Assessment of Current Gene Therapy Practices in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the fifth most common cancer worldwide. HCC is recognized as the fourth most common cause of cancer related deaths worldwide due to the lack of effective early diagnostic tools, which often leads to individuals going undiagnosed until the cancer has reached late stage development. The current FDA approved treatments for late stage HCC provide a minimal increase in patient survival and lack tumor specificity, resulting in toxic systemic side effects. Gene therapy techniques, such as chimeric antigen receptor (CAR)-T Cells, viral vectors, and nanoparticles, are being explored as novel treatment options in various genetic diseases. Pre-clinical studies using gene therapy to treat in vitro and in vivo models of HCC have demonstrated potential efficacy for use in human patients. This review highlights genetic targets, techniques, and current clinical trials in HCC utilizing gene therapy.

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The Good, the Bad, the Question–H19 in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers12051261 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1261 ◽

Cited By ~ 3

Author(s):

Lysann Tietze ◽

Sonja M. Kessler

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Therapy ◽

Liver Cancer ◽

Primary Liver Cancer ◽

Human Patient ◽

In Vivo Models ◽

Study Results ◽

Novel Target

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is challenging to treat due to its typical late diagnosis, mostly at an advanced stage. Therefore, there is a particular need for research in diagnostic and prognostic biomarkers and therapeutic targets for HCC. The use of long noncoding (lnc) RNAs can widen the list of novel molecular targets improving cancer therapy. In hepatocarcinogenesis, the role of the lncRNA H19, which has been known for more than 30 years now, is still controversially discussed. H19 was described to work either as a tumor suppressor in vitro and in vivo, or to have oncogenic features. This review attempts to survey the conflicting study results and tries to elucidate the potential reasons for the contrary findings, i.e., different methods, models, or readout parameters. This review encompasses in vitro and in vivo models as well as studies on human patient samples. Although the function of H19 in HCC remains elusive, a short outlook summarizes some ideas of using the H19 locus as a novel target for liver cancer therapy.

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Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches

Cancer Cell International ◽

10.1186/s12935-021-01924-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zahra Farzaneh ◽

Massoud Vosough ◽

Tarun Agarwal ◽

Maryam Farzaneh

Keyword(s):

Hepatocellular Carcinoma ◽

Small Molecules ◽

Signaling Pathways ◽

Treatment Options ◽

Liver Carcinoma ◽

Induce Cell Cycle Arrest ◽

In Vivo Models ◽

Cell Propagation

AbstractHepatocellular carcinoma (HCC) is the second leading cause of death due to cancer. Although there are different treatment options, these strategies are not efficient in terms of restricting the tumor cell’s proliferation and metastasis. The liver tumor microenvironment contains the non-parenchymal cells with supportive or inhibitory effects on the cancerous phenotype of HCC. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of liver carcinoma cells. Recent studies have established new approaches for the prevention and treatment of HCC using small molecules. Small molecules are compounds with a low molecular weight that usually inhibit the specific targets in signal transduction pathways. These components can induce cell cycle arrest, apoptosis, block metastasis, and tumor growth. Devising strategies for simultaneously targeting HCC and the non-parenchymal population of the tumor could lead to more relevant research outcomes. These strategies may open new avenues for the treatment of HCC with minimal cytotoxic effects on healthy cells. This study provides the latest findings on critical signaling pathways governing HCC behavior and using small molecules in the control of HCC both in vitro and in vivo models.

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Karonudib is a promising anticancer therapy in hepatocellular carcinoma

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919866960 ◽

2019 ◽

Vol 11 ◽

pp. 175883591986696 ◽

Cited By ~ 6

Author(s):

Xiangwei Hua ◽

Kumar Sanjiv ◽

Helge Gad ◽

Therese Pham ◽

Camilla Gokturk ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Protein Level ◽

Kinase Inhibitors ◽

Viral Infections ◽

Treatment Options ◽

In Vivo Models ◽

Polymerase Chain

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is generally caused by viral infections or consumption of mutagens, such as alcohol. While liver transplantation and hepatectomy is curative for some patients, many relapse into disease with few treatment options such as tyrosine kinase inhibitors, for example, sorafenib or lenvatinib. The need for novel systemic treatment approaches is urgent. Methods: MTH1 expression profile was first analyzed in a HCC database and MTH1 mRNA/protein level was determined in resected HCC and paired paracancerous tissues with polymerase chain reaction (PCR) and immunohistochemistry. HCC cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA. 8-oxoG was measured by the modified comet assay. The effect of MTH1 inhibition on tumor growth was explored in HCC xenograft in vivo models. Results: MTH1 protein level is elevated in HCC tissue compared with paracancerous liver tissue and indicates poor prognosis. The MTH1 inhibitor Karonudib (TH1579) and siRNA effectively introduce toxic oxidized nucleotides into DNA, 8-oxoG, and kill HCC cell lines in vitro. Furthermore, we demonstrate that HCC growth in a xenograft mouse model in vivo is efficiently suppressed by Karonudib. Conclusion: Altogether, these data suggest HCC relies on MTH1 for survival, which can be targeted and may open up a novel treatment option for HCC in the future.

