Cited by 16 | Viewed by 2542
Abstract
The comprehensive assessment of the transplantable tumor (TT) proposed and included in the last Italian consensus meeting still deserve validation. All consecutive patients with hepatocellular carcinoma (HCC) listed for liver transplant (LT) between January 2005 and December 2015 were post-hoc classified by the [...] Read more.
The comprehensive assessment of the transplantable tumor (TT) proposed and included in the last Italian consensus meeting still deserve validation. All consecutive patients with hepatocellular carcinoma (HCC) listed for liver transplant (LT) between January 2005 and December 2015 were post-hoc classified by the tumor/patient stage as assessed at the last re-staging-time (ReS-time) before LT as follow: high-risk-class (HRC) = stages TTDR, TTPR; intermediate-risk-class (IRC) = TT0NT, TTFR, TTUT; low-risk-class (LRC) = TT1, TT0L, TT0C. Of 376 candidates, 330 received LT and 46 dropped-out. Transplanted patients were: HRC for 159 (48.2%); IRC for 63 (19.0%); LRC for 108 (32.7%). Cumulative incidence function (CIF) of tumor recurrence after LT was 21%, 12%, and 8% at 5-years and 27%, 15%, and 12% at 10-years respectively for HRC, IRC, and LRC (P = 0.011). IRC patients had significantly lower CIF of recurrence after LT if transplanted >2-months from ReS-time (28% vs. 3% for <2 and >2 months, P = 0.031). HRC patients had significantly lower CIF of recurrence after-LT if transplanted <2 months from the ReS-time (10% vs. 33% for <2 and >2 months, P = 0.006). The proposed TT staging system can adequately describe the post-LT recurrence, especially in the LRC and HRC patients. The intermediate-risk-class needs to be better defined and further studies on its ability in defining intention-to-treat survival (ITT) and drop-out are required. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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22 pages, 3585 KiB  
Article
Establishment and Characterization of a New Intrahepatic Cholangiocarcinoma Cell Line Resistant to Gemcitabine
by Chiara Varamo, Caterina Peraldo-Neia, Paola Ostano, Marco Basiricò, Chiara Raggi, Paola Bernabei, Tiziana Venesio, Enrico Berrino, Massimo Aglietta, Francesco Leone and Giuliana Cavalloni
Cancers 2019, 11(4), 519; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040519 - 11 Apr 2019
Cited by 24 | Viewed by 3837
Abstract
Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. Late diagnosis and chemotherapy resistance contribute to the scarce outfit and poor survival. Resistance mechanisms are still poorly understood. Here, we established a Gemcitabine (GEM) resistant model, the MT-CHC01R1.5 cell line, obtained [...] Read more.
Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. Late diagnosis and chemotherapy resistance contribute to the scarce outfit and poor survival. Resistance mechanisms are still poorly understood. Here, we established a Gemcitabine (GEM) resistant model, the MT-CHC01R1.5 cell line, obtained by a GEM gradual exposure (up to 1.5 µM) of the sensitive counterpart, MT-CHC01. GEM resistance was irreversible, even at high doses. The in vitro and in vivo growth was slower than MT-CHC01, and no differences were highlighted in terms of migration and invasion. Drug prediction analysis suggested that Paclitaxel and Doxycycline might overcome GEM resistance. Indeed, in vitro MT-CHC01R1.5 growth was reduced by Paclitaxel and Doxycycline. Importantly, Doxycycline pretreatment at very low doses restored GEM sensitivity. To assess molecular mechanisms underlying the acquisition of GEM resistance, a detailed analysis of the transcriptome in MT-CHC01R1.5 cells versus the corresponding parental counterpart was performed. Transcriptomic analysis showed that most up-regulated genes were involved in cell cycle regulation and in the DNA related process, while most down-regulated genes were involved in the response to stimuli, xenobiotic metabolism, and angiogenesis. Furthermore, additional panels of drug resistance and epithelial to mesenchymal transition genes (n = 168) were tested by qRT-PCR and the expression of 20 genes was affected. Next, based on a comparison between qRT-PCR and microarray data, a list of up-regulated genes in MT-CHC01R1.5 was selected and further confirmed in a primary cell culture obtained from an ICC patient resistant to GEM. In conclusion, we characterized a new GEM resistance ICC model that could be exploited either to study alternative mechanisms of resistance or to explore new therapies. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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13 pages, 2295 KiB  
Article
Assessment of a High Sensitivity Method for Identification of IDH1 R132x Mutations in Tumors and Plasma of Intrahepatic Cholangiocarcinoma Patients
by Caterina Peraldo-Neia, Maria Scatolini, Enrico Grosso, Pasquale Lombardi, Roberto Filippi, Chiara Raggi, Caterina Marchiò, Giuliana Cavalloni, Massimo Aglietta and Francesco Leone
Cancers 2019, 11(4), 454; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040454 - 30 Mar 2019
Cited by 5 | Viewed by 3157
Abstract
Hotspot codon 132 mutations (R132xIDH1m) are frequent in intrahepatic cholangiocarcinoma (ICC), are druggable by anti-IDH1m agents, and could represent a marker of disease progression. Developing an assay to identify R132xIDH1m would provide a useful tool to select [...] Read more.
