Tumor Microenvironment: Necroptosis Switches the Subtype of Liver Cancer While Necrosis Promotes Tumor Recurrence and Progression

Liver cancer is a heterogeneous group of solid tumors that include mainly epithelial tumors. As with other solid carcinomas, tumor development results from an accumulation of genetic and epigenetic alterations. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma, derived from malignant transformation of hepatocytes and cholangiocytes, respectively, are 2 primary types of liver cancers. However, it has been shown that the same kind of cell can give rise to different types of cancer, depending on manner of cell death in the tumor microenvironment. In a recent animal study, hepatocytes gave rise to both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Oncogenically activated hepatocytes were shown to give rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending on cell death type of neighboring cells. Hepatocytes within the necroptotic microenvironment gave rise to intrahepatic cholangiocarcinoma; however, hepatocytes harboring the same oncogenic driver gave rise to hepatocellular carcinoma within the apoptotic microenvironment. The hepatic cytokine microenvironment structured by the necroptosis can also switch hepatocellular carcinoma to intrahepatic cholangiocarcinoma independently of the oncogenic drivers. Cell death by necrosis in damaged livers can also lead to development of carcinoma. Cancer cells are known to be resistant to apoptosis as a result of p53 mutation. Therefore, necrosis is the primary cell death pathway in cancer therapy. Necrosis is associated with high levels of angiogenesis, tumor-associated macrophages, and increased inflammation in the tumor microenvironment. Patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma characterized by necrosis and tumor-associated macrophages have reduced overall survival and recurrence-free survival. Cytotoxicity from anticancer therapy can also lead to accelerated necrosis. The content of cells undergoing necrosis triggers cytokine secretion, which designs cancer progression via inflammatory and noninflammatory pathways. Thus, the tumor microenvironment and manner of cell death (necrosis, apoptosis, or necroptosis) are crucial factors in the development of primary liver cancers and tumor progression.