Tumor Metabolic Reprogramming: Mechanisms, Regulatory Networks, And Therapeutic Opportunities

Abstract

Metabolic reprogramming is one of the basic hallmarks of malignant tumors—that is, a whole set of adaptive responses by which tumor cells organize their metabolism in a way that suits fluctuating microenvironments, permits unchecked growth, and helps them withstand treatment pressures. Contrary to normal cells, which in general depend upon mitochondrial oxidative phosphorylation for energy generation under aerobic circumstances, tumor cells usually get their energy via glycolysis even if they are exposed to large amounts of oxygen (a situation called the Warburg effect).But now it is clear that tumor metabolic reprogramming is not just an exaggerated form of glycolysis, nor merely a localized change—rather, it entails an organized readjustment of several pathways (of glucose, of lipids, of amino acids, or of nucleotides). From the molecular standpoint, the basic regulatory factors HIF-1, MYC, p53, and mTORC1 are part of a complex signaling system which brings together nutrient sensing and signals for cancer as well as for transcriptional control. At the microenvironment level, interactions of all three kinds—tumor cells, immune cells, and fibroblasts linked to cancer—help to shape (often unfavorably) the local immunological situation. From the standpoint of clinical translational research, a number of approaches—lactate transporter inhibitors, fatty acid synthase inhibitors, and glutaminase inhibitors—related to metabolic vulnerability are now being tested clinically. The present work analyzes in detail the molecular bases, control circuits, interactions with the microenvironment, and treatment options for tumor metabolic reprogramming, as well as the main difficulties and likely developments connected with this area of study.