Hotspot codon 132 mutations (R132xIDH1m) are frequent in intrahepatic cholangiocarcinoma (ICC), are druggable by anti-IDH1m agents, and could represent a marker of disease progression. Developing an assay to identify R132xIDH1m would provide a useful tool to select patients benefitting from targeted treatments. We tested a quantitative real-time allele-specific polymerase chain reaction (qPCR)-based method to detect the main R132xIDH1m in an Italian ICC series (n = 61) of formalin-fixed paraffin-embedded (FFPE) samples, and on circulating-free DNA samples. The outcomes were compared with nested PCR/Sanger sequencing. Reconstitution experiments of plasmids harboring the different R132xIDH1m mixed with wild-type (WT) DNA demonstrated that qPCR is able to detect at least 2% of all mutated allele. High efficiency was also observed on patient-derived mutated DNA mixed with WT DNA (up to 10% and 0.3 ng of mutated template); qPCR detected 16.4% of mutated samples (one R132G, three R132C and six R132L) while nested PCR/Sanger sequencing only 8.2% (four R132L and one R132G). In a single patient with an R132C-mutated tumor, qPCR was also performed on plasma samples collected at four time-points, observing an increase correlating with disease progression. In conclusion, we developed a qPCR assay which could represent a fast, inexpensive and sensitive tool both for detection of R132xIDH1m in ICC samples and monitoring disease progression from liquid biopsy. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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Review

Jump to: Research

13 pages, 1302 KiB  
Review
Animal Modeling of Pediatric Liver Cancer
by Richard S. Whitlock, Tianyou Yang, Sanjeev A. Vasudevan and Sarah E. Woodfield
Cancers 2020, 12(2), 273; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020273 - 22 Jan 2020
Cited by 10 | Viewed by 3192
Abstract
Hepatoblastoma (HB) is the most common pediatric liver malignancy. Management of HB requires multidisciplinary efforts. The 5-year overall survival of this disease is about 80% in developed countries. Despite advances in the care of these patients, survival in recurrent or treatment-refractory disease is [...] Read more.
Hepatoblastoma (HB) is the most common pediatric liver malignancy. Management of HB requires multidisciplinary efforts. The 5-year overall survival of this disease is about 80% in developed countries. Despite advances in the care of these patients, survival in recurrent or treatment-refractory disease is lower than 50%. This is due to more complex tumor biology, including hepatocellular carcinoma (HCC)-like mutations and expression of aggressive gene signatures leading to chemoresistance, vascular invasion, and metastatic spread. The current treatment protocols for pediatric liver cancer do not incorporate targeted therapies, and the ability to test these therapies is limited due to the inaccessibility of cell lines and mouse models. In this review, we discuss the current status of preclinical animal modeling in pediatric liver cancer, primarily HB. Although HB is a rare cancer, the research community has worked together to develop a range of interesting and relevant mouse models for diverse preclinical studies. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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16 pages, 708 KiB  
Review
Genetically Engineered Mouse Models for Liver Cancer
by Kyungjoo Cho, Simon Weonsang Ro, Sang Hyun Seo, Youjin Jeon, Hyuk Moon, Do Young Kim and Seung Up Kim
Cancers 2020, 12(1), 14; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010014 - 19 Dec 2019
Cited by 25 | Viewed by 5464
Abstract
Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, comprising approximately 80% of cases. Murine models of HCC, such as chemically-induced models, xenograft models, [...] Read more.
Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, comprising approximately 80% of cases. Murine models of HCC, such as chemically-induced models, xenograft models, and genetically engineered mouse (GEM) models, are valuable tools to reproduce human HCC biopathology and biochemistry. These models can be used to identify potential biomarkers, evaluate potential novel therapeutic drugs in pre-clinical trials, and develop molecular target therapies. Considering molecular target therapies, a novel approach has been developed to create genetically engineered murine models for HCC, employing hydrodynamics-based transfection (HT). The HT method, coupled with the Sleeping Beauty transposon system or the CRISPR/Cas9 genome editing tool, has been used to rapidly and cost-effectively produce a variety of HCC models containing diverse oncogenes or inactivated tumor suppressor genes. The versatility of these models is expected to broaden our knowledge of the genetic mechanisms underlying human hepatocarcinogenesis, allowing the study of premalignant and malignant liver lesions and the evaluation of new therapeutic strategies. Here, we review recent advances in GEM models of HCC with an emphasis on new technologies. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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41 pages, 5674 KiB  
Review
Liver Cancer: Current and Future Trends Using Biomaterials
by Sue Anne Chew, Stefania Moscato, Sachin George, Bahareh Azimi and Serena Danti
Cancers 2019, 11(12), 2026; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11122026 - 16 Dec 2019
Cited by 27 | Viewed by 6813
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the [...] Read more.
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to efficiently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches—e.g., cell capture—as promising future trends in the application of biomaterials to treat HCC. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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32 pages, 4182 KiB  
Review
MicroRNAs in Animal Models of HCC
by Francesca Fornari, Laura Gramantieri, Elisa Callegari, Ram C. Shankaraiah, Fabio Piscaglia, Massimo Negrini and Catia Giovannini
Cancers 2019, 11(12), 1906; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121906 - 01 Dec 2019
Cited by 24 | Viewed by 4705
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression [...] Read more.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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18 pages, 279 KiB  
Review
Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research
by Oihane Erice, Adrian Vallejo, Mariano Ponz-Sarvise, Michael Saborowski, Arndt Vogel, Diego F. Calvisi, Anna Saborowski and Silvestre Vicent
Cancers 2019, 11(12), 1868; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121868 - 26 Nov 2019
Cited by 5 | Viewed by 3967
Abstract
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic [...] Read more.
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
16 pages, 9975 KiB  
Review
Mouse Models for Immunotherapy in Hepatocellular Carcinoma
by Enya Li, Li Lin, Chia-Wei Chen and Da-Liang Ou
Cancers 2019, 11(11), 1800; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111800 - 15 Nov 2019
Cited by 22 | Viewed by 13120
Abstract
Liver cancer is one of the dominant causes of cancer-related mortality, and the survival rate of liver cancer is among the lowest for all cancers. Immunotherapy for hepatocellular carcinoma (HCC) has yielded some encouraging results, but the percentage of patients responding to single-agent [...] Read more.
