Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

R Brooks Robey 1, Judith Weisz 2, Nancy B Kuemmerle 3, Anna C Salzberg 2, Arthur Berg 2, Dustin G Brown 4, Laura Kubik 5, Roberta Palorini 6, Fahd Al-Mulla 7, Rabeah Al-Temaimi 7, Annamaria Colacci 8, Chiara Mondello 9, Jayadev Raju 10, Jordan Woodrick 11, A Ivana Scovassi 9, Neetu Singh 12, Monica Vaccari 8, Rabindra Roy 11, Stefano Forte 13, Lorenzo Memeo 13, Hosni K Salem 14, Amedeo Amedei 15, Roslida A Hamid 16, Graeme P Williams 17, Leroy Lowe 18, Joel Meyer 5, Francis L Martin 19, William H Bisson 20, Ferdinando Chiaradonna 6, Elizabeth P Ryan 4

Affiliations

06 January 2015

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doi: 10.1093/carcin/bgv037

Abstract

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.

Figures

Figure 1. Dysregulated metabolism in cancer development due to environmental exposures and potential relationships to other cancer hallmarks. The specific sequence, priority and relevance of reprogramming and dysregulated metabolism in the (often decades-long) carcinogenic continuum between environmental exposures and cancer development are incompletely understood. Specific relationships between altered metabolism and other cancer hallmarks are also poorly delineated. Much of our specific knowledge of cancer metabolism is largely associative in nature, and a deeper understanding of the numerous remaining mechanistic ‘black boxes’ (A) is needed before specific metabolic changes can be optimally exploited for preventative or therapeutic benefit. For example, it is not clear whether altered metabolism is a cause or a consequence of cancer development—or both. In principle, the contributions of metabolism to carcinogenesis may operate in series (B, C), in parallel (D, E) or even in opposition (E) to the contributions of other hallmarks of cancer (e.g. via modulation of oxidative stress). Temporally, changes in metabolism may also precede (C), follow (B) or coincide with (D, E) other key determinants of the carcinogenic program. Since metabolism is not a singular entity, the specific type of relationship observed for a given aspect of metabolism is not mutually exclusive of different types of relationships with other aspects of metabolism.

Figure 1. Dysregulated metabolism in cancer development due to environmental exposures and potential relationships to other cancer hallmarks. The specific sequence, priority and relevance of reprogramming and dysregulated metabolism in the (often decades-long) carcinogenic continuum between environmental exposures and cancer development are incompletely understood. Specific relationships between altered metabolism and other cancer hallmarks are also poorly delineated. Much of our specific knowledge of cancer metabolism is largely associative in nature, and a deeper understanding of the numerous remaining mechanistic ‘black boxes’ (A) is needed before specific metabolic changes can be optimally exploited for preventative or therapeutic benefit. For example, it is not clear whether altered metabolism is a cause or a consequence of cancer development—or both. In principle, the contributions of metabolism to carcinogenesis may operate in series (B, C), in parallel (D, E) or even in opposition (E) to the contributions of other hallmarks of cancer (e.g. via modulation of oxidative stress). Temporally, changes in metabolism may also precede (C), follow (B) or coincide with (D, E) other key determinants of the carcinogenic program. Since metabolism is not a singular entity, the specific type of relationship observed for a given aspect of metabolism is not mutually exclusive of different types of relationships with other aspects of metabolism.

Figure 2. Selected metabolic pathways and targets implicated in cancer development and progression. Major interactions between Glc and lipid metabolism are highlighted, and the fundamental interchangeability of corresponding metabolic intermediates with amino acid metabolism via the major amphibolic pathways, glycolysis and the TCA cycle, is indicated. Gln and Ser metabolism and coupled processes such as glyceroneogenesis and one-carbon metabolism are not depicted but are addressed in the text. Major anaplerotic inputs needed to counterbalance cataplerotic carbon losses from the TCA cycle are indicated by dashed arrows. Major transport mechanisms for the transcellular movement of Glc (GLUT), amino acids (l-type amino acid transporters [LAT], A-type Na+-linked amino acid transporters [SNAT]), FA (CD36) and monocarboxylates such as pyruvate and lactate (monocarboxylate transporters [MCT]) are also depicted. Both intracellular (MAGL, SCD) and extracellular (LPL) lipases are responsible for the liberation of FA moieties from more complex intracellular and extracellular lipids such as TAG and lysophospholipids.

