Beyond the convergence of metabolic reprogramming in primary liver cancer: a comprehensive review on energy and lipids metabolism.

Hepatocellular carcinoma and cholangiocarcinoma, the most common primary liver cancers, are usually considered quite different pathologies. However, convergent metabolic reprogramming across different progenitor cells can result in similar molecular alterations and, even in a combined form of cancer that is characterized by transitional features and a shared phenotype. In this review, we summarize essential steps in glucose and lipid metabolism to distinguish similarities in glucose and energy metabolism reprogramming from divergent lipid remodeling in different types of primary liver cancers. We show the convergent nature of metabolic alterations in glucose decomposition and related mitochondrial enzymes. Also, we outline the essential role of lactate in promoting cell viability, adaptation to increased biomass synthesis, and fueling surrounding cancer cells to support their growth and proliferation. Lipid metabolism, in contrast, was found to be dramatically different between primary liver cancers. Hepatocellular carcinoma relies on de novo fatty acids synthesis, for which mitochondrial activity shifts from energy production to citrate efflux. Cholangiocarcinoma, in contrast, relies on fatty acids uptake from the extracellular space and, at later stages, even engages in beta-oxidation, which is uncharacteristic of hepatocellular carcinoma. This yields an altered lipid portrait for these pathologies despite the overall convergent alterations in energy metabolism. With this review, we provide not only fundamental insights for further primary liver tumor metabolism investigation, but also an emphasis on the independence of lipid alterations from energy metabolism reprogramming, vital for further basic and translational applications of metabolomics and lipidomics to a broad range of cancers.