Liver cancer is one of the dominant causes of cancer-related mortality, and the survival rate of liver cancer is among the lowest for all cancers. Immunotherapy for hepatocellular carcinoma (HCC) has yielded some encouraging results, but the percentage of patients responding to single-agent therapies remains low. Therefore, potential directions for improved immunotherapies include identifying new immune targets and checkpoints and customizing treatment procedures for individual patients. The development of combination therapies for HCC is also crucial and urgent and, thus, further studies are required. Mice have been utilized in immunotherapy research due to several advantages, for example, being low in cost, having high success rates for inducing tumor growth, and so on. Moreover, immune-competent mice are used in immunotherapy research to clarify the role that the immune system plays in cancer growth. In this review paper, the advantages and disadvantages of mouse models for immunotherapy, the equipment that are used for monitoring HCC, and the cell strains used for inducing HCC are reviewed. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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15 pages, 584 KiB  
Review
Animal Models of Hepatocellular Carcinoma Prevention
by Ram C. Shankaraiah, Laura Gramantieri, Francesca Fornari, Silvia Sabbioni, Elisa Callegari and Massimo Negrini
Cancers 2019, 11(11), 1792; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111792 - 14 Nov 2019
Cited by 9 | Viewed by 3869
Abstract
Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC [...] Read more.
Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC and improve patient prognosis. Nonetheless, there has been no clinical advancement in instituting HCC chemopreventive strategies. Some of the major challenges are heterogenous genetic aberrations of HCC, significant modulation of tumor microenvironment and incomplete understanding of HCC tumorigenesis. To this end, animal models of HCC are valuable tools to evaluate biology of tumor initiation and progression with specific insight into molecular and genetic mechanisms involved. In this review, we describe various animal models of HCC that facilitate effective ways to study therapeutic prevention strategies that have translational potential to be evaluated in a clinical context. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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18 pages, 1035 KiB  
Review
Recreating Tumour Complexity in a Dish: Organoid Models to Study Liver Cancer Cells and their Extracellular Environment
by Gilles S. van Tienderen, Bas Groot Koerkamp, Jan N. M. IJzermans, Luc J. W. van der Laan and Monique M. A. Verstegen
Cancers 2019, 11(11), 1706; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111706 - 01 Nov 2019
Cited by 26 | Viewed by 6408
Abstract
Primary liver cancer, consisting predominantly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remains one of the most lethal malignancies worldwide. This high malignancy is related to the complex and dynamic interactions between tumour cells, stromal cells and the extracellular environment. Novel in vitro [...] Read more.
Primary liver cancer, consisting predominantly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remains one of the most lethal malignancies worldwide. This high malignancy is related to the complex and dynamic interactions between tumour cells, stromal cells and the extracellular environment. Novel in vitro models that can recapitulate the tumour are essential in increasing our understanding of liver cancer. Herein, primary liver cancer-derived organoids have opened up new avenues due to their patient-specificity, self-organizing ability and potential recapitulation of many of the tumour properties. Organoids are solely of epithelial origin, but incorporation into co-culture models can enable the investigation of the cellular component of the tumour microenvironment. However, the extracellular component also plays a vital role in cancer progression and representation is lacking within current in vitro models. In this review, organoid technology is discussed in the context of liver cancer models through comparisons to other cell culture systems. In addition, the role of the tumour extracellular environment in primary liver cancer will be highlighted with an emphasis on its importance in in vitro modelling. Converging novel organoid-based models with models incorporating the native tumour microenvironment could lead to experimental models that can better recapitulate liver tumours in vivo. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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19 pages, 691 KiB  
Review
Models for Understanding Resistance to Chemotherapy in Liver Cancer
by Jose J. G. Marin, Elisa Herraez, Elisa Lozano, Rocio I. R. Macias and Oscar Briz
Cancers 2019, 11(11), 1677; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111677 - 29 Oct 2019
Cited by 24 | Viewed by 5317
Abstract
The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding [...] Read more.
The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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16 pages, 648 KiB  
Review
Role of Non-Coding RNAs in the Progression of Liver Cancer: Evidence from Experimental Models
by April O’Brien, Tianhao Zhou, Christopher Tan, Gianfranco Alpini and Shannon Glaser
Cancers 2019, 11(11), 1652; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111652 - 25 Oct 2019
Cited by 12 | Viewed by 2293
Abstract
Liver cancer is a devastating cancer that ranges from relatively rare (around 2% of all cancers in the United States) to commonplace (up to 50% of cancers in underdeveloped countries). Depending upon the stage of pathogenesis, prognosis, or functional liver tissue present, transplantation [...] Read more.
