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.

Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

“…This observation goes beyond answering a biological question, as metformin is a widely used drug in patients with type 2 diabetes (Singh, 2014). Indeed, its inhibition of trained immunity might have undesired consequences on antimicrobial host defense; on the other hand, it may represent a potential new drug to be employed in certain inflammatory diseases with excessive inflammation (Robey et al, 2015; Singhal et al, 2014; Tan et al, 2015). In contrast to glycolysis, the oxidative branch of PPP does not seem to have a major impact on trained immunity.…”

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

“…Recent studies have shown that changes in cellular metabolism can alter the expression of specific microRNAs and promote epigenetic changes in tumor cells (Arora et al, 2015; Bishop and Ferguson, 2015; Chan et al, 2015). Although some of these interactions are mentioned above, in-depth discussions of all of the interactions that occur between cancer and metabolism are beyond the scope of this review and the reader is referred to a number of reviews on these subjects (Gatenby and Gillies, 2004; Vander Heiden et al, 2009; Cantor and Sabatini, 2012; Ward and Thompson, 2012; Semenza, 2013; Gaude and Frezza, 2014; Masson and Ratcliffe, 2014; Boroughs and DeBerardinis, 2015; Casey et al, 2015; Robey et al, 2015; Asati et al, 2016; Barron et al, 2016; Bost et al, 2016; Molon et al, 2016; Pavlova and Thompson, 2016; Pérez-Escuredo et al, 2016). The fact that metabolic dysregulation is seen in virtually all tumor cells has led to suggestions that a promising therapeutic strategy may be to exploit this feature.…”

Nrf2 and AhR in metabolic reprogramming after contaminant exposure

“…these observations, mechanistic studies in animal and cell models have shown that metabolic dysfunction upon contaminants exposure occurs in various cell type and tissue, such as liver, muscle, adipose tissue and skin [15][16][17]. Pollutant induced-metabolic reprogramming is characterized by alterations in glucose metabolism (reduced gluconeogenesis and glycogenogenolysis), lipid metabolism (stimulated lipogenesis and qualitative changes in lipid species), and a strong impairment in energy metabolism due, at least in part, to a major mitochondrial dysfunction [18].…”

“…The hierarchical relationship between AhR, metabolic reprogramming, and EMT/migration upon AhR remain to decipher. AhR ligands should be challenged in order to determine if the AhR-induced metabolic shift is required to achieve EMT and migration, or whether it is the AhR-induced EMT that triggers metabolic changes [18].…”