Metabolic Alterations in Cancer and Their Potential as Therapeutic Targets

Abstract

Otto Warburg's discovery in the 1920s that tumor cells took up more glucose and produced more lactate than normal cells provided the first clues that cancer cells reprogrammed their metabolism. For many years, however, it was unclear as to whether these metabolic alterations were a consequence of tumor growth or an adaptation that provided a survival advantage to these cells. In more recent years, interest in the metabolic differences in cancer cells has surged, as tumor proliferation and survival have been shown to be dependent upon these metabolic changes. In this educational review, we discuss some of the mechanisms that tumor cells use for reprogramming their metabolism to provide the energy and nutrients that they need for quick or sustained proliferation and discuss the potential for therapeutic targeting of these pathways to improve patient outcomes.

Figure 1. Metabolic Reprogramming In Tumor Cells: The Warburg Effect

(A.) Under normoxic conditions, normal tissues convert the glycolytic product of pyruvate to Acetyl-CoA, which is used in the mitochondria for the TCA Cycle to begin the process of oxidative phosphorylation. In the absence of oxygen, pyruvate is converted to lactate and sustained anaerobic glycolysis is used to meet requirements for energy and nutrients. (B.) Tumor cells convert the majority of the glycolytic product pyruvate to lactate and replenish their nutrients and energy through sustained aerobic glycolysis., but maintain mitochondrial function and some oxidative respiration.

Figure 2. Metabolic Alterations In Renal Cell Carcinoma Subsets

Clear Cell RCC (blue background) frequently exhibits mutations in VHL, resulting in stabilization of HIFs and their transcriptional targets, including VEGF and GLUT1, and thus is characterized by increased angiogenesis and upregulated glycolysis. Mutations in FH and SDH in Papillary RCC (green background), inhibit completion of the TCA cycle and result in accumulation of fumarate and/or succinate. Chromophobe RCC (pink background) is rare, but associated with mutations in mitochondrial complex I enzymes, such as MT-ND5, leading to an inhibition of electron transport chain reactions and an accumulation of defective mitochondria.