Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development
Introduction
The generation of ATP from glucose is an essential eukaryote cellular process that results in either the production of lactate via glycolysis or carbon dioxide and water via oxidative phosphorylation (OXPHOS) [1]. Also, yeast which are eukaryote facultative anaerobes can perform alcoholic fermentation, but this will not be discussed further because the focus of this review is on the metabolism of the different cell types in human tumors. Cells utilize glucose to generate ATP, maintain redox equilibrium, or generate biomass [2]. Non-cancer or normal cells and tissues rely primarily on OXPHOS, which takes place in the mitochondria and is the more energetically efficient process; only in the absence of oxygen do non-cancer cells shift to glycolysis [3]. It has long been recognized that cancer cell metabolism differs from that of non-cancer cells [4]. However, the exact nature of the difference continues to be elucidated and debated.
German scientist Otto Warburg proposed his influential theory of tumor cell metabolism in the 1920s. He and his colleagues observed that, even in the presence of adequate oxygen, tumor cells utilized more glucose and produced more lactate than surrounding normal cells; a process that they coined “aerobic glycolysis” [5]. As an explanation for why tumor cells would favor this relatively inefficient process, Warburg hypothesized that they must have dysfunctional mitochondria that are irreversibly damaged [6]. A very small group of familial human cancers, which include paragangliomas and renal cell cancers, have irreversible mitochondrial damage because of mutations in the tricarboxylic acid cycle enzymes succinate dehydrogenase and fumarate hydratase [7], [8]. Despite evidence that the majority of cancer cell mitochondria are not dysfunctional and that many different tumor metabolic profiles exist, this theory, known as the “Warburg Effect,” has been a prevailing theory of tumor metabolism [9], [10], [11].
The Warburg Effect only partially explains tumor metabolism. Studies have shown that there is metabolic heterogeneity within tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize OXPHOS [2], [9], [12]. This is made possible by a complex interplay between different metabolic compartments. Interactions between cancer cells and cells in the tumor microenvironment allow metabolites to be shifted from stromal cells to meet metabolic demands and maintain ATP production in cancer cells [2]. A newer theory, termed the “Reverse Warburg Effect,” describes a two-compartment model in which stromal cells are induced by cancer cells to undergo “aerobic glycolysis” and then transfer the products back to the cancer cells for utilization for mitochondrial OXPHOS [1], [13], [14], [15]. This cellular metabolic coapting of stromal and cancer cells allows tumors to respond to variations in nutrient availability to maximize cellular proliferation and growth [2].
Section snippets
Mitochondrial OXPHOS in the cancer cell
Contrary to Warburg’s hypothesis, cancer cells have increased mitochondrial activity in a subgroup of human cancers [4], [11], [16], [17], [18], [19], [20], [21]. TOMM20 (translocase of outer mitochondrial membrane 20) is the receptor subunit of the mitochondrial membrane import pore, which allows the import of nuclear encoded OXPHOS subunits and induces OXPHOS [22]. TOMM20 can be stained by immunohistochemistry, and has been used as a marker of mitochondrial mass and metabolic activity [23].
Monocarboxylate transporters (MCTs)
The monocarboxylate transporters (MCTs) are a family of proton-linked membrane transporters that are responsible for the movement of single-carboxylate molecules, such as lactate and pyruvate, in and out of cells. Fourteen MCTs have been identified; however, only MCTs 1–4 are able to transport monocarboxylates bidirectionally [27]. Both MCT1 and MCT4 have been identified as playing an important role in the metabolic relationship between cancer cells and fibroblasts [1], [28], [29], [30], [31].
Caveolin-1, HIF1A, and NF-kB
Caveolae are plasma membrane invaginations that are considered a distinct subset of plasma membrane lipid rafts. Coated by unique proteins called caveolins, caveolae are found on multiple different cells types, including endothelial cells, fibroblasts, muscle cells, and adipocytes, and have been shown to be involved in cell signaling, among other functions [49]. The caveolin family of proteins consists of three members, caveolin-1 (CAV1), caveolin-2 (CAV2), and caveolin-3 (CAV3). Here, we focus
Tigar
The p53 tumor suppressor gene has long been recognized as a mediator of cell cycle arrest, apoptosis, and the cellular response to hypoxia. More recently, however, p53 has been shown to play a role in cellular metabolism. In 2006, Bensaad et al [63] described a novel protein called TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR), a glycolytic inhibitor that is regulated by p53. It functions as a bisphosphatase that decreases the level of the key glycolytic
Clinical Implications
There are potential clinical implications associated with the expanding knowledge of tumor metabolic heterogeneity. From a prognostic standpoint, markers of metabolism may be useful in predicting disease behavior and outcomes. For example, in triple negative breast cancer, high expression of MCT1 on carcinoma cells has been associated with decreased PFS and increased risk of recurrence [34]; in cytogenetically normal AML, high TIGAR expression has been correlated with decreased survival [69];
Conclusion
The metabolic heterogeneity that exists within a tumor allows cancer and stromal cells to couple and transfer metabolites between them to support maximal cellular growth. Recognition of this complex dynamic has led to the development of a model of tumor metabolism, referred to as the “Reverse Warburg Effect.” Along with it, new prognostic markers and therapeutic targets have been identified. Exploiting the metabolic differences between cancer and stromal cells may have a therapeutic effect that
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