Liver cancer is a devastating cancer that ranges from relatively rare (around 2% of all cancers in the United States) to commonplace (up to 50% of cancers in underdeveloped countries). Depending upon the stage of pathogenesis, prognosis, or functional liver tissue present, transplantation or partial hepatectomy may be the only available treatment option. However, due to the rise in metabolic syndrome and the increasing demand for livers, patients often wait months or years for available organs. Due to this shortage, doctors must have other treatment options available. One promising area of cancer research lies in understanding the role of regulatory non-coding RNAs (ncRNAs) as oncogenic drivers and potential targets for prospective therapies. While the role of these ncRNAs was not initially clear, many of them have since been recognized to function as important players in the regulation of gene expression, epigenetic modification, and signal transduction in both normal and cancer cell cycles. Dysregulation of these different ncRNA subtypes has been implicated in the pathogenesis and progression of many major cancers including hepatocellular carcinoma. This review summarizes current findings on the roles noncoding RNAs play in the progression of liver cancer and the various animal models used in current research to elucidate those data. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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14 pages, 666 KiB  
Review
Genomic Perspective on Mouse Liver Cancer Models
by Sun Young Yim and Ju-Seog Lee
Cancers 2019, 11(11), 1648; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111648 - 25 Oct 2019
Cited by 8 | Viewed by 4093
Abstract
Selecting the most appropriate mouse model that best recapitulates human hepatocellular carcinoma (HCC) allows translation of preclinical mouse studies into clinical studies. In the era of cancer genomics, comprehensive and integrative analysis of the human HCC genome has allowed categorization of HCC according [...] Read more.
Selecting the most appropriate mouse model that best recapitulates human hepatocellular carcinoma (HCC) allows translation of preclinical mouse studies into clinical studies. In the era of cancer genomics, comprehensive and integrative analysis of the human HCC genome has allowed categorization of HCC according to molecular subtypes. Despite the variety of mouse models that are available for preclinical research, there is a lack of evidence for mouse models that closely resemble human HCC. Therefore, it is necessary to identify the accurate mouse models that represent human HCC based on molecular subtype as well as histologic aggressiveness. In this review, we summarize the mouse models integrated with human HCC genomic data to provide information regarding the models that recapitulates the distinct aspect of HCC biology and prognosis based on molecular subtypes. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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20 pages, 1984 KiB  
Review
Validation of Hepatocellular Carcinoma Experimental Models for TGF-β Promoting Tumor Progression
by Serena Mancarella, Silke Krol, Alberto Crovace, Stefano Leporatti, Francesco Dituri, Martina Frusciante and Gianluigi Giannelli
Cancers 2019, 11(10), 1510; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101510 - 09 Oct 2019
Cited by 21 | Viewed by 4126
Abstract
Transforming growth factor beta (TGF-β) is a pleiotropic cytokine with dual role in hepatocellular carcinoma (HCC). It acts as tumor-suppressor and tumor-promoter in the early and late stage respectively. TGF-β influences the tumor-stroma cross-talk affecting the tumoral microenvironment. Therefore, inhibiting the TGF- β [...] Read more.
