Aberrant Metabolism in Hepatocellular Carcinoma Provides Diagnostic and Therapeutic Opportunities

Abstract

Hepatocellular carcinoma (HCC) accounts for over 80% of liver cancer cases and is highly malignant, recurrent, drug-resistant, and often diagnosed in the advanced stage. It is clear that early diagnosis and a better understanding of molecular mechanisms contributing to HCC progression is clinically urgent. Metabolic alterations clearly characterize HCC tumors. Numerous clinical parameters currently used to assess liver functions reflect changes in both enzyme activity and metabolites. Indeed, differences in glucose and acetate utilization are used as a valid clinical tool for stratifying patients with HCC. Moreover, increased serum lactate can distinguish HCC from normal subjects, and serum lactate dehydrogenase is used as a prognostic indicator for HCC patients under therapy. Currently, the emerging field of metabolomics that allows metabolite analysis in biological fluids is a powerful method for discovering new biomarkers. Several metabolic targets have been identified by metabolomics approaches, and these could be used as biomarkers in HCC. Moreover, the integration of different omics approaches could provide useful information on the metabolic pathways at the systems level. In this review, we provided an overview of the metabolic characteristics of HCC considering also the reciprocal influences between the metabolism of cancer cells and their microenvironment. Moreover, we also highlighted the interaction between hepatic metabolite production and their serum revelations through metabolomics researches.

Figure 1

Metabolic reprogramming in HCC. Glucose enters the cancer cell via glucose transporters 1 and 2 (GLUT1 and GLUT2), and it is mainly used in the glycolytic pathway due to the overexpression of enzymes such as hexokinase 2 (HK2) and hexokinase domain containing 1 (HKDC1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and pyruvate kinase 2 (PK2). The glycolytic pathway mainly produces, by the overexpression of lactate dehydrogenase A (LDHA) isoform, lactate (Lac) which is transported outside of the cell mainly throughout the monocarboxylate transporter isoform 4 (MCT4). Fatty acids enter cancer cells thanks to the upregulation of fatty acid translocase CD36. Nevertheless, fatty acid synthesis can also start from acetate (Ace), which is transported in the cell by MCT and converted into acetyl-CoA (Ac-CoA) by the mitochondrial isoform of acetyl-CoA synthase 1 (ACSS1). Moreover, glutamine (Gln) takes part in lipid synthesis after conversion into glutamate by mitochondrial glutaminase enzymes (GLS/GLS2). Glutamate is then converted into α-ketoglutarate (αKG) which can enter the tricarboxylic acid (TCA) cycle. Alternatively, αKG can undergo a reductive carboxylation by which it is transformed in citrate in the mitochondria (red arrow) or in the cytosol. In glutamine-free conditions, pyruvate (Pyr) can be converted into oxaloacetate (OAA) by the anaplerotic reaction catalysed by pyruvate carboxylase (PyC) enzyme. The de novo fatty acids synthesis is increased in cancer cells, and it is associated with a high expression of key enzymes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). This latter metabolic pathway is associated to a high production of reducing equivalents in the form of reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is mainly produced in the first reaction of the pentose phosphate pathway (PPP) catalysed by glucose-6-phosphate dehydrogenase (G6PD) and by the malic enzyme (ME).

Figure 2

Metabolic connections between HCC and immune cells. Tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are the major components of tumor-infiltrate and are abundant in HCC microenvironment, with a key role in supporting tumor initiation, progression, angiogenesis, metastasis, and drug resistance. HCC cells acquire an altered metabolism resulting in increased levels of LDH and lactate that, on the one hand, promote TAM polarization in M2-like phenotype, favoring the EMT, cancer stem cell-like properties, and drug resistance, and, on the other hand, increase the number of MDSC and inhibit NK cell function.