From MAFLD to hepatocellular carcinoma and everything in between.

ABSTRACT: Metabolic (dysfunction) associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease, is the most common cause of chronic liver disease worldwide. Many risk factors contribute to the pathogenesis of MAFLD with metabolic dysregulation being the final arbiter of its development and progression. MAFLD poses a substantial economic burden to societies, which based on current trends is expected to increase over time. Numerous studies have addressed various aspects of MAFLD from its risk associations to its economic and social burden and clinical diagnosis and management, as well as the molecular mechanisms linking MAFLD to end-stage liver disease and hepatocellular carcinoma. This review summarizes current understanding of the pathogenesis of MAFLD and related diseases, particularly liver cancer. Potential therapeutic agents for MAFLD and diagnostic biomarkers are discussed.

Aptamer-mediated doxorubicin delivery reduces HCC burden in 3D organoids model.

Epithelial cell adhesion molecule (EpCAM) is a surface marker which is frequently overexpressed in hepatocellular carcinoma (HCC) but minimally expressed on mature hepatocytes. We developed a specific aptamer against EpCAM (EpCAM-apt) and tested its potential as a drug delivery agent for HCC. The targeting ability of EpCAM-apt was confirmed in vitro and in vivo after which the complex was conjugated with doxorubicin (Dox) to form EpCAM-apt-Dox. The targeting efficacy of the drug-loaded complex against liver cancer stem-like cells (LCSCs) and therapeutic effects in HCC were evaluated. EpCAM-expressing (EpCAM+) HCC cells showed characteristics of stem like cells including greater proliferative capacity and tumour sphere formation. EpCAM-apt-Dox selectively delivered Dox to EpCAM+ HCC cells with high drug retention and accumulation versus control. EpCAM-apt-Dox reduced the self-renewal capacity and stem-like cell frequency in vitro. Elimination of cancer stem-like cells (CSCs) with EpCAM-apt-Dox significantly inhibited the growth of HCC cells and patient-derived HCC organoids but exerted minimal cytotoxicity to normal liver organoids. Moreover, EpCAM-apt-Dox suppressed the growth of xenograft tumours derived from HCC organoids in vivo and prolonged mouse survival without inducing adverse effects to major organs. Thus, aptamer-based drug delivery to the stem-like cell population is a promising strategy for HCC treatment.

Role of the constitutive androstane receptor (CAR) in human liver cancer.

BACKGROUND: The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily (subfamily 1, group I, member 3, also known as NR1I3) that is almost exclusively expressed in the liver. CAR interacts with key signalling pathways such as those involved in drug, energy and bilirubin metabolism. In mouse models, activation of CAR leads to tumorigenesis by inducing pro-proliferative and anti-apoptotic signalling. However, many previous reports have shown species differences between CAR activity in animal models and humans. Recent studies have demonstrated that the mode of action of CAR in rodent liver tumorigenesis is not applicable to humans. Despite this, many studies still continue to study the role of CAR in animal models, hence, there is a need to further explore the role of CAR in human diseases particularly cancers. While there is limited evidence for a role of CAR in human cancers, some studies have proposed a tumour-suppressive role of CAR in liver cancer. In addition, recent studies exploring CAR in human livers demonstrated a hepato-protective role for CAR in and more specifically, its ability to drive differentiation and liver regeneration. This review will discuss the role of CAR in liver cancer, with a focus on species differences and its emerging, tumour-suppressive role in liver cancer and its role in the regulation of liver cancer stem cells.

The Application of Induced Pluripotent Stem Cells Against Liver Diseases: An Update and a Review.

Liver diseases are a major health concern globally, and are associated with poor survival and prognosis of patients. This creates the need for patients to accept the main alternative treatment of liver transplantation to prevent progression to end-stage liver disease. Investigation of the molecular mechanisms underpinning complex liver diseases and their pathology is an emerging goal of stem cell scope. Human induced pluripotent stem cells (hiPSCs) derived from somatic cells are a promising alternative approach to the treatment of liver disease, and a prospective model for studying complex liver diseases. Here, we review hiPSC technology of cell reprogramming and differentiation, and discuss the potential application of hiPSC-derived liver cells, such as hepatocytes and cholangiocytes, in refractory liver-disease modeling and treatment, and drug screening and toxicity testing. We also consider hiPSC safety in clinical applications, based on genomic and epigenetic alterations, tumorigenicity, and immunogenicity.

Application of organoids in translational research of human diseases with a particular focus on gastrointestinal cancers.

Gastrointestinal (GI) cancers constitute the largest portion of all human cancers and represent a significant health burden on modern society. Conventional therapeutic approaches such as chemotherapy and surgical resections often fail due to poor treatment response or tumour relapse. Unfortunately, drug discovery for GI cancers has stalled as current cancer models fail to recapitulate critical features of the parent tumour, leading to poor translation from bench to bedside. Recent advances in three-dimensional (3D) cell culturing techniques have driven the surge of interest in stem cell-derived organoid models, a promising platform with a plethora of potential applications due to its ability to retain crucial architectural, genomic and transcriptional properties of the native tissue. In this review article, we discuss current applications and advantages of organoid models in the translational research of GI cancers with a particular focus on primary liver cancer that currently lack effective curative treatments.