Liver Cancer: Molecular Mechanisms and Targeted Therapies

A special issue of Medicina (ISSN 1648-9144).

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 38631

Special Issue 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) is a highly frequent and lethal tumor globally, with limited therapeutic options. Although surgical resection and liver transplantation represent effective and potentially curative treatments in the early stages of the disease, the therapeutic options for advanced PLC remain unsatisfactory to date. The only two drugs approved for the treatment of advanced hepatocellular carcinoma (HCC) are the multikinase inhibitors Sorafenib and Regorafenib, yet being associated with limited benefits to the patients in terms of patients’ overall survival. Thus, the treatment of PLC represent a major health concern worldwide.

Despite a growing number of studies on the genetic and epigenetic events associated with PLC development and progression, the understanding of the same phenomena and their functional interplay remain poorly understood. Consequently, the molecular pathogenesis of this deadly disease remains poorly characterized. Therefore, a better understanding of the available data, as well as a further investigation of the molecular mechanisms responsible for human PLC, is imperative in order to significantly improve its prevention, detection, and therapy.

Given the importance of PLC in the field of medicine and research, the journal Medicina is launching this Special Issue.

We encourage you and your co-workers to submit your articles reporting on this topic. Reviews or original articles dealing with the biochemical and molecular aspects associated with PLC pathogenesis in experimental models and humans, as well as articles providing an up-to-date overview of the use of circulating/tissue biomarkers in early diagnosis and management, are particularly welcome. In addition, we warmly invite you to submit articles reporting on evidence and expectations from innovative molecular therapeutics, with special focus on individualized approaches.

Prof. Dr. Diego Francesco Calvisi
Guest Editor

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Keywords

  • Primary liver cancer
  • Hepatocellular carcinoma
  • Cholangiocarcinoma
  • Hepatoblastoma
  • Signaling pathways
  • Epigenetics
  • Experimental models
  • Biomarkers
  • Targeted therapies
  • Precision medicine

Published Papers (7 papers)

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Research

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16 pages, 5085 KiB  
Article
Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma
by Antonio Cigliano, Maria Giulia Pilo, Marta Mela, Silvia Ribback, Frank Dombrowski, Giovanni Mario Pes, Antonio Cossu, Matthias Evert, Diego Francesco Calvisi and Kirsten Utpatel
Medicina 2020, 56(1), 1; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina56010001 - 18 Dec 2019
Cited by 5 | Viewed by 2909
Abstract
Background and Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a pernicious tumor characterized by a dismal outcome and scarce therapeutic options. To substantially improve the prognosis of iCCA patients, a better understanding of the molecular mechanisms responsible for development and progression of this disease [...] Read more.
Background and Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a pernicious tumor characterized by a dismal outcome and scarce therapeutic options. To substantially improve the prognosis of iCCA patients, a better understanding of the molecular mechanisms responsible for development and progression of this disease is imperative. In the present study, we aimed at elucidating the role of the maternal embryonic leucine zipper kinase (MELK) protooncogene in iCCA. Materials and Methods: We analyzed the expression of MELK and two putative targets, Forkhead Box M1 (FOXM1) and Enhancer of Zeste Homolog 2 (EZH2), in a collection of human iCCA by real-time RT-PCR and immunohistochemistry (IHC). The effects on iCCA growth of both the multi-kinase inhibitor OTSSP167 and specific small-interfering RNA (siRNA) against MELK were investigated in iCCA cell lines. Results: Expression of MELK was significantly higher in tumors than in corresponding non-neoplastic liver counterparts, with highest levels of MELK being associated with patients’ shorter survival length. In vitro, OTSSP167 suppressed the growth of iCCA cell lines in a dose-dependent manner by reducing proliferation and inducing apoptosis. These effects were amplified when OTSSP167 administration was coupled to the DNA-damaging agent doxorubicin. Similar results, but less remarkable, were obtained when MELK was silenced by specific siRNA in the same cells. At the molecular level, siRNA against MELK triggered downregulation of MELK and its targets. Finally, we found that MELK is a downstream target of the E2F1 transcription factor. Conclusion: Our results indicate that MELK is ubiquitously overexpressed in iCCA, where it may represent a prognostic indicator and a therapeutic target. In particular, the combination of OTSSP167 (or other, more specific MELK inhibitors) with DNA-damaging agents might be a potentially effective therapy for human iCCA. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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10 pages, 3025 KiB  
Article
The Novel Nature Microtubule Inhibitor Ivalin Induces G2/M Arrest and Apoptosis in Human Hepatocellular Carcinoma SMMC-7721 Cells In Vitro
by Fangyuan Liu, Shiqi Lin, Caiyun Zhang, Jiahui Ma, Zhuo Han, Fujuan Jia, Weidong Xie and Xia Li
Medicina 2019, 55(8), 470; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina55080470 - 12 Aug 2019
Cited by 12 | Viewed by 2797
Abstract
Background and Objectives: Microtubules are an attractive target for cancer chemotherapy. Previously, we reported that Ivalin exhibited excellent anti-migration and anti-invasion activities in human breast cancer cells. Here, we examined the microtubule inhibition effect of Ivalin in human hepatocellular carcinoma SMMC-7721 cells. [...] Read more.
Background and Objectives: Microtubules are an attractive target for cancer chemotherapy. Previously, we reported that Ivalin exhibited excellent anti-migration and anti-invasion activities in human breast cancer cells. Here, we examined the microtubule inhibition effect of Ivalin in human hepatocellular carcinoma SMMC-7721 cells. Materials and Methods: We used the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate the cell proliferation effect of Ivalin and flow cytometry analysis to detect the apoptotic and cell cycle arrest effects of Ivalin. Immunofluorescence staining was used to measure the effect of Ivalin on the cytoskeleton network, and Western blotting was used to detect the expression levels of Bax, Bcl-2, Cdc2, phosphor-Cdc2, Cdc25A, Cyclin B1, and tubulin. Results: Ivalin induced cell cycle G2/M arrest and subsequent triggered apoptosis in human hepatocellular carcinoma SMMC-7721 cells. Furthermore, microtubules were shown to be involved in Ivalin-meditated apoptosis. In this connection, Ivalin treatment suppressed cellular microtubule network formation by regulating microtubule depolymerization. Moreover, Western blotting revealed Cdc25A and Cyclin B1 were upregulated in Ivalin-meditated cell cycle arrest. Subsequently, the induction of Bax (a proapoptotic protein) and reduction of Bcl-2 (an anti-apoptotic protein) expression were observed in Ivalin-treated SMMC-7721 cells. Conclusion: Ivalin induced microtubule depolymerization, then blocked cells in mitotic phase, and eventually resulted in apoptosis in SMMC-7721 cells. Collectively, these data indicate that Ivalin, acting as a novel inhibitor of microtubules, could be considered as a promising lead in anticancer drug development. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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Review

