Metabolic control of tumor progression : contribution of glycolysis and monocarboxylate transporter 1 to tumor angiogenesis and tumor cell migration

Abstract

Cancer development is a multistep evolutionary process. On a temporal scale, the onset of hypoxia is an early event initially affecting tumor cells outgrowing their oxygen supply. It imposes a selection pressure promoting three main adaptations: (1) a glycolytic switch corresponding to uncoupling glycolysis from oxidative phosphorylation of the TCA cycle, thereby allowing oxygen-independent ATP production and further promoting cell proliferation; (2) an angiogenic switch corresponding to the initiation of vascular extension from preexisting blood vessels; and (3) a metastatic switch during which some cancer cells acquire the phenotypic characteristics necessary to escape from the primary tumor in order to colonize distant organs. In this thesis we hypothesized the existence of a necessary coordination between these three events, and focused on the influence of glycolysis on tumor angiogenesis and tumor cell migration. More particularly, we tested whether tumor progression could be promoted by lactate, the end-product of glycolysis, and monocarboxylate transporter 1 (MCT1), a lactate-proton symporter that primarily facilitates lactate uptake by tumor cells. We first found that glycolysis promotes tumor angiogenesis. Indeed, we documented that lactate is a pro-angiogenic agent that can activate the transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor and in endothelial cells. In these cells, lactate competes with 2-oxoglutarate to inhibit prolylhydroxylase-2 (PHD2), an enzyme normally inactivating HIF-1 under normoxia. Consequently, lactate activates several HIF-1-driven pro-angiogenic pathways in normoxic tumor and endothelial cells, thus mimicking hypoxia at distance from hypoxic sites. Based on this new knowledge, we evidenced that lactate signaling can be blocked when targeting MCT1, resulting in decreased tumor angiogenesis and tumor growth in vivo. MCT1 inhibitors simultaneously exert antimetabolic and anti-angiogenic effects, underlying the druggability of this pathway. We therefore studied the influence of the tumor microenvironment on the regulation of MCT1 and of its chaperone protein CD147/basigin, itself involved in the aggressive malignant phenotype. We found that glucose deprivation posttranslationally stabilizes MCT1-CD147 heterocomplexes at the plasma membrane of tumor cells, including in F-actin-positive cell protrusions normally involved in tumor cell migration. While on the one hand the response was evidenced to originate from a mitochondrial activity associated to the generation of reactive oxygen species (ROS), on the other hand MCT1-CD147 was shown to promote tumor cell migration towards glucose. Hence, the use of antioxidants but also importantly the pharmacological inhibition of MCT1 prevented the migration of glucose-starved tumor cells, making MCT1 inhibitors suitable antimigratory/antimetastatic drugs. From a translational point of view, our thesis work demonstrates that, in addition to its well-known antimetabolic effects, MCT1 inhibition exerts anti-angiogenic and antimigratory activities in tumors. The multimodal function of the transporter in tumors and its limited contribution to normal tissue physiology offers clinical relevance for the development of new, specific MCT1 inhibitors.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201