Targeting Wnt/β-Catenin Pathways in Primary Liver Tumours: From Microenvironment Signaling to Therapeutic Agents

SIMPLE SUMMARY: Human primary liver cancers have a poor prognosis. At present, there are limited treatment alternatives, and to understand the molecular aspects of liver tumorigenesis it is essential to develop more efficient pharmaceutic modalities. Liver tumors have mutations in genes encoding key components of Wnt/β-catenin signaling, and two different molecular pathways have been identified, termed non-canonical and canonical networks. In this review, we discuss the dysregulation of the Wnt/β-catenin signaling network, especially in hepatocellular carcinoma, in cholangiocarcinoma and in patients with hepatoblastoma. Based on the current literature we propose an update of molecular mechanisms focusing on Wnt/β-catenin pathways in physiological conditions and in human primary liver carcinomas, together with an overview of preclinical and clinical studies. The clinical implication of Wnt inhibitors in association with conventional surgical and lo-co-regional therapies is reviewed. ABSTRACT: Primary liver cancers (PLCs) are steadily increasing in incidence and mortality in the world. They have a poor prognosis due to their silent nature, late discovery and resistance to common chemotherapy. At present, there are limited treatment alternatives, and the understanding of PLC molecular aspects is essential to develop more efficient drugs and therapeutic surgical and loco-regional strategies. A clear causal link with liver damage, inflammation, and regeneration has been found in the occurrence of PLC over the last few decades. Physiologically, Wingless/It (Wnt)-β-catenin signaling plays a key role in liver development, metabolic zonation and regeneration. Loss of functional homeostasis of this pathway appears to be a major driver of carcinogenesis in the liver parenchyma. In the hepatic microenvironment, molecular deregulations that exceed the Wnt signaling biological capacity can induce tumor initiation and progression. Indeed, somatic mutations are identified in key components of canonical and non-canonical Wnt signaling and in PLCs and precancerous lesions. In this review, the altered functions of Wnt/β-catenin signaling are considered in human PLCs, with emphasis on hepatocellular carcinomas (HCC), cholangiocarcinomas (CCA) and hepatoblastomas (HB). Based on recent literature, we also focused on liver cancerogenesis through Wnt deregulation. An overview of preclinical and clinical studies on approved and experimental drugs, targeting the Wnt/β-catenin cascade in PLCs, is proposed. In addition, the clinical implication of molecule inhibitors that have been shown to possess activity against the Wnt pathway in association with conventional surgical and loco-regional therapies are reviewed.