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

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.

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 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.

Figure 5.

The metabolic phenotypes associated with carcinogenesis and during latency—and their specific relationship(s) to both parental cell phenotypes and the metabolic hallmarks of established cancer—represent key knowledge gaps. Carcinogenic exposure(s) may not result in characteristic cancer phenotypes for years or even decades. It is not presently known, however, whether the classical hallmarks of metabolic reprogramming and dysregulated metabolism precede or follow development of other recognizable cancer phenotypes. Little is known about the metabolic phenotype(s) of cells or tissues destined to produce cancer during periods of latency between exposure and the development of overt histopathological changes. Where metabolic changes occur in this disease continuum remain to be established, and their direction, magnitude, reversibility and relationships to established cancer phenotypes will require careful characterization. Once delineated, it will be incumbent on future studies to establish whether or not such changes are binary and whether they are necessary and/or sufficient for cancer development.

Figure 6.

Direct and indirect genotoxic and non-genotoxic contributions to metabolic dysregulation. Genotoxicity may directly influence metabolism by mutagenic disruption of either metabolic gene product function (a) or cis-acting elements important for expression (b). By extension, genotoxicity may indirectly influence the same processes via disruption of upstream regulatory gene product function (c) or expression (d). Alternatively, genotoxic effects (e,f) may disrupt important epistatic interactions between distant genetic loci. Non-genotoxic effects (g,h) may also contribute to metabolic phenotype development. By definition, both direct and indirect genotoxic effects, as well as non-genotoxic effects, must interact with other dynamic drivers of metabolism to determine the ultimate metabolic phenotype. As a consequence, this phenotype may not always be fixed

Figure 7.

Possible hierarchical relationships between environmental exposures, carcinogenesis and metabolism. (A) Metabolic changes may be either a direct (d) or indirect (i) consequences of environmental exposure. Only those subsets of exposure associated with both carcinogenesis and dysregulated metabolism (i and d) are considered above. The metabolic hallmarks of cancer may represent either a cause (B) or a consequence (C) of cancer development. (D) In principle, associated metabolic changes could also represent epiphenomena arising in parallel but bearing no direct causal relationship to cancer development per se. The absence of such a direct causal relationship does not preclude important roles for adaptive metabolic selection advantages. Most experimental approaches to the study of metabolic reprogramming and dysregulated metabolism in cancer have not been designed to distinguish between these scenarios.