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Non-Viral Vectors for Gene Delivery

Nanoscience &Nanotechnology-Asia ◽

10.2174/2210681208666180110154233 ◽

2018 ◽

Vol 9 (1) ◽

pp. 4-11 ◽

Cited By ~ 5

Author(s):

Aparna Bansal ◽

Himanshu

Keyword(s):

Gene Therapy ◽

Viral Vectors ◽

Transfection Efficiency ◽

Gene Transfection ◽

Expression System ◽

Target Cells ◽

Specific Expression ◽

Naked Dna

Introduction: Gene therapy has emerged out as a promising therapeutic pave for the treatment of genetic and acquired diseases. Gene transfection into target cells using naked DNA is a simple and safe approach which has been further improved by combining vectors or gene carriers. Both viral and non-viral approaches have achieved a milestone to establish this technique, but non-viral approaches have attained a significant attention because of their favourable properties like less immunotoxicity and biosafety, easy to produce with versatile surface modifications, etc. Literature is rich in evidences which revealed that undoubtedly, non–viral vectors have acquired a unique place in gene therapy but still there are number of challenges which are to be overcome to increase their effectiveness and prove them ideal gene vectors. Conclusion: To date, tissue specific expression, long lasting gene expression system, enhanced gene transfection efficiency has been achieved with improvement in delivery methods using non-viral vectors. This review mainly summarizes the various physical and chemical methods for gene transfer in vitro and in vivo.

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Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma

Analytical Cellular Pathology ◽

10.1155/2021/1840069 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Argyrios Periferakis ◽

Georgios Tsigas ◽

Aristodemos-Theodoros Periferakis ◽

Ioana Anca Badarau ◽

Andreea-Elena Scheau ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Primary Liver Cancer ◽

Somatostatin Receptors ◽

Metastatic Potential ◽

Cancer Staging ◽

Complete Evaluation ◽

Specific Effects

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.

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Codon optimization of human factor VIII cDNAs leads to high-level expression

Blood ◽

10.1182/blood-2010-05-282707 ◽

2011 ◽

Vol 117 (3) ◽

pp. 798-807 ◽

Cited By ~ 109

Author(s):

Natalie J. Ward ◽

Suzanne M. K. Buckley ◽

Simon N. Waddington ◽

Thierry VandenDriessche ◽

Marinee K. L. Chuah ◽

...

Keyword(s):

Gene Therapy ◽

Factor Viii ◽

Viral Vectors ◽

Hemophilia A ◽

Lentiviral Vector ◽

Wild Type ◽

Fviii Activity ◽

Human Factor Viii

Abstract Gene therapy for hemophilia A would be facilitated by development of smaller expression cassettes encoding factor VIII (FVIII), which demonstrate improved biosynthesis and/or enhanced biologic properties. B domain deleted (BDD) FVIII retains full procoagulant function and is expressed at higher levels than wild-type FVIII. However, a partial BDD FVIII, leaving an N-terminal 226 amino acid stretch (N6), increases in vitro secretion of FVIII tenfold compared with BDD-FVIII. In this study, we tested various BDD constructs in the context of either wild-type or codon-optimized cDNA sequences expressed under control of the strong, ubiquitous Spleen Focus Forming Virus promoter within a self-inactivating HIV-based lentiviral vector. Transduced 293T cells in vitro demonstrated detectable FVIII activity. Hemophilic mice treated with lentiviral vectors showed expression of FVIII activity and phenotypic correction sustained over 250 days. Importantly, codon-optimized constructs achieved an unprecedented 29- to 44-fold increase in expression, yielding more than 200% normal human FVIII levels. Addition of B domain sequences to BDD-FVIII did not significantly increase in vivo expression. These significant findings demonstrate that shorter FVIII constructs that can be more easily accommodated in viral vectors can result in increased therapeutic efficacy and may deliver effective gene therapy for hemophilia A.

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Role of antioxidants in the treatment of hepatocellular carcinoma: Integrative review

Research Society and Development ◽

10.33448/rsd-v10i1.12028 ◽

2021 ◽

Vol 10 (1) ◽

pp. e46310112028

Author(s):

Claudriana Locatelli ◽

Joyce Kelly Busolin Jardim ◽

Vilmair Zancanaro

Keyword(s):

Hepatocellular Carcinoma ◽

Radical Scavenging Activity ◽

Treatment Options ◽

Radical Scavenging ◽

Integrative Review ◽

Advanced Hepatocellular Carcinoma ◽

Rate Dependent

Theorical framework: Hepatocellular carcinoma is a unique cancer that typically arises in the setting of chronic liver disease at a rate dependent upon the complex interplay between the host, disease, and environmental factors. Unfortunately, with contemporary management, patients with advanced hepatocellular carcinoma have few treatment options, and the prognosis is poor. Objective: Evaluate the role of antioxidants in the treatment of hepatocellular carcinoma. Methodology: It is an integrative review, with a qualitative approach. Based on research on ScienceDirect and PubMed databases, 12 articles were selected that were consistent with the theme and the inclusion and exclusion criteria, through the association of descriptors and keywords. Results: Studies in vivo demonstrated a positive correlation of antioxidants in the treatment of hepatocellular carcinoma. The antioxidants were able to promote inhibition of development tumor through promotes decrease of proinflammatory cytokines IL-1 and IL-6 and changes the ratios of Bax/Bcl2 that supports apoptosis. In oxidative stress, may be able to direct free radical scavenging activity. Among the main antioxidants with advanced preclinical evidence in the treatment of hepatocellular carcinoma is curcumin with tests in humans, and gallic acid, quercetin and resveratrol with several tests in vitro and in vivo. Conclusion: This study highlights that antioxidants can be a promising therapy in the treatment of hepatocellular carcinoma.

