Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

SIMPLE SUMMARY: The progression of liver tumors is highly influenced by the interactions between cancer cells and the surrounding environment, and, consequently, can determine whether the primary tumor regresses, metastasizes, or establishes micrometastases. In the context of liver cancer, cell death is a double-edged sword. On one hand, cell death promotes inflammation, fibrosis, and angiogenesis, which are tightly orchestrated by a variety of resident and infiltrating host cells. On the other hand, targeting cell death in advanced hepatocellular carcinoma could represent an attractive therapeutic approach for limiting tumor growth. Further studies are needed to investigate therapeutic strategies combining current chemotherapies with novel drugs targeting either cell death or the tumor microenvironment. ABSTRACT: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the contribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorigenesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution.