Rôle du métabolisme du glucose dans le phénotype tumoral hépatocytaire

Hepatocellular carcinoma (HCC) is a morphologically and functionally heterogeneous cancer. For several decades, the involvement of glucose metabolism in tumor cells has been widely studied and several key features have been observed including increased glucose consumption, increased lactate production, or a "metabolic switch" more commonly known as the Warburg effect. The adaptability of cancer cells in a nutrient-restricted microenvironment becomes evident since they can easily modify their metabolic phenotype under different conditions. On the other hand, the intense metabolic activity displayed by the liver complicates the detection of primary tumor foci by clinical imaging especially by positron emission tomography (PET). This medical imaging technique, based on the substantial ability of neoplastic cells to consume large amounts of glucose, does not efficiently allow to differentiate between healthy and HCC tumor cells. Therefore, studies closely related to the metabolism of HCC cells are of great interest not only to understand their glucose dependence but also their capacity to adapt to a harsh microenvironment. The main objective of this project was to functionally characterize HCC cells by comparing their metabolism to that of non-tumor cells. In this context, we first studied primary cultures of normal hepatocytes as control cells: we demonstrated that major metabolic alterations occurred immediately after hepatocytes are removed from the liver and that these changes could persist or increase during culture. Indeed, a drastic decrease in metabolites related to antioxidative stress, Krebs cycle activity (TCA) and energy production was noted, accompanied by a significant reduced respiratory capacity when compared to liver cells in situ. The study of HCC Dt81Hepa1-6 cells, a derivative of Hepa1-6 cells, demonstrated enhanced tumorigenicity in vivo when compared to their parental cell line. Furthermore, we showed that the tumorigenic potential of these Dt81Hepa1-6 cells was partly based on their capacity to uptake surrounding glucose but also on their ability to use their stored fatty acids under glucose-restricted conditions. Targeting HCC Dt81Hepa1-6 cell metabolic reprogramming by sodium oxamate, a known inhibitor of lactate dehydrogenase (LDH), not only confirmed their greater metabolic plasticity with decreased tumorigenicity but also increased mortality when combined with cisplatinium (CP). Moreover, the association of glycolytic gene overexpression with increased tumorigenicity and mortality in patients with HCC led us to consider the possibility of targeting the metabolic processes used by highly tumorigenic HCC cells to potentiate the effectiveness of current chemotherapeutic drugs. Metabolomic analysis also allowed us to note that besides the intrinsic ability of Dt81Hepa1-6 cells to efficiently adapt to their microenvironment, HCC cells rapidly display a metabolic strategy by preferentially activating some specific metabolic pathways that favors their tumorigenicity both in vitro and in vivo. Therefore, we have been able to identify a metabolic signature associated with increased tumorigenicity in HCC that heralds glycolytic and hypoxia pathways as being critical.

Keyphrases: Glucose, Hepatocellular carcinoma, Metabolism, Adaptability, Tumorigenicity