Figure 2. Selected metabolic pathways and targets implicated in cancer development and progression. Major interactions between Glc and lipid metabolism are highlighted, and the fundamental interchangeability of corresponding metabolic intermediates with amino acid metabolism via the major amphibolic pathways, glycolysis and the TCA cycle, is indicated. Gln and Ser metabolism and coupled processes such as glyceroneogenesis and one-carbon metabolism are not depicted but are addressed in the text. Major anaplerotic inputs needed to counterbalance cataplerotic carbon losses from the TCA cycle are indicated by dashed arrows. Major transport mechanisms for the transcellular movement of Glc (GLUT), amino acids (l-type amino acid transporters [LAT], A-type Na+-linked amino acid transporters [SNAT]), FA (CD36) and monocarboxylates such as pyruvate and lactate (monocarboxylate transporters [MCT]) are also depicted. Both intracellular (MAGL, SCD) and extracellular (LPL) lipases are responsible for the liberation of FA moieties from more complex intracellular and extracellular lipids such as TAG and lysophospholipids.

Figure 3. Major cellular metabolic coupling mechanisms. Energetic coupling between ATP generating mechanisms (i.e. glycolysis and the TCA cycle) and cellular adenosine triphosphatase (ATPase) activity is depicted (left panel). General redox coupling mechanisms for both the PPP (G6PDH and 6PD; upper center panel) and glycolytic (GAPDH, upper right panel) flux are similarly depicted alongside representative competing NAD(P)H-regenerating mechanisms (unshaded boxes). Ongoing metabolic flux through these pathways and cellular energy homeostasis are critically dependent upon the maintenance of these coupling mechanisms.

Figure 3. Major cellular metabolic coupling mechanisms. Energetic coupling between ATP generating mechanisms (i.e. glycolysis and the TCA cycle) and cellular adenosine triphosphatase (ATPase) activity is depicted (left panel). General redox coupling mechanisms for both the PPP (G6PDH and 6PD; upper center panel) and glycolytic (GAPDH, upper right panel) flux are similarly depicted alongside representative competing NAD(P)H-regenerating mechanisms (unshaded boxes). Ongoing metabolic flux through these pathways and cellular energy homeostasis are critically dependent upon the maintenance of these coupling mechanisms.

Figure 4. (A) Oxidant stress reflects the dynamic balance between oxidant stressors (e.g. ROS) and antioxidant coping mechanisms. As such, unmatched primary increases in ROS or primary decreases in antioxidant capacity—or both—may lead to phenotypically indistinguishable increases in net oxidant stress. (B) Intermediary metabolism contributes to both ROS generation and opposing antioxidant coping mechanisms. Imbalances resulting in net oxidant stress can lead to oxidative modification of macromolecules, organelles and cellular effectors with functional consequences that directly or indirectly contribute to cancer development (highlighted area). Net oxidant stress can also feedback to influence metabolic flux and thereby attenuate or intensify these contributions.

Figure 4. (A) Oxidant stress reflects the dynamic balance between oxidant stressors (e.g. ROS) and antioxidant coping mechanisms. As such, unmatched primary increases in ROS or primary decreases in antioxidant capacity—or both—may lead to phenotypically indistinguishable increases in net oxidant stress. (B) Intermediary metabolism contributes to both ROS generation and opposing antioxidant coping mechanisms. Imbalances resulting in net oxidant stress can lead to oxidative modification of macromolecules, organelles and cellular effectors with functional consequences that directly or indirectly contribute to cancer development (highlighted area). Net oxidant stress can also feedback to influence metabolic flux and thereby attenuate or intensify these contributions.

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