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LIM homeobox-2 suppresses hallmarks of adult and pediatric liver cancers by inactivating MAPK/ERK and Wnt/beta-catenin pathways

Liver Cancer ◽

10.1159/000521595 ◽

2021 ◽

Author(s):

Nicola Mosca ◽

Fatma Zohra Khoubai ◽

Sandrine Fedou ◽

Juan Carrillo-Reixach ◽

Stefano Caruso ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Wnt Pathway ◽

Hepatoma Cells ◽

Beta Catenin ◽

In Vivo Models ◽

Xenopus Embryos ◽

Pediatric Liver ◽

Liver Cancers

Introduction: Hepatocellular carcinoma and hepatoblastoma are two liver cancers characterized by gene deregulations, chromosomal rearrangements, and mutations in Wnt/beta-catenin (Wnt) pathway-related genes. LHX2, a transcriptional factor member of the LIM homeobox gene family, has important functions in embryogenesis and liver development. LHX2 is oncogenic in many solid tumors and leukemia but its role in liver cancer is unknown. Methods: We analyzed the expression of LHX2 in hepatocellular carcinoma and hepatoblastoma samples using various transcriptomic datasets and biological samples. The role of LHX2 was studied using lentiviral transduction, in vitro cell-based assays (growth, migration, senescence, apoptosis), molecular approaches (phospho-kinase arrays, RNA-seq), bioinformatics and two in vivo models in chicken and Xenopus embryos. Results: We found a strong connection between LHX2 down-regulation and Wnt activation in these two liver cancers. In hepatoblastoma, LHX2 downregulation correlated with multiple poor outcome parameters including higher patient age, intermediate- and high-risk tumors and low patients’ survival. Forced expression of LHX2 reduced the proliferation, migration and survival of hepatoma cells in vitro through the inactivation of MAPK/ERK and Wnt signals. In vivo, LHX2 impeded the development of tumors in chick embryos and repressed the Wnt pathway in Xenopus embryos. RNA-sequencing data and bioinformatic analyses confirmed the deregulation of many biological functions and molecular processes associated with cell migration, cell survival and liver carcinogenesis in LHX2-expressing hepatoma cells. At a mechanistic level, LHX2 mediated the disassembling of beta-catenin/T-cell factor 4 complex and induced expression of multiple inhibitors of Wnt (e.g. TLE/Groucho) and MAPK/ERK (e.g. DUSPs) pathways. Conclusion: Collectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.

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Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms20061288 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1288 ◽

Cited By ~ 9

Author(s):

Aldona Kasprzak ◽

Agnieszka Adamek

Keyword(s):

Primary Liver Cancer ◽

Morphological Differentiation ◽

Basic Research ◽

Clinical Value ◽

Aberrant Expression ◽

In Vivo Models ◽

Mucin Expression

Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), are critical in maintaining cellular functions, particularly those of epithelial surfaces. Their aberrant expression and/or altered subcellular localization is a factor of tumour growth and apoptosis induced by oxidative stress and several anti-cancer agents. Abnormal expression of mucins was observed in human carcinomas that arise in various gastrointestinal organs. It was widely believed that hepatocellular carcinoma (HCC) does not produce mucins, whereas cholangiocarcinoma (CC) or combined HCC-CC may produce these glycoproteins. However, a growing number of reports shows that mucins can be produced by HCC cells that do not exhibit or are yet to undergo, morphological differentiation to biliary phenotypes. Evaluation of mucin expression levels in precursors and early lesions of CC, as well as other types of primary liver cancer (PLC), conducted in in vitro and in vivo models, allowed to discover the mechanisms of their action, as well as their participation in the most important signalling pathways of liver cystogenesis and carcinogenesis. Analysis of mucin expression in PLC has both basic research and clinical value. Mucins may act as oncogenes and tumour-promoting (e.g., MUC1, MUC13), and/or tumour-suppressing factors (e.g., MUC15). Given their role in promoting PLC progression, both classic (MUC1, MUC2, MUC4, MUC5AC, MUC6) and currently tested mucins (e.g., MUC13, MUC15, MUC16) have been proposed to be important diagnostic and prognostic markers. The purpose of this review was to summarize and update the role of classic and currently tested mucins in pathogenesis of PLC, with explaining the mechanisms of their action in HCC carcinogenesis. It also focuses on determination of the diagnostic and prognostic role of these glycoproteins in PLC, especially focusing on HCC, CC and other hepatic tumours with- and without biliary differentiation.

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