Elsevier

Seminars in Oncology

Volume 44, Issue 3, June 2017, Pages 198-203
Seminars in Oncology

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

https://doi.org/10.1053/j.seminoncol.2017.10.004Get rights and content

abstract

Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis, or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation. Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize oxidative phosphorylation. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation, and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate, and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism, are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.

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

References (107)

  • M.L. Goodwin et al.

    Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment

    Cancer Cell

    (2014)
  • M.S. Ullah et al.

    The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism

    J Biol Chem

    (2006)
  • J.M. Johnson et al.

    MCT1 in invasive ductal carcinoma: monocarboxylate metabolism and aggressive breast cancer

    Front Cell Dev Biol

    (2017)
  • L. Yang et al.

    Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth

    Cell Metab

    (2016)
  • Z.T. Schug et al.

    Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress

    Cancer Cell

    (2015)
  • T. Valencia et al.

    Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis

    Cancer Cell

    (2014)
  • H. Zhang et al.

    Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia

    J Biol Chem

    (2008)
  • G. Garcia-Cardena et al.

    Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo

    J Biol Chem

    (1997)
  • N. Erez et al.

    Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner

    Cancer Cell

    (2010)
  • K. Bensaad et al.

    TIGAR, a p53-inducible regulator of glycolysis and apoptosis

    Cell

    (2006)
  • Y.H. Ko et al.

    TIGAR metabolically reprograms carcinoma and stromal cells in breast cancer

    J Biol Chem

    (2016)
  • C. Wanka et al.

    Tp53-induced glycolysis and apoptosis regulator (TIGAR) protects glioma cells from starvation-induced cell death by up-regulating respiration and improving cellular redox homeostasis

    J Biol Chem

    (2012)
  • K.Y. Won et al.

    Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer

    Hum Pathol

    (2012)
  • A.K. Witkiewicz et al.

    An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers

    Am J Pathol

    (2009)
  • M.Y. El-Mir et al.

    Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I

    J Biol Chem

    (2000)
  • D.Y. Gui et al.

    Environment dictates dependence on mitochondrial complex I for NAD+ and aspartate production and determines cancer cell sensitivity to metformin

    Cell Metab

    (2016)
  • X. Liu et al.

    Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers

    Cell Metab

    (2016)
  • K. Fowdar et al.

    The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: a meta-analysis and systematic review

    Heart Lung

    (2017)
  • G. Wu et al.

    Glutathione metabolism and its implications for health

    J Nutr

    (2004)
  • M. Skrtic et al.

    Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia

    Cancer Cell

    (2011)
  • Y. Kim et al.

    Expression of lactate/H(+) symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses

    Hum Pathol

    (2015)
  • C.S. Hong et al.

    MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4

    Cell Rep

    (2016)
  • U.E. Martinez-Outschoorn et al.

    Cancer metabolism: a therapeutic perspective

    Nat Rev Clin Oncol

    (2017)
  • C.S. Ahn et al.

    Mitochondria as biosynthetic factories for cancer proliferation

    Cancer Metab

    (2015)
  • O. Warburg

    On the origin of cancer cells

    Science

    (1956)
  • O. Warburg

    On respiratory impairment in cancer cells

    Science

    (1956)
  • M. Sciacovelli et al.

    Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition

    Nature

    (2016)
  • D.C. Wallace

    Mitochondria and cancer

    Nat Rev Cancer

    (2012)
  • R.J. DeBerardinis et al.

    Fundamentals of cancer metabolism

    Sci Adv

    (2016)
  • F. Weinberg et al.

    Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity

    Proc Natl Acad Sci U S A

    (2010)
  • P. Sonveaux et al.

    Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

    J Clin Invest

    (2008)
  • S. Pavlides et al.

    The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma

    Cell Cycle

    (2009)
  • U.E. Martinez-Outschoorn et al.

    Caveolae and signalling in cancer

    Nat Rev Cancer

    (2015)
  • L.K. Boroughs et al.

    Metabolic pathways promoting cancer cell survival and growth

    Nat Cell Biol

    (2015)
  • A. Viale et al.

    Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function

    Nature

    (2014)
  • C.A. Wurm et al.

    Nanoscale distribution of mitochondrial import receptor Tom20 is adjusted to cellular conditions and exhibits an inner-cellular gradient

    Proc Natl Acad Sci U S A

    (2011)
  • J.M. Curry et al.

    Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer

    Cell Cycle

    (2013)
  • D. Whitaker-Menezes et al.

    Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue

    Cell Cycle

    (2011)
  • A.P. Halestrap

    Monocarboxylic acid transport

    Compr Physiol

    (2013)
  • D. Whitaker-Menezes et al.

    Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts

    Cell Cycle

    (2011)
  • Cited by (222)

    • Metastatic outgrowth via the two-way interplay of autophagy and metabolism

      2024, Biochimica et Biophysica Acta - Molecular Basis of Disease
    • The dual role of citrate in cancer

      2023, Biochimica et Biophysica Acta - Reviews on Cancer
    View all citing articles on Scopus
    View full text