Selvaggi Federico, Catalano Teresa, Cotellese Roberto, Aceto Gitana Maria
Unit of General Surgery, Ospedale Floraspe Renzetti, 66034 Lanciano, Chieti, Italy.
Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy.
Cancers (Basel). 2022 Apr 10;14(8):1912. doi: 10.3390/cancers14081912.
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.
原发性肝癌（PLCs）在全球的发病率和死亡率正稳步上升。由于其隐匿性、发现较晚以及对常规化疗耐药，其预后较差。目前，治疗选择有限，了解PLC的分子层面对于开发更有效的药物以及治疗性手术和局部区域治疗策略至关重要。在过去几十年中，已发现PLC的发生与肝损伤、炎症和再生之间存在明确的因果关系。生理上，无翅型/整合型（Wnt）-β-连环蛋白信号通路在肝脏发育、代谢分区和再生中起关键作用。该信号通路功能稳态的丧失似乎是肝实质致癌的主要驱动因素。在肝脏微环境中，超过Wnt信号生物学能力的分子失调可诱导肿瘤发生和进展。事实上，在经典和非经典Wnt信号通路的关键成分以及PLC和癌前病变中已发现体细胞突变。在本综述中，我们将探讨Wnt/β-连环蛋白信号通路在人类PLC中的功能改变，重点关注肝细胞癌（HCC）、胆管癌（CCA）和成肝细胞癌（HB）。基于最近的文献，我们还聚焦于Wnt失调导致的肝癌发生机制。本文概述了针对PLC中Wnt/β-连环蛋白级联反应的已批准和实验性药物的临床前和临床研究。此外，还综述了已证明对Wnt通路具有活性的分子抑制剂与传统手术和局部区域治疗联合应用的临床意义。
