Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts

Figure 1

Metabolic reprogramming of tumour microenvironment, a three-compartment model. Tumour growth and progression are sustained by a metabolic interplay between catabolic tumour cells, normal fibroblasts, and catabolic activated CAFs that contribute to the anabolic reprogramming of cancer cells. This crosstalk is mediated by ROS, soluble factors, energy-rich fuels, and catabolite transporters, such as monocarboxylate transporter 1 (MCT-1), monocarboxylate transporter 4 (MCT-4), and glucose transporter protein (GLUT-1). In particular, mitochondrial dysfunction in catabolic cancer cells is associated with glycolysis switch (“Warburg effect”). These catabolic tumour cells show an increase of glucose uptake, upregulation of NOX-1 and NOX-4, and high level both of ROS and energy-rich fuels extrusion. The differentiation of normal fibroblasts into activated CAFs is ROS modulated. ROS, produced by catabolic cancer cells, upregulate HIF-1α whose levels are also increased by the loss of caveolin-1 (Cav-1). These events are involved in CAFs glycolytic switch. Hence, CAFs show a catabolic phenotype characterized by an inhibition of OXPHOS, a reduction of proliferation marker Ki-67, and release of energy-rich fuels. These molecules, represented by lactate, pyruvate, ketone bodies, etc., feed cancer cells that acquire an anabolic phenotype, where the high request of ATP is satisfied by an efficient mitochondrial OXPHOS.