Understanding the Intersections between Metabolism and Cancer Biology

Abstract

Transformed cells adapt metabolism to support tumor initiation and progression. Specific metabolic activities can participate directly in the process of transformation or support the biological processes that enable tumor growth. Exploiting cancer metabolism for clinical benefit requires defining the pathways that are limiting for cancer progression and understanding the context specificity of metabolic preferences and liabilities in malignant cells. Progress toward answering these questions is providing new insight into cancer biology and can guide the more effective targeting of metabolism to help patients.

Figure 1. Classification of reprogrammed metabolic activities

Some enzyme mutations result in perturbed metabolic activities or metabolite levels that contribute to cancer initiation (transforming activities). Mutations in oncogenes and tumor suppressor genes transform cells, in part, by activating proliferative signaling and/or by inducing broad changes in gene expression that favor cell proliferation, both of which induce metabolic reprogramming. Some metabolic alterations enable cancer progression while others are neutral and not required for cancer cell proliferation or survival. Enzyme mutations resulting in transforming activities may also induce metabolic network changes that are enabling or neutral for tumor progression.

Figure 2. Nutrient availability and the metabolic network both influence metabolic phenotypes

Both nutrient availability and metabolic network configuration affect how cells use metabolism to produce ATP, generate macromolecules, and regulate redox state. Key reactions in central carbon metabolism are shown, including how the TCA cycle and the electron transport chain are involved in purine and pyrimidine synthesis. Some of the reactions catalyzed by enzymes and metabolites discussed in this review are also shown for reference. PKM2, pyruvate kinase M2; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; PC, pyruvate carboxylase; IDH, isocitrate dehydrogenase; SDH, succinate dehydrogenase; FH, fumarate hydratase; GLS, glutaminase; DHODH, dihydroorotate dehydrogenase; Ox PPP, oxidative pentose phosphate pathway; Non-Ox PPP, non-oxidative pentose phosphate pathway; αKG, α-ketoglutarate; OAA, oxaloacetate; ROS, reactive oxygen species.

Figure 3. Role of redox cofactors in energy generation and biosynthesis

Cells rely on nutrient oxidation to generate ATP (energy), either through glycolysis or via NADH generation to fuel oxidative phosphorylation. Generating biomass can involve either nutrient reduction or nutrient oxidation. Continued nutrient oxidation requires cycling of NADH back to NAD+, which necessitates transfer of electrons to an electron acceptor such as oxygen.

Figure 4. Intrinsic and extrinsic influences on cancer cell metabolic reprogramming

Reprogrammed metabolic pathways, including pathways involved in bioenergetics, anabolism, and redox homeostasis are common features of tumor tissue. The metabolic phenotype of cancer cells is the cumulative result of a variety of processes both intrinsic and extrinsic to the malignant cell. An integrated understanding of the relative contributions of all processes, in the context of intact tumors, will be necessary to exploit metabolic reprogramming in the clinic. Both intrinsically and extrinsically regulated pathways provide opportunities for clinical translation, including new targets for therapy and for non-invasive imaging to detect and monitor cancer.