Metabolic Reprogramming and Tumor Microenvironment Formation in Liver Cancer

Abstract

Liver cancer, or hepatocellular carcinoma (HCC), is the fifth most common and second most fatal cancer worldwide. HCC cells undergo extensive metabolic reprogramming to produce metabolites favoring tumor growth. Due to their metabolically active nature and hypoxia, HCC cells experience high level of oxidative stress which could damage different cellular components. HCC cells have multiple adaptation systems to overcome oxidative stress. HCC cells could decelerate the electron transfer in the mitochondria through the HIF/NDUFA4L2 pathway to reduce reactive oxygen species (ROS) production. Meanwhile, HCC cells could turn on their antioxidant (NADPH)-producing pathways including pentose phosphate pathway and folate cycle through NRF2 to counteract ROS. Recently, we found that metabolic reprogramming not only affects metabolites intracellularly but extracellularly. We found that extracellular AMP creates an immune-suppressive microenvironment in HCC by maintaining the myeloid-derived suppressor cells (MDSCs) in the tumor niche. Targeting the underlying molecular pathways represents an attractive therapeutic strategy for HCC.