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16 pages, 830 KiB  
Review
Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib
by Oronzo Brunetti, Antonio Gnoni, Antonella Licchetta, Vito Longo, Angela Calabrese, Antonella Argentiero, Sabina Delcuratolo, Antonio Giovanni Solimando, Andrea Casadei-Gardini and Nicola Silvestris
Medicina 2019, 55(10), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina55100707 - 21 Oct 2019
Cited by 58 | Viewed by 5935
Abstract
Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed [...] Read more.
Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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11 pages, 706 KiB  
Review
Emerging Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
by Vito Longo, Oronzo Brunetti, Antonio Gnoni, Antonella Licchetta, Sabina Delcuratolo, Riccardo Memeo, Antonio Giovanni Solimando and Antonella Argentiero
Medicina 2019, 55(10), 698; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina55100698 - 17 Oct 2019
Cited by 44 | Viewed by 4675
Abstract
Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70–80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standard care for almost a [...] Read more.
Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70–80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standard care for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results in an alternative first-line treatment for the Chinese clinical oncology guidelines. Moreover, nivolumab and pembrolizumab, two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approved for subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessment of new ICIs-based combinatory approaches. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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22 pages, 1843 KiB  
Review
Hepatocellular Carcinoma: Molecular Mechanisms and Targeted Therapies
by Ali Alqahtani, Zubair Khan, Abdurahman Alloghbi, Tamer S. Said Ahmed, Mushtaq Ashraf and Danae M. Hammouda
Medicina 2019, 55(9), 526; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina55090526 - 23 Aug 2019
Cited by 151 | Viewed by 8650
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide. HCC is a complex process that is associated with several etiological factors, which in turn result in aberrant activation of different cellular and molecular pathways and the disruption of [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide. HCC is a complex process that is associated with several etiological factors, which in turn result in aberrant activation of different cellular and molecular pathways and the disruption of balance between activation and inactivation of protooncogenes and tumor suppressor genes, respectively. Since HCC most often occurs in the setting of a diseased or cirrhotic liver and most of the patients are diagnosed at the late stage of disease, prognosis is generally poor. At present, limited treatment options with marginal clinical benefits are available. Systemic therapy, particularly in the form of conventional cytotoxic drugs, are generally ineffective. In recent years, molecular-targeted therapies have been clinically used to treat various cancers, including liver cancer. This approach inhibits the growth of tumor cells by interfering with molecules that are involved in carcinogenesis, which makes it more selective and specific than cytotoxic chemotherapy. Many clinical trials have been carried out while using molecular targeted drugs in advanced HCC with many more in progress. The clinical trials in HCC to date have evaluated a single-targeted therapy alone, or two or more targeted therapies in parallel. The aim of this review is to provide insight of various molecular mechanisms, leading to HCC development and progression, and also the range of experimental therapeutics for patients with advanced HCC. The review will summarize different clinical trials data the successes and failures of these treatments, as well as the most effective and approved drugs designed against HCC. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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24 pages, 3108 KiB  
Review
Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma
by Rosa M. Pascale, Graziella Peitta, Maria M. Simile and Francesco Feo
Medicina 2019, 55(6), 296; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina55060296 - 21 Jun 2019
Cited by 30 | Viewed by 6303
Abstract
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a [...] Read more.
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of MAT1A gene under-regulation associated with up-regulation of the MAT2A gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT2A and MAT2B expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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16 pages, 1560 KiB  
Review
Targeted Therapies in Cholangiocarcinoma: Emerging Evidence from Clinical Trials
by Maria Maddalena Simile, Paola Bagella, Gianpaolo Vidili, Angela Spanu, Roberto Manetti, Maria Antonietta Seddaiu, Sergio Babudieri, Giordano Madeddu, Pier Andrea Serra, Matteo Altana and Panagiotis Paliogiannis
Medicina 2019, 55(2), 42; https://0-doi-org.brum.beds.ac.uk/10.3390/medicina55020042 - 08 Feb 2019
Cited by 60 | Viewed by 6028
Abstract
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs [...] Read more.
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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