Transforming growth factor beta (TGF-β) is a pleiotropic cytokine with dual role in hepatocellular carcinoma (HCC). It acts as tumor-suppressor and tumor-promoter in the early and late stage respectively. TGF-β influences the tumor-stroma cross-talk affecting the tumoral microenvironment. Therefore, inhibiting the TGF- β mediated pathway alone and/or in combination with chemotherapeutics represents an important therapeutic option. Experimental models to dissect the role of TGF-β in HCC tumor progression as well as the effectiveness of specific inhibitors are tricky. HCC cell lines respond to TGF-β according to their epithelial phenotype. However, the mesenchymal and more aggressive HCC cell lines in vitro, do not develop tumors when transplanted in vivo, thus hampering the understanding of molecular pathways that dictate outcome. In addition, in this model the native immune system is abolished, therefore the contribution of inflammation in hepatocarcinogenesis is unreliable. Different strategies have been set up to engineer HCC animal models, including genetically modified mice, chemically induced HCC, or hydrodynamic techniques. Patient-derived xenograft is currently probably the most fascinating model, keeping in mind that models cannot mirror all the reality. In this context, we discuss the different available HCC mouse models including our experimental model treated with inhibitor of TGF-β receptor Type I kinase (Galunisertib) and a potential role of exosomes in TGF-β moderated tumor progression of HCC. Unfortunately, no positive results were obtained in our treated orthotopic model because it does not reproduce the critical tumor-stroma interactions of the HCC. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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12 pages, 1824 KiB  
Review
Animal Models of Hepatocellular Carcinoma: The Role of Immune System and Tumor Microenvironment
by Zuzana Macek Jilkova, Keerthi Kurma and Thomas Decaens
Cancers 2019, 11(10), 1487; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101487 - 02 Oct 2019
Cited by 44 | Viewed by 10368
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and has one of the highest mortality rates of solid cancers. Ninety percent of HCCs are associated with liver fibrosis or cirrhosis developed from chronic liver injuries. The immune system [...] Read more.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and has one of the highest mortality rates of solid cancers. Ninety percent of HCCs are associated with liver fibrosis or cirrhosis developed from chronic liver injuries. The immune system of the liver contributes to the severity of the necrotic-inflammatory tissue damage, the establishment of fibrosis and cirrhosis, and the disease progression towards HCC. Immunotherapies have emerged as an exciting strategy for HCC treatment, but their effect is limited, and an extensive translation research is urgently needed to enhance anti-tumor efficacy and clinical success. Establishing HCC animal models that are analogous to human disease settings, i.e., mimicking the tumor microenvironment of HCC, is extremely challenging. Hence, this review discusses different animal models of HCC by summarizing their advantages and their limits with a specific focus on the role of the immune system and tumor microenvironment. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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26 pages, 3428 KiB  
Review
Experimental Models to Define the Genetic Predisposition to Liver Cancer
by Rosa M. Pascale, Maria M. Simile, Graziella Peitta, Maria A. Seddaiu, Francesco Feo and Diego F. Calvisi
Cancers 2019, 11(10), 1450; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101450 - 27 Sep 2019
Cited by 12 | Viewed by 3910
Abstract
Hepatocellular carcinoma (HCC) is a frequent human cancer and the most frequent liver tumor. The study of genetic mechanisms of the inherited predisposition to HCC, implicating gene–gene and gene–environment interaction, led to the discovery of multiple gene loci regulating the growth and multiplicity [...] Read more.
Hepatocellular carcinoma (HCC) is a frequent human cancer and the most frequent liver tumor. The study of genetic mechanisms of the inherited predisposition to HCC, implicating gene–gene and gene–environment interaction, led to the discovery of multiple gene loci regulating the growth and multiplicity of liver preneoplastic and neoplastic lesions, thus uncovering the action of multiple genes and epistatic interactions in the regulation of the individual susceptibility to HCC. The comparative evaluation of the molecular pathways involved in HCC development in mouse and rat strains differently predisposed to HCC indicates that the genes responsible for HCC susceptibility control the amplification and/or overexpression of c-Myc, the expression of cell cycle regulatory genes, and the activity of Ras/Erk, AKT/mTOR, and of the pro-apoptotic Rassf1A/Nore1A and Dab2IP/Ask1 pathways, the methionine cycle, and DNA repair pathways in mice and rats. Comparative functional genetic studies, in rats and mice differently susceptible to HCC, showed that preneoplastic and neoplastic lesions of resistant mouse and rat strains cluster with human HCC with better prognosis, while the lesions of susceptible mouse and rats cluster with HCC with poorer prognosis, confirming the validity of the studies on the influence of the genetic predisposition to hepatocarinogenesis on HCC prognosis in mouse and rat models. Recently, the hydrodynamic gene transfection in mice provided new opportunities for the recognition of genes implicated in the molecular mechanisms involved in HCC pathogenesis and prognosis. This method appears to be highly promising to further study the genetic background of the predisposition to this cancer. Full article
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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