Pathogenesis to management of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. Although early-stage HCC can be potentially curable through liver resection, liver-directed therapies, or transplantation, patients usually present with intermediate to advanced disease, which continues to be associated with a poor prognosis. This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models. These efforts ultimately aim to develop clinically relevant biomarkers and discover molecular targets for new therapies. For example, until recently, there was only one approved systemic therapy for advanced or metastatic HCC in the form of sorafenib. Through these efforts, several additional targeted therapies have gained approval in the United States, although much progress remains to be desired. This review will focus on the link between characterizing the pathogenesis of HCC with current and future HCC management.

Keywords: HCC management; genomic heterogeneity; pathogenesis; targeted therapy.

Figure 1. The liver diseases and cancer continuum.

Advances in the prevention, early detection, and prognostication of HCC through epidemiological studies, histological classification, genomics, biomarkers, and animal models will enable risk stratification and improved patient management.

Figure 2. Laboratory research to clinical research pathway.

The goal is to start with laboratory research in mouse models, translate relevant findings to human hepatocellular carcinoma, and finally arrive at testable new clinical therapeutics that will impact future cancer management.

Figure 3. Barcelona clinic liver cancer (BCLC): update on staging, prognostication and treatment.

Adapted from: Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado A,Kelley RK et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J of Hepatology 2022; 76:681–93. Abbreviations: LT: liver transplant; PS: Eastern Cooperative Oncology Group performance status; TACE: transarterial chemoembolization.

Figure 4. Molecular pathways and targeted therapeutics in hepatocellular carcinoma.

Abbreviations: APC: antigen presenting cell; AXL is a cell surface receptor tyrosine kinase, part of the TAM family of kinases; CD: cluster differentiation; CTLA4: cytotoxic T-lymphocyte–assoc+iated antigen 4; ERK: extracellular signal-regulated kinase; FGFR: Fibroblast growth factor receptors; KIT: tyrosine-protein kinase; MEK: mitogen-activated protein kinase; MET: Mesenchymal Epithelial Transition; PDGFR: platelet-derived growth factor receptor; PD-L1: Programmed cell death ligand 1; RAF: rapidly accelerated fibrosarcoma; Tie2 is a receptor tyrosine kinase; VEGF: Vascular endothelial growth factor.