Sartorius, Kurt

Chronic hepatitis B virus (CHB) infection remains a major cause of hepatocellular carcinoma (HCC), yet the premalignant microenvironment that links to HBV-associated HCC (HBV-HCC) is still poorly defined. This review synthesizes evidence that HBV-infected hepatocytes function as signaling hubs that, through microRNA (miRNA)-regulated crosstalk with Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells and cancer-associated fibroblasts (CAFs), progressively remodel the liver from an antiviral tissue into a premalignant and early tumor microenvironment. Across the HBV-HCC continuum, a core set of dysregulated miRNAs, including miR-21, miR-29a/b, miR-122, miR-146a, miR-155, miR-200a, miR-126, miR-210 and the miR-130/301 family, coordinates transition from innate antiviral responses to HSC activation, extracellular matrix deposition, mechanotransduction, angiogenesis, chronic inflammation and cancer-associated CAF programing. By mapping these stage-specific miRNA networks onto acute infection, CHB, early fibrogenesis, advanced fibrosis and CAF-rich dysplastic states, the review reframes HBV-HCC pathogenesis as a sequence of miRNA-guided hepatocyte–stromal states rather than a purely hepatocyte-intrinsic process. This perspective suggests that composite, cell-type-resolved miRNA signatures in serum or liver tissue could serve as biomarkers for identifying CHB patients who are entering a premalignant microenvironment before conventional surveillance markers become abnormal. It further highlights miRNA hubs that couple antiviral, fibrogenic, angiogenic and CAF-associated signaling as potential therapeutic targets for reprograming the HBV-driven premalignant microenvironment, with the long-term goal of intercepting HBV-HCC development at earlier, microenvironmentally defined stages.

The incidence and mortality of hepatocellular carcinoma (HCC) in Sub-Saharan Africa is projected to increase sharply by 2040 against a backdrop of limited diagnostic and therapeutic options. Two large South African-based case control studies have developed a serum-based miRNome for Hepatitis B-associated hepatocellular carcinoma (HBV-HCC), as well as identifying their gene targets and pathways. Using a combination of RNA sequencing, differential analysis and filters including a unique molecular index count (UMI) ≥ 10 and log fold change (LFC) range > 2: <−0.5 (p < 0.05), 91 dysregulated miRNAs were characterized including 30 that were upregulated and 61 were downregulated. KEGG analysis, a literature review and other bioinformatic tools identified the targeted genes and HBV-HCC pathways of the top 10 most dysregulated miRNAs. The results, which are based on differentiating miRNA expression of cases versus controls, also develop a serum-based miRNA diagnostic panel that indicates 95.9% sensitivity, 91.0% specificity and a Youden Index of 0.869. In conclusion, the results develop a comprehensive African HBV-HCC miRNome that potentially can contribute to RNA-based diagnostic and therapeutic options.

Non-alcoholic fatty liver disease (NAFLD) is a fast-growing public health problem and predisposes to hepatocellular carcinoma (HCC) in a significant proportion of patients. Metabolic alterations might underlie the progression of NAFLD to HCC, but the magnitudes of risk and population-attributable risk fractions (PAFs) for various metabolic conditions that are associated with HCC risk in patients with NAFLD are unknown. We investigated the associations between metabolic conditions and HCC development in individuals with a prior history of NAFLD. The study included 11,245 participants in the SEER-Medicare database, comprising 1310 NAFLD-related HCC cases and 9835 NAFLD controls. We excluded individuals with competing liver diseases (e.g., alcoholic liver disease and chronic viral hepatitis). Baseline pre-existing diabetes mellitus, dyslipidemia, obesity, hypertension, hypothyroidism, and metabolic syndrome were assessed. Multivariable-adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). PAFs were also calculated for each metabolic condition. The results show that diabetes (OR = 2.39, 95% CI: 2.04–2.79), metabolic syndrome (OR = 1.73, 95% CI: 1.49–2.01), and obesity (OR = 1.62, 95% CI: 1.43–1.85) were associated with a higher HCC risk in individuals with NAFLD. The highest PAF for HCC was observed for pre-existing diabetes (42.1%, 95% CI: 35.7–48.5), followed by metabolic syndrome (28.8%, 95% CI: 21.7–35.9) and obesity (13.2%, 95% CI: 9.6–16.8). The major predisposing factors for HCC in individuals with NAFLD are diabetes mellitus, metabolic syndrome, and obesity, and their control would be critically important in mitigating the rising incidence of NAFLD-related HCC.

Gastric cancer (GC) is one of the most malignant neoplasms worldwide, accounting for about 770,000 deaths in 2020. The incidence of gastric cancer bone metastasis (GC-BM) is low, about 0.9–13.4%, and GC patients develop GC-BM because of a suitable bone microenvironment. Osteoblasts, osteoclasts, and tumor cells interact with each other, secreting cytokines such as PTHrP, RANK-L, IL-6, and other growth factors that disrupt the normal bone balance and promote tumor growth. The functions and numbers of immune cells in the bone microenvironment are continuously inhibited, resulting in bone balance disorder due to the cytokines released from destroyed bone and growing tumor cells. Patients with GC-BM are generally younger than 65 years old and they often present with a later stage of the disease, as well as more aggressive tumors. They usually have shorter overall survival (OS) because of the occurrence of skeletal-related events (SREs) and undetected bone destruction due to the untimely bone inspection. Current treatments of GC-BM focus mainly on gastric cancer and SRE-related treatment. This article reviews the clinical features, possible molecular pathogeneses, and the most commonly used diagnostic methods and treatments of bone metastasis in gastric cancer.

Abstract Hepatocellular carcinoma (HCC) is a disease of global public health significance with mortality on the rise, despite the preventable nature of its risk factors especially in Africa. It is now the sixth most common cancer worldwide, fifth in males, and ninth in females. HCC incidence and mortality are predicted to increase in African countries constrained by limited resources to combat endemic levels of viral infection and synergistic environmental risk factors. The changing nature of HCC etiology is particularly illustrated here with the traditional risk factors like viral hepatitis coexisting alongside high human immunodeficiency virus (HIV) prevalence and rapidly increasing urbanization that have promoted a sharp increase in additional risk factors like coinfection, type 2 diabetes mellitus, and obesity. Although there are some differences in etiology between North Africa and sub-Saharan Africa, risk factors like chronic viral hepatitis B and C, aflatoxin exposure, and iron overload predominate. Aggressive hepatitis B genotypes, combined with hepatitis B virus/hepatitis C virus/HIV coinfections and aflatoxin exposure, promote a more aggressive molecular phenotype. In parallel to a better understanding of the molecular etiology of HCC, policy and planning initiatives to address the burden of HCC must be anchored within the reality of the limited resources available. Establishment and coordination of cancer registries across Africa is needed to improve the quality of data necessary to galvanize action. Preventive measures including hepatitis B vaccination programs, measures to prevent maternal-to-child and child-to-child transmission, delivery of universally accessible antiretroviral and antiviral treatments, and reduction of dietary aflatoxin exposure can contribute markedly to reduce HCC incidence. Finally, the development of biomarkers and new therapeutic interventions will need a better understanding of the unique genetic and epigenetic characteristics of HCC on the continent. We present a narrative review of HCC in Africa, discussing present and future trends.